The clinical significance of FAM19A4 methylation in high-risk HPV-positive cervical samples for the detection of cervical (pre)cancer in Chinese women

Michaela had a Papanicolaou (Pap) test at age 17, less than 3 months from her first intercourse. The test was interpreted as atypical squamous cells of undetermined significance (ASC-US) and the laboratory automatically “reflexed” this to human papillomavirus (HPV) testing. Michaela tested positive for high-risk (carcinogenic) HPV, had colposcopy and biopsy and cryotherapy for cervical intraepithelial neoplasia, grade 1 (CIN 1). The result from her 4-month postcryo Pap test was ASC-US HPV positive.So what is the problem with Michaela's story? Everything! According to national guidelines, (1) she should not have had her first Pap test until 3 years after her first intercourse or age 211–4; (2) she should not have had HPV testing after the ASC-US interpretation of her Pap test unless she was at least 21 years old34; and (3) as an adolescent, she should not have had colposcopy for a minor Pap test abnormality or cryotherapy to treat cervical intraepithelial neoplasia 1 (CIN 1).34Why is it so important to adhere to national guidelines? Don't we (clinicians) know what is best for our patients? Well, clinically we know our patient best, and guidelines cannot foresee every variation in real clinical practice. However, guidelines created through rigorous evaluation of evidence-based data and a consensus process provide a framework for providing care that is optimum for most women at each phase in the timeline of their life. Guidelines cannot, and should not, trump clinical decisions for a unique patient situation.34 But variations from recommended guidelines should be the exception rather than the rule in clinical practice.Perhaps we need to go back to the beginning, to the dialogue between the King and the white rabbit in Lewis Carroll's wonderful Alice in Wonderland: “Where shall I begin, please, your majesties?” Like the King we will say, “Begin at the beginning and go until you come to the end. Then stop!” So, to understand how we can best protect our patients from cervical cancer, let's begin at the beginning …Cervical cancer is the first cancer identified as having a single obligatory cause, cervical infection by human papillomavirus (HPV).5 However, HPV is common; cervical cancer is not. Almost all who are sexually active have had 1 or more HPV infections in their life.5 Some HPV types are associated with cervical precancer and cancer and are therefore called “high risk” (also carcinogenic or oncogenic) HPV types. Other types that do not cause cancer are called “low-risk” HPV types. Most HPV infections, including those caused by high-risk HPV types, are benign, transient, and resolve spontaneously within a year or 2. Less commonly, high-risk HPV infections persist. The longer high-risk HPV infections persist, the more likely they are to cause a precancerous lesion, which, if not detected and treated in a timely fashion, can become cancerous.5 Fortunately, cancer is an uncommon outcome for an infection virtually everyone gets. The entire process of cervical carcinogenesis, from causal infection to invasive cancer, is usually slow, taking many years or decades. The success of cervical cytology, despite its limitations in sensitivity,67 has been the result of repeated screening, detection, and therapeutic intervention during the long sojourn from causal infection to invasion.8Testing for the virus that causes cervical cancer certainly makes sense because cervical cancer rarely, if ever, occurs without HPV. However, the natural history of HPV-induced carcinogenesis and the ubiquitous nature of HPV must temper and guide how we use HPV testing. Most young women are infected with HPV within a few years of becoming sexually active, but exceedingly few have precancer and far fewer still have cancer. Meanwhile older women have fewer HPV infections and are at greater risk for having precancer and cancer if they test positive for HPV. Misuse of HPV testing in young women identifies too many women with HPV who are not at risk for cervical cancer.For Michaela the harm was a Pap test when she had no risk of cervical cancer, while the likelihood of obtaining an abnormal cervical cytology result was very, very high; a HPV test at an age when HPV is ubiquitous and carries little prognostic value; the anxiety and discomfort of triage to colposcopy and cervical biopsy for HPV lesions of little risk; and the mental and physical trauma of cervical treatment for often transient CIN 1, a diagnosis that is synonymous with HPV infection. Although cryotherapy has not been shown to cause adverse reproductive outcomes, too many young women with minor abnormalities are being treated by cervical excision procedures (eg, loop electrosurgical excision or laser cone) that may increase the risk 2 to 4 fold of premature delivery and low-birth-weight infants.9–11Such a risk is acceptable if necessary to prevent progression to cervical cancer. But since there is so little cancer risk at Michaela's young age, our primary consideration is to avoid harm when there is little benefit. (The US rates of cervical cancer in women under the age of 25 are 2 in 100 000, only slightly higher than the rates of vaginal cancer, for which there is no screening recommended.) This is such an important tenet that if HPV testing is inadvertently performed in an adolescent, the results should be ignored and not be used to influence patient management.4As summarized by the HPV DNA Test Utilization Statement,12—based on the consensus guidelines developed by the American Society for Colposcopy and Cervical Pathology4 and endorsed by the American Cancer Society, American Society for Clinical Pathology, American Society for Colposcopy and Cervical Pathology, American Society of Cytopathology, American Society for Cytotechnology, College of American Pathologists, International Academy of Cytology, and Papanicolaou Society of Cytopathology— there is clear, documented benefit for HPV testing in the circumstances listed in the document.Human papillomavirus testing must be for high-risk HPV (HR-HPV) types only and should use an FDA-approved or equivalent test that has undergone peer review of a rigorous, masked evaluation involving an adequate sample size.13 Testing for low-risk HPV types that do not cause cervical cancer has no clinical benefit and therefore cannot be justified or condoned.13 Other than the indications listed in the HPV DNA Test Utilization Statement, HR-HPV testing generally should not be done because it potentially creates more harm than benefit. Importantly, cotesting with the Pap and HPV tests in women age 30 and older should not be done more frequently than every 3 years if both tests are negative. This combination of tests provides safety for at least 3 years, with recent studies1415 suggesting safety may extend for at least 6 years. Hence, testing more often of women who are at virtually no risk of having precancer adds cost without benefit. Excessive screening all too often identifies transient HPV infections and minor cytologic abnormalities that would resolve on their own if given wider screening intervals,16 adding unnecessary evaluations and procedures that create patient harm.Human papillomavirus testing should be avoided as a reflex test to any abnormal Pap test other than in cases of ASC-US, except in postmenopausal women with low-grade squamous intraepithelial lesion (LSIL). Less than 50% of postmenopausal women have LSIL due to HPV, and those with HPV-negative LSIL are at low risk for cancer and do not need colposcopy.Neither should HPV testing be done during the initial management of women with atypical glandular cells (AGC). Women with AGC may not have HPV-induced lesions—ie, tubal metaplasia of the endocervix, reactive endocervical cell changes, atypical endometrial hyperplasia, endometrial carcinoma, glandular lesions in the fallopian tubes, and ovary and glandular cancers from a variety of sources metastatic to the pelvis. However, once possible sources of a non-HPV induced lesion have been eliminated and colposcopy has not detected CIN or adenocarcinoma in situ (AIS), HPV testing can provide important information regarding the best follow-up option for women with AGC “not otherwise specified” (AGC NOS). Women with AGC NOS who are positive for high-risk HPV are at greater risk for subsequent detection of CIN 2/3 or AIS and are best followed up with a repeated Pap test and HPV test in 6 months, with referral back to colposcopy if either is abnormal. This is 1 of only 2 exceptions to the general rule that a positive HPV test result should not be repeated in less than a year. The other exception is in the 6-month surveillance period of women treated for CIN 2/3.There are a number of other areas for which HPV testing should not be done but are not mentioned in the HPV DNA Test Utilization Statement. Human papillomavirus testing should never be used as a screening test for sexually transmitted diseases (STDs) because HPV is so common and, unlike most STDs, has no treatment that would follow detection. Human papillomavirus testing should not be done as a screen prior to administering the HPV vaccine. The FDA-approved HPV test identifies a pool of high-risk HPV types and is not restricted to the 4 HPV types in the vaccine (HPV 6, 11, 16, and 18). Additionally, there is no commercially available serologic test that would identify past exposure to these 4 HPV types. The cost of prevaccination screening of all sexually active women would escalate the cost of vaccine administration. Human papillomavirus vaccination programs should target populations that will glean the greatest benefit for the cost: girls in early adolescence who are mostly naïve to HPV infections.17The HPV DNA Test Utilization Statement represents a convergence of many professional societies for the best practice of HPV testing in the screening and management of women for prevention of cervical cancer. The underpinnings for these recommendations, based on the ASCCP guidelines,4 are the natural history and epidemiology of HPV and cervical cancer. The underlying principle for using any screening or diagnostic test is to differentiate effectively those at risk of disease from those who are not.1819However, there must be an acknowledgment that no test, diagnostic procedure, or treatment is error-free. No measures can be taken to provide absolute reassurance against cervical cancer. As tests for high-risk HPV have become available, there is the misconception that its exhaustive use might eliminate all cervical cancer. Yet, excessive screening may result in excessive management and harmful treatment for benign conditions, while minimally reducing cancer incidence; most cases of cervical cancer (60%) occur in pockets of underscreened populations (http://www.cdc.gov/cancer/cervical/). For women of Michaela's age group, it is unproven whether additional or more sensitive screening can eliminate any of the rare cancers in women younger than 25 years.For those clinicians, laboratories, and pathologists conducting (or promoting) more HPV testing for financial gain,20 it is important to understand the risks being taken. The Pap test has been the most successful cancer screening test in the history of modern medicine. As a result, we have seen a drop in incidence of cervical cancer and its precursors. Consequently, a “positive” Pap test result is more likely to be a false-positive than a true-positive. The reason that HPV testing is such a powerful adjunct to cervical cytology is that it clarifies risk: women (aged 21 or older) with HPV-negative ASC-US are at exceedingly low risk of precancerous lesions21 and can return to routine screening without further clinical intervention, while women with HPV-positive ASC-US have a risk comparable to that associated with an LSIL cytologic profile. Prior to the advent of HPV testing, the patients with equivocal Pap results would most often have repeated Pap tests, multiple colposcopic evaluations with possibly multiple biopsies, all of which could lead to patient morbidity. With HPV testing, we can weigh the risk of having significant cervical disease against the costs of unnecessary intervention and harm.For HPV testing to fulfill its promise, clinicians must understand under which circumstances it should be used and under which it should not. Laboratories must question their client clinicians when HPV testing is ordered in a situation that is more likely to cause harm than benefit. Clinicians must not threaten to move their business to another laboratory as has been done when the laboratory refuses to do HPV testing that is not clinically indicated by the guidelines. Clinicians must also question the motives of laboratorians that urge HPV testing that is not in accordance with guidelines. We all share in the responsibility of making our patients as safe from harm as reasonably possible and making medicine as protective and cost-effective as possible. “Where shall I begin, please, your majesties?” Begin with understanding how common HPV is, yet how it can cause cervical cancer. Use your understanding of the natural history of HPV to make sage decisions that lead you to the best choices for your patients, choices that emphasize benefit and minimize harm. When we all reach that goal, we can feel confident that we have fulfilled that promise that we made when we took the Hippocratic oath, “First do no harm.”

Chromosomal Biomarkers for Detection of Human Papillomavirus Associated Genomic Instability in Epithelial Cells of Cervical Cytology Specimens

The aim of this study was to investigate the clinical performance of high risk (HR) HPV E6/E7 mRNA assay in detecting cervical high-grade intraepithelial neoplasia and cancer among women with atypical squamous cells of undetermined significance (ASCUS) Papanicolaou (Pap) smears. A total of 160 patients with ASCUS who underwent HR-HPV DNA assay, HR-HPV E6/E7 mRNA assay and colposcopy biopsy at Third Affiliated Hospital of Zhengzhou University, China, from December 2015 to March 2017, were enrolled. Logistic regression analysis was used to evaluate the relationship between pathological results with clinical biologic factors. Univariate analysis showed that the qualitative results of HR-HPV DNA, qualitative results of HR-HPV E6/E7 mRNA and expression levels of HR-HPV E6/E7 mRNA were risk factors of high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer (all P<0.05). Multivariable analysis found that only the expression levels of HR-HPV E6/E7 mRNA was associated with high-grade CIN and cervical cancer (OR=8.971, 95% CI=2.572-31.289, P=0.001). An optimal cut-off value of≥558.26 copies/ml was determined using receiver operating characteristic curve, and specificity of cut-off value were higher than E6/E7 mRNA qualitative assay and DNA qualitative assay. HPV E6/E7 mRNA quantitative assay may be a valuable tool in triage of ASCUS pap smears. A high specificity of E6/E7 mRNA quantitative assay as a triage test in women with ASCUS can be translated into a low referral for colposcopy.

Cervical cancer remains a significant global health concern, ranking as the fourth most prevalent cancer among women worldwide. Human papillomaviruses (HPV) transcribe many genes that might be responsible for cervical cancer development. This study aims to investigate the correlation between the expression of HPV16 early genes and the mRNA expression of human FOXO3a, a tumor suppressor gene, in association with various stages of cervical precancerous lesions. Eighty-five positive HPV16 DNA cervical swab samples were recruited and categorized based on cytology stages, i.e., negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cell cannot exclude HSIL (ASC-H), high-grade squamous intraepithelial lesion (HSIL). RT-qPCR was performed to amplify HPV16E1, E4, E6, E6*I, E7, and human FOXO3a mRNA expression in all samples. The relative expression of those genes was calculated using GAPDH as a control. Detection of FOXO3a mRNA expression in the cervical cancer cell line by RT-qPCR and meta-analysis of FOXO3a expression using the RNA-Seq dataset by GEPIA2 were analyzed to support the conclusions. Among the cervical samples, HPV16E1 and E7 were significantly increased expression correlating to disease severity. HPV16E4 mRNA expression was 100% detected in all LSIL samples, with a significant increase observed from normal to LSIL stages. Conversely, FOXO3a mRNA expression decreased with disease severity, and the lowest expression was observed in HSIL/squamous cell carcinoma (SCC) samples. In addition, similar results of FOXO3a downregulation were also found in the cervical cancer cell line and RNA-Seq dataset of cervical cancer samples. HPV16 early mRNA levels, including E1 and E7, increase during cancer progression, and downregulation of FOXO3a mRNA is a characteristic of cervical cancer cells and HSIL/SCC. Additionally, HPV16E4 mRNA expression was consistently detected in all LSIL samples, suggesting the presence of active viral replication. These findings might lead to further investigation into the interplay between HPV gene expression and host cell factors for targeted therapeutic strategies in cervical cancer management.

Objective To analyze the cervical cancer screening results of married women in Dongming County of Shandong Province, and to provide scientific evidence for cervical cancer prevention in this region. Methods A retrospective study on the cytological results of 23 088 married women in Dongming County, from September 2016 to June 2017 was performed. Cervical swabs of 23 088 married women were referred to Jinan KingMed Diagnostics. The age of these married women is 19~90 years old. They were divided into 5 groups: 810 cases in group<30 years old, 5174 cases in group 30~39, 9301 cases in group 40~49, 5707 cases in group 50~59 and 2096 cases in group of over 60 years old. At the same time, 61 cases of high risk human papillomavirus (high-risk human papillomavirus, hrHPV) and 438 cases of abnormal cytology with tissue biopsy were followed up, and analyzed. Results A total of 1177 women (5.1%) were interpreted as cytological abnormalities, including 729 cases (3.2%) of atypical squamous cells of unknown significance (ASC-US), 43 cases (0.2%) of atypical squamous cells cannot exclude HSIL (ASC-H)/atypical glandular cells (AGC), 289 cases (1.3%) of low grade squamous intraepithelial lesions (LSIL), and 116 cases (0.5%) of high grade squamous intraepithelial lesions (HSIL). Of these cases with abnormal cytological results, 31 cases (50%) had hrHPV testing positive, and 200 cases (45.6%) had follow-up histological positive. The positive rates of ASC-US (χ2=5.502, P=0.019) and LSIL (χ2=3.956, P=0.047) significantly varied among different age groups. The highest positive rate of ASC-US was found in the 50~59 years old group (197 cases, 3.5%), while the lowest positive rate was found in the 30~39 years old group (134 cases, 2.6%). The highest positive rate of LSIL was observed in<30 (12 cases) and 30~39 (76 cases) years old groups (1.5% for both groups), while the lowest positive rate was observed in the 50~59 years old group (50 cases, 0.9%). Histopathologic follow-ups demonstrated obvious variations in different cytological results. Normal biopsy (χ2=113.536, P<0.001) accounted for the highest proportion in ASC-US (75.4%) and the lowest proportion in HSIL (9.8%); cervical intraepithelial neoplasia 1(CIN1) (χ2=37.817, P<0.001) was the most frequent in LSIL, but the least frequent in HSIL; CIN2/3/AIS/SCC (χ2=603.863, P<0.001) was the most common in HSIL but the least common in ASC-US. Significant variations in hrHPV testing were also observed in different cytological abnormalities (χ2=7.946, P=0.019) and different histopathologic results (χ2=3.925, P=0.048). The hrHPV-positive rates were 34.5%, 58.3% and 87.5% for ASC-US/ASC-H/AGC, LSIL and HSIL, respectively, and 37.5%, 60% and 75% for normal biopsy, CIN1 and CIN2/3/AIS/SCC, respectively. Conclusions The present study showed that cervical cytology screening can effectively detect cervical invasive cancer and its precancerous lesions. The severity of cytological abnormalities and the hrHPV-positive rates correlated well with the severity of histological abnormal findings. These results can provide a scientific basis for establishing cervical cancer screening strategies in this region. Key words: Cervical cancer; Cervical cytology; Screening; High-risk human papillomavirus

Correlation of high-risk human papilloma viruses but not of herpes viruses or Chlamydia trachomatis with endometriosis lesions

Objective To explore the clinical value of high risk human papillomavirus(HR-HPV) test in shunting monitoring of atypical squamous cell of undetermined significance (ASCUS) and to seek the best treatment for patients with ASCUS.Methods 470 patients with ASCUS tested by TCT were given HR-HPV testing and biopsy under colposcopy.The clinical characteristics were analyzed.Results 470 cases of ASCUS contained a variety of cervical lesions:inflammation/acuminate accounted for 69.15％ (325/470),cervical intraepithelial neoplasia (CIN)accounted for 29.57％ (139/470),and invasive carcinoma accounted for 1.28％ (6/470).The positive rate of cervical pathological examination was 30.85％ (≥ CIN Ⅰ,145/470).The positive rate of HR-HPV was 50.43％(237/470).The detection rate of ≥CIN Ⅰ in HR-HPV positive group and negative group was 55.27％ (131/237)and 6.01％ (14/233),while the detection rate of ≥ CIN Ⅱ in HR-HPV positive group and negative group was 36.71％ (87/237) and 1.29％ (3/233).The differences were statistically significant(P ＜ 0.01).Incidence of ≥ CIN Ⅰ and invasive carcinoma in HR-HPV positive group was about 19.332 fold of that in HR-HPV negative group(95％ CI =10.632 ～ 35.152),while the incidence of ≥CIN Ⅱ and invasive carcinoma was about 44.467 fold of HR-HPV negative group (95％ CI =13.812 ～ 143.152).The detection sensitivity,specificity,positive predictive value,negative predictive value(NPV) of HR-HPV in the≥ CIN Ⅰ patients were 90.34％,67.38％,61.60％,93.99％.Those of ≥ CIN Ⅱ patients were 96.67％,60.53％,36.71％,98.71％.Conclusion ASCUS included partial CIN of high grades and cervical cancer,and the proportion of HPV infection is large,detection of high risk HPV-DNA is an effective shunting management method of ASCUS. Key words: Alpha papillomavirus; Neoplasms, squamous cell; Cervical intraepithelial neoplasia; DNA probes, HPV

Background: Invasive cervical cancer develops from a pre-invasive state named cervical intraepithelial neoplasia (CIN).CIN 1 represents mild dysplasia and is now classified as low-grade squamous intraepithelial lesion (LGSIL); CIN 2 and 3lesions encompass moderate-to-severe dysplasia and are now classified as high-grade squamous intraepithelial lesions(HGSILs) based on the Bethesda cervical cytology reporting system. Most LGSIL lesions resolve spontaneously, whereasHGSIL lesions are more likely to progress to invasive cervical cancer. However, HGSILs are typically detected an averageof 10 to 15 years before invasive cervical cancer. In women, the typical age range for diagnosis of invasive cancer isgreater than 40 years. High-risk Human Papilloma Virus (HRHPV) infection is required for the development of virtuallyall cervical cancer, and the time from initial HPV infection to development of cervical cancer usually exceeds 10 years.Colposcopies that are performed for abnormal papanicolaou (pap) smears of LGSIL and HRHPV can include ectocervicaland endocervical biopsies. Given the likelihood of (a) spontaneous resolution of LGSIL and HRHPV, (b) the time todevelopment of cervical cancer after initial diagnosis of HPV and (c) the improbability of invasive cervical cancerdeveloping in women less than 40 years of age, there is evidence to suggest that endocervical curettage at the time ofcolposcopy is not necessary in a subgroup of women who are at low risk of developing invasive cervical cancer. At thecurrent time, no evidence based guidelines exist about the necessity of endocervical curettage (ECC) at the time ofcolposcopy in women who are at low risk for invasive cervical cancer. Therefore, a literature review was conducted toanalyze literature as it related to ECC at the time of colposcopy in who are at low risk for invasive cervical cancer. Aparticular subgroup of women that are at low risk for development of cervical cancer are less than 35 years of age withLGSIL or HRHPV cytology, and women who are less than 35 years of age are at an even lower risk of developing invasivecervical cancer because of their more robust immune system. The purpose of the literature review was to summarizefindings about endocervical curettage at the time of colposcopy to propose a study that could be conducted to establishevidence based guidelines for ECC that could be utilized in practice. Methods: The literature review summarizes current empirical and theoretical knowledge related to ECC at the time ofcolposcopy in women who are less than 35 years of age with LGSIL or HRHPV cytology. Concepts and keywords of theproposed literature review include: ECC-based diagnosis in each of three categories (benign, CIN 1 and CIN >1),ectocervical-based biopsy in each of three categories (benign, CIN 1 and CIN >1), LGSIL, HRHPV, colposcopy, andcervical cancer. Primary and secondary literature was examined to elucidate gaps in the literature related to evidence basedguidelines for ECC at the time of colposcopy. Results: The literature review includes an analysis of the literature related to ECC at the time of colposcopy in womenwho were less than 35 years of age with Cervical Cytology of LGSIL or HRHPV. Additionally, the literature reviewprovides a critique of the studies that were reviewed, details gaps in the literature and enumerates the problem of noevidence based guidelines for ECC curettage at the time of colposcopy. Conclusions: There is an absence in the literature about evidence based guidelines for performing ECC at the time ofcolposcopy in women who are less than 35 years of age with LGSIL or HRHPV; and additionally a paucity exists in theliterature about ECC at the time of colposcopy in this same subgroup of women. Therefore, the literature reviewestablishes the foundation and background for future studies that examine the need for ECC in Women less than 35 yearsof age with Cervical Cytology of LGSIL or HRHPV at the time of colposcopy.

Use of immunohistochemical staining for p16 in gynecological cytology.

Background: The epidemiology of human papillomavirus (HPV) and co-infections with herpes simplex virus type 2 (HSV-2) remains poorly characterized in Africa. High risk HPV (hrHPV) infection is the primary cause of 99.7% all cervical cancer especially in the presence of genital ulcer disease (GUD) which is usually caused by HSV-2. Herpes simplex virus-2 might interact directly with hrHPV to increase the risk of cervical cancer. Co-infection of HPV and HSV-2 in asymptomatic women could provide a clue to early diagnosis of cervical cancer and this could aid in the development of new strategies for effective management and improvement of the quality of life of women who are infected. If the synergy between HPV and HSV-2 can be prevented, there may be significant reduction of the incidence of cervical cancer. Methodology: This was a descriptive cross-sectional study of 515 randomly selected apparently healthy women of reproductive age whose cervical samples were screened for HPV and HSV-2 in Kaduna State, Nigeria. The cervical samples were collected by liquid-based cytology (LBC) for detection of cervical epithelial cell abnormalities (CEA) and molecular detection of HPV and HSV-2 using conventional polymerase chain reaction (PCR) assay. Extracted viral DNAs from the samples were amplified by convectional PCR using specific hrHPV (HPV 16,18, 31 and 45) primer sets and a broad spectrum MY09/11 and GP5+/6+ primers for a wider range of HPV genotypes while HSV-2 DNA was detected by florescence-based PCR assay with HSV-2 gG primers and probes. Results: PCR assay revealed that 14.7% (n=76) of the 515 selected women harbored HPV, HSV-2 or both. The prevalence of HPV, hrHPV, HSV-2 and HPV/HSV-2 co-infection among in the study participants are 11.8% (n=61), 9.3% (n=48), 5.6% 4% (n=29) and 2.3% (n=12) respectively. The frequency of HPV detection in HSV-2 infected participants (41.4%, 12/29) was significantly higher (OR=6.295, p&lt;0.0001) than in HSV-2 negative participants (10.1%, 49/437), but only co-infections of HPV-31 (p=0.004) and HPV-18 (p=0.040) with HSV-2 were significantly associated. Cervical cytology reports on the smears revealed prevalence of cervical epithelial abnormalities (CEA) of 16.7% (n=86), with cervical dysplasia prevalence of 6.4% (n=33), consisting of high grade squamous intraepithelial lesion (HGSIL) of 1.6% (n=8), low grade squamous intraepithelial lesion (LGSIL) of 4.1% (n=21) and atypical squamous cells of uncertain significance (ASCUS) of 0.8% (n=4). The frequency of HPV detection in women with cervical dysplasia (93.9%, 31/33) was significantly higher (OR=14.22, p&lt;0.0001) than in women without cervical dysplasia (6.2%, 30/482), and all HPV genotypes were significantly associated (p&lt;0.05) with cervical dysplasia except HPV 16 (p=0.051). Also, the frequency of HPV/HSV-2 co-infection among women with cervical dysplasia (15.2%, 5/33) was significantly higher than among women without cervical dysplasia (1.5%, 7/482) (OR=12.12, p&lt;0.0001). Comparing women with cervical inflammatory and atrophic changes (n=53), women with cervical dysplasia (HGSIL, LGSIL and ASC-US) had significantly higher frequency of HPV infection (χ2=42.829, p=0.000), HSV-2 infection (χ2=25.140, p=0.001) and HPV/HSV-2 co-infections (χ2=66.602, p=0.000). Conclusion: Co-infection rate of hrHPV and HSV-2 among women in Kaduna State is 2.3%. Demographic factors significantly influencing the rate of co-infections included age and marital status. In spite of the screening method using the traditional Pap smear, GUD and cervical cancer continues to be a major public health problem, thus more sensitive and specific methods such as liquid based cytology technique and polymerase chain reaction for early detection of cervical dysplasia and hrHPV or HSV-2 in asymptomatic women should be adopted for routine use

To investigate the significance of DNA ploidy analysis in diagnosis of atypical squamous cell of undetermined significance (ASCUS). From Jan.2009 to Jul.2011, 875 women with ASCUS confirmed by liquid based thin layer cytology technique underwent DNA ploid analysis in Hubei Maternal and Child Health Hospital. Among 294 women underwent high risk HPV detection. All subjective were examined colposcopy directed biopsy at day 3 to 10 after menstruation. Among 875 ASCUS cases, 553 cases with histologically as chronic cervicitis (63.2%), 165 cases with cervical intraepithelial neoplasia (CIN)I (18.9%), 45 cases with CINII (5.1%), 79 cases with CINIII (9.0%) and 33 cases with cervical invasive cancer (3.8%) were confirmed by colposcopy. Totally 532 cases were observed with DNA heteroploid, and 343 were not observed with DNA heteroploid. When DNA heteroploid negative and more than or equal to three ploid were used to predict CINII or more severe cervical diseases, the sensitivity, specificity, positive predictive values and negative predictive values were 98.7% and 90.3%, 47.5% and 46.1%, 29.1% and 40.8%, 99.4% and 92.1%, respectively. The amount of heteroploid cells > 2.5c and > 5c among every 100 detected cells in chronic cervicitis and CINI, CINII, CINIII and cervix cancer were respectively 2.53 ± 1.99 and 0.10 ± 0.07, 2.24 ± 1.69 and 0.20 ± 0.11, 4.10 ± 1.91 and 0.28 ± 0.19, 7.97 ± 7.33 and 1.27 ± 1.23, 8.99 ± 7.33 and 0.36 ± 0.33, there was no statistical difference in amount of heteropolid cells between >2.5c and > 5c at group of chronic cervicitis and CINI, CINIII and cervix cancer (P > 0.05). However, the amount of heteroploid cells at > 2.5c and > 5c at group of chronic cervicitis, CINI, CINIII and cervical were higher than that of CINII significantly (P < 0.05). Among 294 cases with high risk (HR) HPV detection, 216 cases were HR-HPV positive, and 78 cases were HR-HPV negative. The pathology result by colposcopy at group of negative heteroploid, heteroploid < 3, or ≥ 3 showed statistical distribution (χ(2) = 115.2775, P < 0.01). DNA ploidy analysis can be used for ASCUS diagnosis, which can avoid excessive biopsy under colposcopy, in the mean time, CIN and cervical cancer could decrease missed diagnosis.

[Objective]To investigate the significance of the high-risk human papilloma virus (HPV)detection in the screening and diagnosis of cervical lesions.[Methods] The high-risk HPV DNA test results of 797 patients with cervical lesions who all accepted cytology and histopathology test were collected and analyzed retrospectively.[Results]The high-risk HPV DNA positive rates in cervicitis,cervical intraepithelial neoplasia(CIN)Ⅰ,CIN Ⅱ,CIN Ⅲ and cervical cancer were 53.41％(188/352),70.91％(117/165),87.63％(85/97),97.90％(140/143),97.50％(39/40),respectively.The sensitivity and negative predictive value of the high-risk HPV DNA detection for CIN Ⅱ and more serious lesions were 96.66％(318/329),93.29％(153/164),respectively.The detection rate of CIN Ⅱ and more serious lesions in patients with atypical squamous cells of undetermined significance(ASCUS)and positive high-risk HPV DNA was 30.03％(94/313),while the rate in patients with negative high-risk HPV DNA was 1.55％(2/129).[Conclusions] The more serious the cervical lesion is,the higher high-risk HPV DNA positive rate is.It is most closely related with CIN 11 and cervical cancer.The high-risk HPV DNA detection has high sensitivity and negative predictive value for CIN Ⅱ and more serious lesions.The high-risk HPV DNA detection has high negative predictive value in CIN Ⅱ and more serious lesions in ASCUS. Key words: Uterine cervical diseases; Human papillomavirus; Cervical screening

Recently, practice guideline for the early detection of cervical cancer in Korea has been released in this journal [1].It was developed based on preexisting guidelines generated by the American Society for Colposcopy and Cervical Pathology (ASCCP) [2], the National Comprehensive Cancer Network [3], the United States Preventive Services Task Force [4], and the Institute for Clinical Systems Improvement [5].Coincidentally, updated versions of ASCCP guideline [6] and American Cancer Society (ACS) guideline [7] have been issued around the same time.Therefore, the updated contents of the abovementioned guidelines are not reflected in ours.The essential changes of the 2012 ASCCP guidelines from prior 2006 version are as follows [6]: 1) cytology reported as negative but lacking endocervical cells can be managed without any repeat, 2) cytology reported as unsatisfactory requires repeat even if human papillomavirus (HPV) is negative, 3) For atypical squamous cells of undetermined significance (ASC-US) cytology, immediate colposcopy is not an option.The serial cytology option for ASC-US incorporates cytology at 12 months, and then if negative, cytology every 3 years, 4) ASC-US and HPVnegative results should be followed with co-testing at 3 years rather than 5 years, 5) ASC-US and HPV-negative results are insufficient to allow exit from screening at age 65 years, 6) women aged 21-24 years are managed conservatively.Recently reported rates of cytology results reported as negative but lacking endocervical cells have ranged from 10% to 20% [8].Prior guidelines recommended early repeat cytology [9].A recent meta-analysis found that negative cytology had favorable specificity and negative predictive value despite absent endocervical cell component [10].Given that most cytology is performed using liquid-based media, unsatisfactory cytology results arise mainly from insufficient squamous cells [11].The 2012 ASCCP guidelines recommended repeat cytology in 2 to 4 months for women with an unsatisfactory cytology result.Those two issues regarding specimen adequacy were not included in our guidelines.The management of women with ASC-US has also been

The relationship between the expression of Stathmin and tumor immune cell infiltration in primary cervical carcinoma and its prognostic diagnostic value

Objective : To evaluate the utility of human papillomavirus (HPV) DNA detection, we conducted a study to determine accuracy of Hybrid capture test kit for detection of cervical intraepithelial neoplasia and cancer by biopsy results. Methods : We enrolled women referred to a colposcopy clinic. All 2010 women had a sample for HPV DNA test. and underwent colposcopically directed biopsies or loop electrode excision procedure. We used the Hybrid capture I test kit for HPV testing. Results : Among 681 women with biopsy specimens showing cervical intraepithelial neoplasia Ill and in 470 with cervical carcinoma, 73.4% and 76.4% had high-risk HPV DNA detected. Of 163 women with ASCUS on Papanicolaou smear, 65.8% had high-risk HPV DNA detected, and of 232 with low-grade squamous intraepithelial lesions, 48.0% had high-risk HPV detected. Conclusion : High-risk HPV testing appears to be of value to identify women with high grade cervical intraepithelial lesion and cervical cancer. But it does not appear to be of value to identify women with low-grade squamous intraepithelial lesions.