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HPV-dependency in cervical cancer types, according to the WHO Classification of Tumors; NOS-not otherwise specified.
Source publication
False negative (FN) results in cervical cancer (CC) screening pose serious risks to women. We present a comprehensive literature review on the risks and reasons of obtaining the FN results of primary CC screening tests and triage methods and discuss their clinical and public health impact and implications. Misinterpretation or true lack of abnormal...
Context in source publication
Context 1
... to the International Endocervical Adenocarcinoma Criteria and Classification, two groups of ADCs were extracted, depending on the HPV infection status: (1) non-HPV-associated (endometrioid, gastric type, serous, clear cell, and mesonephric carcinoma) and (2) HPV-associated (usual, villoglandular, mucinous (not otherwise specified), mucinous intestinal, mucinous signet ring, and invasive stratified mucin-producing carcinoma) [95]. Detailed information on HPV-dependent and -independent CC types is presented in Table 2, based on the current WHO Classification of Tumors [5]. In general, HPV(−) CC cases were shown to be associated with higher age, worse prognosis, diagnosis of ADC, and higher risk of relapse and distant metastases [85,[96][97][98][99]. ...Similar publications
Aim. To assess the feasibility of using immunocytochemical studies as a marker of proliferative activity in cervical intraepithelial neoplasia. Materials and methods. A comprehensive examination of 78 women, aged 25 to 45 years, with the presence of cervical intraepithelial neoplasia was carried out. Verification of the diagnosis was carried out on...
Citations
... However, its specificity for predicting dysplasia severity remains limited. Cervicovaginal cytology is particularly valuable for population screening, but a significant percentage of cervical lesions may yield false-negative results [83,84], a range that aligns with the findings of this study. Combining HPV testing with cytology enhances the sensitivity of the Papanicolaou test for detecting high-grade lesions from 50-85% to 100% [85,86]. ...
Cervical intraepithelial neoplasia (CIN) is a premalignant cervical condition closely linked to persistent high-risk HPV infection, a major risk factor for cervical cancer. This study aims to investigate the relationship between cervicovaginal infections, HPV infection, and CIN development in 94 Romanian women with cervical lesions. Comprehensive assessments included HPV genotyping, cytology, colposcopy, and histopathology. In 53.20% of cases, vaginal infections were identified, with Candida albicans most frequently associated with HPV. Histopathology revealed 48.94% low-grade CIN, 42.55% high-grade CIN, and 8.51% invasive carcinoma. There was a strong correlation between high-risk HPV types (especially HPV 16 and 18), colposcopic findings, histopathology, and age. This study emphasizes the mutual effect of cervicovaginal infections and HPV infection in increasing the risk of developing CIN and cervical cancer among Romanian women. Persistent infection with high-risk HPV types, particularly HPV 16 and 18, has been confirmed as a primary driver of CIN and cervical cancer progression.
... This shift is alarming, as adenocarcinoma generally has a more severe prognosis compared to its squamous counterpart, with its overall and stage-specific survival rates being particularly lower [9,10]. Furthermore, traditional cytologic screening methods are less effective in detecting adenocarcinoma [11,12]. ...
This comprehensive review critically assesses tailored management strategies for clear cell carcinoma of the cervix (cCCC), an uncommon subtype of cervical adenocarcinomas. A globally prevalent condition, cCCC affects individuals across diverse racial and ethnic groups. Notably, a significant risk factor associated with cCCC is intrauterine exposure to diethylstilbestrol (DES), a synthetic estrogen historically prescribed to address pregnancy-related complications.
Intriguingly, almost two-thirds of cCCC cases are linked to DES exposure. Studies reveal a notable surge in cCCC incidence among offspring born to women administered DES during pregnancy, with DES-exposed daughters facing a staggering 40-fold higher risk compared to their non-DES-exposed counterparts.
Turning to the molecular intricacies of cCCC, gene expressions within this subtype exhibit intriguing parallels with clear cell carcinomas found in the ovary, endometrium, and kidney. Additionally, there is a noteworthy exploration of cervical endometriosis as a potential precursor to cCCC. Molecular pathways, specifically the PI3K/AKT and Hippo pathways, have garnered attention in understanding the pathogenesis of cCCC.
From a prognostic standpoint, disparities emerge, with non-DES-related cCCC cases generally exhibiting a grimmer prognosis than their DES-related counterparts. This discrepancy becomes starkly evident in advanced disease stages. Early detection proves crucial, as patients diagnosed in initial stages experience commendable outcomes, markedly superior to those facing advanced or recurrent manifestations. Fertility-preserving treatments are highly endorsed for early-stage patients.
Simultaneously, the therapeutic landscape is evolving, with PD-L1 inhibitors gaining prominence as a burgeoning treatment modality, particularly beneficial for those navigating advanced stages of cCCC. Furthermore, the combination of PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICI) emerges as a promising and innovative treatment alternative for cCCC.
In summary, this review encompasses a detailed exploration of cCCC, spanning risk factors, molecular intricacies, prognostic considerations, early detection strategies, and evolving treatment modalities, presenting a comprehensive understanding of the management approaches tailored for this unique subtype of cervical adenocarcinomas.
... Certain pathological subtypes of CC exhibit more aggressive behavior and are not associated with human papillomavirus (HPV) infection. HPV-negative CC was considered to be associated with a poorer prognosis 26,27 , and the sensitivity of cytological screening for these subtypes was lower than that for cervical squamous cell carcinoma (CSCC) 28 , potentially resulting in delays in diagnosis. In our study, the proportions of nonsquamous cell neoplasms and nonadenocarcinoma types were higher in the young group but still less than 10% (8.4%), which may have had little impact on the overall prognosis. ...
Cervical cancer (CC) ranks as the second highest cause of morbidity and mortality among young women; however, there are currently no age-specific definitions for young cervical cancer or prognostic models tailored to this demographic. Data on CC diagnosed between 2000 and 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Age stratification is based on the relationship between age and cancer-specific mortality, as demonstrated by restricted cubic spline analyses (RCS). Cox proportional hazards regression analyses were employed to identify independent prognostic factors in the young CC group. Two novel nomograms for this population were developed and validated using an external validation cohort obtained from a local hospital database, evaluated with concordance index (C-index) and calibration plots. Receiver operating characteristic (ROC) curves were utilized to compare the accuracy of the established models against the International Federation of Gynaecology and Obstetrics (FIGO) staging system (2018). A total of 27,658 patients from the SEER database were classified into three age groups (<36 years, 36-60 years, >60 years) based on RCS analyses, with 4,990, 16,922, and 5,746 patients in each group, respectively. The independent prognostic factors identified for young CC included stage, tumour size, grade, histologic type, and surgical intervention. The results of the C-index and calibration in both the training and validation sets confirmed that the two nomograms can accurately predict the occurrence and prognosis of young CC patients. The area under the curve (AUC) values indicated that these models demonstrated higher efficacy in predicting overall survival (OS) compared to the FIGO staging system (2018). These models could potentially serve as effective tools for clinicians to estimate the prognosis of young CC patients.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-024-81644-z.
... Failing to diagnose HPV infection (false negatives) with certain serotypes in an individual could have serious long-term implications, such as dissemination of infection and increased risk of cervical cancer in those infected. Besides, the diagnosis of HPV infection in an individual could be associated with stigma, anxiety, and self-blame [22][23][24] and requires costly additional medical investigation [25]. Therefore, wrong diagnoses of HPV infection (false positives) should be avoided as much as possible. ...
Background
Valid diagnostic tests for human papillomavirus (HPV) detection are crucial to identify individuals at high risk of cervical cancer. We assessed and compared the validity of Mehrviru HPV genotyping and Sacace (HPV Genotypes 14 Real-TM Quant) for molecular detection of 14 high-risk human papillomaviruses.
Methods
We used three HPV test results to identify HPV-positive individuals (14 high-risk genotypes) in a specialist gynecology clinic. The HPV test results were collected using Mehrviru®, Sacace®, and a third kit from the clinical diagnostic laboratory. We used Latent class analysis to determine the actual status of HPV infection in study participants. The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, Youden, and area under the ROC curve indices of each diagnostic kit and their 95% confidence intervals were calculated. The agreement between the Mehrviru and Sacace kits was determined using the Kappa statistic.
Results
We examined 117 women at high risk of HPV infection. The mean age (SD) was 37.2 (9.1). According to LCA, 28.6% of participants had an HPV infection. The sensitivity and specificity (95% CI) of the Mehrviru were 90.8% (73.7-97.2%) and 90.9% (82.1-95.6%), and corresponding figures for Sacace were 92.0% (72.3-98.1%) and 97.4% (90.2-99.3%). The kappa index between the Mehrviru and Sacace kits was 69.7% (55.6-83.9%). The area under the ROC curve for Mehrviru and Sacace test were 91.4% (85.7-97.1%) and 94.4% (89.3-99.5%).
Conclusions
There is an excellent agreement between Mehrviru and Sacace test results, and the diagnostic accuracy indices were similar.
... Although false positives are less concerning in a screening context due to follow-up tests such as imaging or biopsy, reducing them is still important to lower patient anxiety and healthcare costs [57]. False negatives, where cases of EC might be missed, pose a greater risk due to potential treatment delays, though they would likely be identified in later diagnostic stages [58]. Mitigation strategies, such as increasing the sample size, especially for benign and control cases, and improving the models, will help minimize both false positives and false negatives. ...
Simple Summary
The incidence of endometrial cancer is increasing, creating a need for fast and efficient diagnostic methods. This study explores a new, non-invasive approach using urinary fluorescence spectroscopy to detect endometrial cancer. By analyzing morning urine samples and utilizing advanced machine learning techniques, we identified prospective spectral markers that differentiate between control, benign, and malignant gynecological patients. Our findings indicate good sensitivity and specificity, with high AUC from machine learning models, suggesting this method could significantly improve early cancer detection. This approach is easier and more affordable, especially in resource-limited settings. It has the potential to change the way endometrial cancer is diagnosed, offering a simpler and more accessible option for patients.
Abstract
Endometrial cancer is becoming increasingly common, highlighting the need for improved diagnostic methods that are both effective and non-invasive. This study investigates the use of urinary fluorescence spectroscopy as a potential diagnostic tool for endometrial cancer. Urine samples were collected from endometrial cancer patients (n = 77), patients with benign uterine tumors (n = 23), and control gynecological patients attending regular checkups or follow-ups (n = 96). These samples were analyzed using synchronous fluorescence spectroscopy to measure the total fluorescent metabolome profile, and specific fluorescence ratios were created to differentiate between control, benign, and malignant samples. These spectral markers demonstrated potential clinical applicability with AUC as high as 80%. Partial Least Squares Discriminant Analysis (PLS-DA) was employed to reduce data dimensionality and enhance class separation. Additionally, machine learning models, including Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), and Stochastic Gradient Descent (SGD), were utilized to distinguish between controls and endometrial cancer patients. PLS-DA achieved an overall accuracy of 79% and an AUC of 90%. These promising results indicate that urinary fluorescence spectroscopy, combined with advanced machine learning models, has the potential to revolutionize endometrial cancer diagnostics, offering a rapid, accurate, and non-invasive alternative to current methods.
... Our data show that 11 (25.6 %) of the 43 CIN2þ cases were false negative in the p16/Ki67 dual-staining test, indicating a false-negative rate comparable with that of LBC. Falsenegative p16Ki67 test results might result from decreased cellularity due to the secondary production of cytologic slides after LBC preparation [37], whereas false-negative LBC results might be due to the scarcity of abnormal cells, sampling errors, and subjectivity of the evaluation [38]. In addition, the false-positive rate of the p16/ Ki67 test was high (36.62 %, 63/172 patients) because a few nontransformed cells can express detectable p16 levels [39] and a few CIN1-positive cells can express Ki67 markers in the superficial layer of the cervical epithelium [40]. ...
... The Pap test has long been used to identify HPV-induced cellular disorder, and HPV mRNA and DNA have recently been utilized for the screening and diagnosis of cervical cancer [5][6][7]. However, most HPV-infected women do not suffer from cervical cancer in their lifetime; while 291 million women have been infected by HPV worldwide, only a small portion of HPV-infected women go on to develop cervical cancer [2,3,8]. Emerging evidence indicates that some cervical cancers are independent of HPV [9,10]. ...
... In addition to HPV, multiple oncogenes trigger the initiation and progression of cervical cancer [8][9][10][11]. However, the mechanisms underlying HPV-independent cervical cancer initiation and progression are unclear. ...
Background
Cancer/testis antigen-45A1 (CT45A1) is overexpressed in various types of cancer but is not expressed in healthy women. The role of CT45A1 in cervical cancer has not yet been described in the literature.
Purpose
The aim of this research was to study the role of CT45A1 in cervical cancer progression and drug resistance, elucidate the mechanisms underlying CT45A1-mediated tumorigenesis and investigate CT45A1 as a biomarker for cervical cancer diagnosis, prognostic prediction, and targeted therapy.
Methods
The CT45A1 levels in the tumors from cervical cancer patients were measured using immunohistochemical staining. The role and mechanisms underlying CT45A1-mediated cervical cancer cell tumor growth, invasion, and drug resistance were studied using xenograft mice, cervical cancer cells, immunohistochemistry, RNA-seq, real-time qPCR, Chromatin immunoprecipitation and Western blotting.
Results
CT45A1 levels were notably high in the tumor tissues of human cervical cancer patients compared to the paracancerous tissues ( p < 0.001). Overexpression of CT45A1 was closely associated with poor prognosis in cervical cancer patients. CT45A1 promoted cervical cancer cell tumor growth, invasion, neovascularization, and drug resistance. Mechanistically, CT45A1 promoted the expression of 128 pro-tumorigenic genes and concurrently activated key signaling pathways, including the oncogenic SRC, ERK, CREB, and YAP/TAZ signaling pathways. Furthermore, CT45A1-mediated tumorigenesis and drug resistance were markedly inhibited by the small molecule lycorine.
Conclusion
CT45A1 promotes cervical cancer cell tumorigenesis, neovascularization, and drug resistance by activating oncogenic SRC and downstream tumorigenic signaling pathways. These findings provide new insight into the pathogenesis of cervical cancer and offer a new platform for the development of novel therapeutics against cervical cancer.
... This study explored Septin9 methylation in HPV-positive patients, while HPV-negative patients were not mentioned. However, more and more studies have found that HPV- negative cervical cancer, which may be caused by low-risk HPV carcinogenesis, "Hit and Run Theory", and sampling errors or laboratory errors (Macios and Nowakowski 2022), suggesting hr-HPV detection alone may miss 10-15% �HSIL lesions. This study indicated the detection rate of Septin9 methylation in cervical cancer scrapings was as high as 95.52%, and in � HSIL lesions was 70.42%. ...
Aberrant Septin9 methylation in cervical cancer has been rarely studied. We aimed to identify its diagnostic value in cervical cancer using cervical scrapings, and its predictive potential in plasma for pelvic nodal metastasis of cervical cancer. The statuses of methylated Septin9 in fresh cervical lesions and cervical scrapings were first evaluated by using quantitative methylation-specific PCR. Subsequently, the relationship between Septin9 methylation in 113 plasma samples and pelvic nodal metastasis of cervical cancer was evaluated. Methylated Septin9 was detected in all cancerous tissues, but not in cervicitis. The degrees of Septin9 methylation increased with growing severity of cervical lesions in cervical scrapings. The sensitivity of methylated Septin9 was lower than that of cytology, while it yielded a high specificity and area under the curve in detecting high-grade squamous intraepithelial lesion or cervical cancer; and when Septin9 methylation combined with HPV16/18 genotyping, the sensitivity would increase from 70.42% to 82.39%. Plasma-based Septin9 methylation had a high discriminatory power in predicting pelvic nodal metastasis of cervical cancer, with an optimal specificity of 81.48%. In conclusion, we demonstrated methylated Septin9 to be an innovative diagnostic biomarker for cervical cancer and its non-invasive predictive potential in plasma for pelvic nodal metastasis of cervical cancer.
Impact statement
What is already known on this subject? The occurrence of cervical cancer is related to Septin9 methylation. In fresh specimens and cervical scrapings, we found the degrees of methylated Septin9 increased with growing severity of cervical lesions. Compared with HPV16/18 genotyping and cytological detection, Septin9 methylation had a better specificity and AUC in detecting ≥ HSIL. Furthermore, plasma-based Septin9 methylation also had a high specificity for pelvic lymphatic metastasis prediction.
What the results of this study add? Methylation analysis of Septin9 indicated a similar sensitivity, specificity and AUC in detecting ≥ HSIL, relative to HPV16/18 genotyping. Compared with cytological method, Septin9 methylation also yielded a higher specificity and AUC in detecting ≥ HSIL. And we also found plasma-based Septin9 methylation had a high discriminatory power in predicting pelvic nodal metastasis of cervical cancer, with an optimal specificity of 81.48%; additionally an increasing sensitivity from 50% to nearly 80% was found when combined with SCCAg.
What the implications are of these findings for clinical practice and/or further research? This study aimed to evaluate the relationship between Septin9 methylation and cervical cancer, and to explore the value of methylated Septin9 in the detection of cervical (pre)cancerous lesions. Moreover, we would explore plasma-based ctDNA biomarkers for pelvic lymphatic metastasis prediction of cervical cancer, to improve non-invasive predictive accuracy of pelvic nodal metastasis and reduce the complications caused by pelvic lymphadenectomy.
... Limitations of HPV−testing methods may allow for false negatives within the HPV− CC cohort, although these possibilities have been minimized within the TCGA dataset. As all samples within the TCGA CC cohort are carcinomas, it is possible that in a sample with no detectable HPV DNA, HPV contributed to carcinogenesis via a hit-and-run mechanism where the basal cells are permanently altered in pre-cancerous lesions, but HPV DNA is lost in the carcinoma [69]. This may affect gene expression within the HPV− CC cohort and would require investigation of pre-cancerous lesions to confirm the presence or absence of HPV DNA. ...
Cervical cancer (CC) is the second most common cancer in women worldwide and the fourth leading cause of cancer-associated death in women. Although human papillomavirus (HPV) infection is associated with nearly all CC, it has recently become clear that HPV−negative (HPV−) CC represents a distinct disease phenotype with increased mortality. HPV−positive (HPV+) and HPV− CC demonstrate different molecular pathology, prognosis, and response to treatment. Furthermore, CC caused by HPV α9 types (HPV16-like) often have better outcomes than those caused by HPV α7 types (HPV18-like). This study systematically and comprehensively compared the expression of genes involved in major histocompatibility complex (MHC) class I and II presentation within CC caused by HPV α9 types, HPV α7 types, and HPV− CC. We observed increased expression of MHC class I and II classical and non-classical genes in HPV+ CC and overall higher expression of genes involved in their antigen loading and presentation apparatus as well as transcriptional regulation. Increased expression of MHC I-related genes differs from previous studies using cell culture models. These findings identify crucial differences between antigen presentation within the tumor immune microenvironments of HPV+ and HPV− CC, as well as modest differences between HPV α9 and α7 CC. These differences may contribute to the altered patient outcomes and responses to immunotherapy observed between these distinct cancers.
BACKGROUND Cervical cancer is most common in Nepalese women. Human papilloma virus (HPV) plays a main role in pathogenesis of cervical cancer. Human papilloma virus serotype 16 is the most common type followed by HPV 18. Liquid based smear cytology (LBC) is a simple, safe, non-invasive and cost effective method for the detection of squamous intraepithelial lesion or squamous cell carcinoma. The aim of this study was to correlate HPV DNA testing result with the findings of Liquid based cytology. METHODS This was a retrospective study conducted for 2 years at Department of Laboratory Medicine Pathology, Nepal Mediciti hospital from 1st may 2021 to 30th April 2023. Total of 1456 cases were included in this study. RESULTS Out of 1456 cases, 100 cases were positive for HPV. The concordance between HPV DNA test and LBC findings is 57%. The highest HPV-positive cases were seen in the age group of 31-40years. The most common HPV genotype study was HPV 16 (28%) followed by HPV 18 (27%). HPV 16 was positive in 57% of ASCUS positive cases of LBC, is statistically significant (P value-0.017). HPV 18 was positive in 37.0% of ASCUS positive cases of LBC, is not statistically significant (P value-0.018). The concordance between HPV positive detection and LBC findings is 57% and discordance is 43%. CONCLUSIONS This study shows the prevalence of HPV is higher in middle to young age group. ASCUS was common finding in LBC in HPV positive cases followed by LSIL,HSIL and SCC. However 43% of HPV positive cases were reported as negative for intraepithelial lesion (NILM) as there was no abnormality in squamous epithelial cells. Both the HPV test and cervical LBC smears are valuable tools for early detection of cervical precursor lesion. However, neither test alone provides conclusive results for comprehensive screening. So, it is recommended to use both test in combination for more accurate and reliable findings in cervical cancer screening.
