Associations of Single Versus Multiple Human Papillomavirus Infections With the Prevalence of Cervical Intraepithelial Neoplasia 2/3 and Squamous Cell Carcinoma Lesions: Human Papillomavirus Type-Specific Attribution.

The risk of developing cervical squamous lesions in women with multiple high-risk human papillomavirus (hrHPV) infections is uncertain. The aim of this retrospective study was to investigate the type-specific attribution and phylogenetic effects of single and multiple hrHPV subtypes in cervical squamous lesions. All cases with cervical histopathologic diagnosis and human papillomavirus (HPV) genotyping results in the 6 months preceding biopsy from October 2018 to December 2022 were studied and analyzed. Over the study period, 70,361 cases with histopathologic follow-up and prior HPV genotyping were identified. The hrHPV-positive rate was 55.6% (39,104/70,361), including single hrHPV detected in 27,182 (38.6%), 2 types of hrHPV detected in 8158 (11.6%), and 3 types of hrHPV detected in 2486 (3.5%). Among 16,457 cases with a histologically diagnosed squamous lesion (cervical intraepithelial neoplasia 1: 11411; cervical intraepithelial neoplasia 2/3: 4192; squamous cell carcinoma: 854 cases), the prevalence of single hrHPV infection increased, but the rate of multiple concomitant hrHPV infections showed negative association as the degree of squamous lesions increased. Among women with a single HPV16 infection, cervical intraepithelial neoplasia 2/3 and squamous cell carcinoma (CIN2+) diagnostic rate was 30.6%, and it increased to 47.6% when coinfected with HPV33 (P < .001) but significantly decreased when coinfected with all other hrHPV types (P < .05). By comparing CIN2+ diagnostic rates in 40 most common 2 types of hrHPV infections with related single hrHPV infection, CIN2+ rates were decreased in 12 combinations (30.0%), equivalent in 26 combinations (65.0%), and increased in 2 combinations (5.0%). The cases with 3 types of HPV infections reduced the risk for CIN2+ compared with related single HPV infections. HPV16+52+53, HPV16+52+68, HPV16+52+51, HPV16+39+52, and HPV16+58+53 significantly decreased the risk of CIN2+ compared with HPV16 single infection (P < .05). This study demonstrates that multiple hrHPV infections are not associated with cumulatively higher risk for CIN2+ development, suggesting that oncogenic progression of multiple hrHPV-associated cervical squamous lesions is neither synergistic nor a cumulative effect at the phylogenetic level, possibly a way of competitive interference.

Assessment of Efficacy and Accuracy of Cervical Cytology Screening With Artificial Intelligence Assistive System.

The role of artificial intelligence (AI) in pathology offers many exciting new possibilities for improving patient care. This study contributes to this development by identifying the viability of the AICyte assistive system for cervical screening, and investigating the utility of the system in assisting with workflow and diagnostic capability. In this study, a novel scanner was developed using a Ruiqian WSI-2400, trademarked AICyte assistive system, to create an AI-generated gallery of the most diagnostically relevant images, objects of interest (OOI), and provide categorical assessment, according to Bethesda category, for cervical ThinPrep Pap slides. For validation purposes, 2 pathologists reviewed OOIs from 32,451 cases of ThinPrep Paps independently, and their interpretations were correlated with the original ThinPrep interpretations (OTPI). The analysis was focused on the comparison of reporting rates, correlation between cytological results and histologic follow-up findings, and the assessment of independent AICyte screening utility. Pathologists using the AICyte system had a mean reading time of 55.14 seconds for the first 3000 cases trending down to 12.90 seconds in the last 6000 cases. Overall average reading time was 22.23 seconds per case compared with a manual reading time approximation of 180 seconds. Usage of AICyte compared with OTPI had similar sensitivity (97.89% vs 97.89%) and a statistically significant increase in specificity (16.19% vs 6.77%) for the detection of cervical intraepithelial neoplsia 2 and above lesions. When AICyte was run alone at a 50% negative cutoff value, it was able to read slides with a sensitivity of 99.30% and a specificity of 9.87%. When AICyte was run independently at this cutoff value, no sole case of high-grade squamous intraepithelial lesions/squamous cell carcinoma squamous lesion was missed. AICyte can provide a potential tool to help pathologists in both diagnostic capability and efficiency, which remained reliable compared with the baseline standard. Also unique for AICyte is the development of a negative cutoff value for which AICyte can categorize cases as "not needed for review" to triage cases and lower pathologist workload. This is the largest case number study that pathologists reviewed OOI with an AI-assistive system. The study demonstrates that AI-assistive system can be broadly applied for cervical cancer screening.

[Application of optical coherence tomography in the evaluation of cervical lesions: a multicenter study].

Objective: To explore the value of optical coherence tomography (OCT) imaging system in evaluating cervical lesions in vivo. Methods: A total of 1 214 patients with cervical lesions were collected from January 2020 to December 2021 in the Third Affiliated Hospital of Zhengzhou University, Maternal and Chlid Heaith Hospital of Gushi County, Xinyang City, Henan Province, and Maternal and Chlid Heaith Hospital of Sui County, Shangqiu City, Henan Province. The age of the patients was (38.9±10.5) years (range: 16-77 years). All patients underwent in vivo cervical OCT examination and cervical biopsy pathology examination, and summarized the OCT image features of in vivo cervical lesions. Using the pathological diagnosis as the "gold standard", the accuracy, specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of OCT image interpretation results were evaluated, as well as the consistency of OCT image diagnosis and pathological diagnosis. At the same time, the in vivo cervical OCT imaging system, as a newly developed screening tool, was compared with the traditional combined screening of human papillomavirus (HPV) and Thinprep cytologic test (TCT), to assess the screening effect. Results: By comparing the OCT images of the cervix in vivo with the corresponding HE images, the OCT image characteristics of the normal cervix and various types of cervical lesions in vivo were summarized. The accuracy, sensitivity, specificity, PPV and NPV of OCT image in the diagnosis of high-grade squamous intraepithelial lesion (HSIL) and above (HSIL+) were 93.4%, 88.5%, 95.0%, 85.0% and 96.2%, respectively. The accuracy, sensitivity, specificity, PPV and NPV of OCT for low-grade squamous intraepithelial lesion (LSIL) were 84.7%, 61.7%, 96.3%, 89.3% and 83.2%, respectively. The consistency between OCT image diagnosis and pathological diagnosis was strong (Kappa value was 0.701).The accuracy, sensitivity and specificity of OCT screening, HPV and TCT combined screening were 83.7% vs 64.9% (χ²=128.82, P<0.001), 77.8% vs 64.5% (χ²=39.01, P<0.001), 91.8% vs 65.4% (χ²=98.12, P<0.001), respectively. The differences were statistically significant. Conclusions: OCT imaging system has high sensitivity and specificity in the evaluation of cervical lesions in vivo, and has the characteristics of non-invasive, real-time and high efficiency. OCT examination is expected to become an effective method for the diagnosis of cervical lesions and cervical cancer screening.

Single and Multiple High-Risk Human Papillomavirus Infections in Histopathologically Confirmed Cervical Squamous Lesions: Incidences, Distribution, and Associated Detection Rates for Precancerous and Cancerous Lesions.

Coinfection with multiple high-risk human papillomavirus (hrHPV) is frequently observed in cervical specimens; however, the clinical significance of concomitant multiple hrHPV infections is poorly understood, and the published results remain inconsistent. A retrospective study at a tertiary care institution was performed, evaluating Tellgenplex human papillomavirus (HPV) 27 genotyping or YanengBio HPV 23 genotyping results and immediate cervical histologic diagnosis (within 6 months after HPV genotyping), between November 2015 and October 2022. Among 49,299 cases with hrHPV genotyping and histologic diagnosis, 24,361 cases were diagnosed as cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma. Among women with cervical squamous lesions, 86.5% (21,070/24,361) had hrHPV infections, and concomitant multiple hrHPV infections accounted for 24.7% of hrHPV-positive cases (5210/21,070). The hrHPV-positive rates in these cervical squamous lesions increased progressively with disease severity; however, the percentages of concomitant multiple hrHPV infection rates among hrHPV-positive cases decreased significantly with increasing degree of squamous abnormalities. There was no increased detection rate of CIN3+ (CIN3 and squamous cell carcinoma) in cases with concomitant 2 or 3 hrHPV genotype infections when compared with those with corresponding single hrHPV infections. Conversely, some combinations of multiple hrHPV infections demonstrated a decrease in the detection rates of CIN3+ lesions. In this large cohort, our results demonstrated that multiple hrHPV infections do not carry an increased risk for developing CIN3+ lesions when compared to the corresponding single-genotype infection. The reduced risk of CIN3+ in women infected with some combinations of hrHPV genotypes compared to those with single-genotype infections supports the concept of intergenotypic competition of hrHPV genotypes in cervical squamous lesions.

Extended human papillomavirus genotype distribution in cervical intraepithelial neoplasia and cancer: Analysis of 40 352 cases from a large academic gynecologic center in China.

Our aim was to conduct a large epidemiologic analysis of the distribution of human papilloma virus (HPV) genotypes associated with cervical neoplasias and cancers at a major Chinese gynecologic center. The pathologic database was searched for cervical histopathologic diagnoses with prior HPV genotyping from liquid cervical cytology specimens obtained ≤6 months before biopsy. HPV testing was performed by using the Tellgenplex HPV27 or YanengBio HPV23 genotyping assays. A total of 40 352 cases meeting study criteria were identified. High risk human papillomavirus (hrHPV) was detected in 94.1% of squamous cancers compared to in only 83.3% of cervical adenocarcinomas. The prevalence of multiple HPV infections was highest in cervical intraepithelial neoplasia 1 (CIN1) (33.8%) and decreased with increasing severity of squamous lesions. The distribution of HPV genotypes was similar between CIN1 and histopathologic-negative cases. HPV16 was one of the three most common hrHPV genotypes before all histopathologic abnormalities, ranging from 72.0% for cervical cancers, 38.7% for CIN2/3/AIS, 13.1% for CIN1, and 9.1% for biopsy-negative cases. HPV16 and HPV18 accounted for over 87.2% of detected hrHPV genotypes for all glandular intraepithelial neoplastic lesions and cancers, whereas squamous lesions did not show this pattern. 80.3% of cervical cancers were associated with genotypes covered by HPV16/18 vaccines and 89.6% with genotypes covered by 9-valent vaccination.

Associations of RBC and Serum Folate Concentrations with Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Genotypes in Female Chinese Adults.

BACKGROUND: Although folate status is associated with cervical carcinogenesis, it is not clear whether folate deficiency is associated with risk of cervical intraepithelial neoplasia (CIN) progression and infection with high-risk human-papillomavirus (hrHPV). OBJECTIVES: To evaluate the associations of RBC and serum folate concentrations with prevalence of CIN grades and hrHPV infection, their interactions with prevalence of CIN grades, and RBC folate with the risk of CIN1 progressing to CIN2. METHODS: Using data from the Shanxi CIN cohort of 2304 female Chinese adults, we used logistic-regression model to estimate ORs and prevalence ratios (PRs) of RBC and serum folate concentrations with prevalence of CIN grades and hrHPV infection. Categoric and spline analyses were used to evaluate the dose-response relations. We estimated the association of RBC folate with risk of CIN1 progressing to CIN2 in the nested case-control cohort. RESULTS: An inverse association was observed between increased RBC folate concentration and the odds of all CIN grades [quartile 1 (Q1) compared with Q4: OR: 2.28; 95% CI: 1.77, 2.93; Ptrend < 0.001]. Significant interaction of RBC folate and hrHPV infection was observed for prevalence of CIN2 or above (Pinteraction < 0.01). No associations were found between RBC and serum folate with PRs of hrHPV in each CIN grade. Over a median follow-up of 21.0 mo, RBC folate was associated with increased risk of CIN1 progressing to CIN2 (Q1 compared with Q4: OR: 3.86; 95% CI: 1.01, 14.76). CONCLUSIONS: Our study indicates that RBC folate concentration is associated with prevalence of CIN grades and CIN1 progression in female Chinese adults. Maintenance of normal folate status is important for reducing the risk of CIN and its progression in women with or without hrHPV infection.

Follow-up Findings in Postconservative Treatment Surveillance for Women With Cervical Adenocarcinoma In Situ.

OBJECTIVES: The risks of adenocarcinoma in situ (AIS) recurrence or progression after conservative treatment are uncertain. The aim of this study was to examine the role of high-risk human papillomavirus (hrHPV) and cytology in the posttreatment surveillance of AIS patients. MATERIALS AND METHODS: Follow-up results of hrHPV status, cytology results, and clinicopathological features of 207 patients were retrospectively analyzed, in whom AIS was initially treated by loop electrosurgical excision procedure (LEEP)/cone biopsy between September 2009 and June 2018. RESULTS: Among 207 patients diagnosed AIS on LEEP/cone biopsy, 30.9% (64/207) had positive margins. Persistent/recurrent AIS rate was substantially higher in the patients with positive margins than in those with negative margins (47.2% vs 9.3%, p < .001). Of 74 patients with hrHPV surveillance, 17 (17/74, 23.0%) were found to have positive hrHPV and 4 (4/17, 23.5%) had the persistent/recurrent AIS regardless of margin status. On the contrast, no AIS were found in negative surveillant hrHPV patients (23.5% vs 0%, p < .001). Lastly, 27.8% patients (22/79) were reported atypical glandular cells on surveillant cytology, and 9 persistent/recurrent AIS cases were further identified on second biopsy or hysterectomy with a positive detection rate of 40.9%. CONCLUSIONS: In this study, we concluded the positive margin on LEEP/cone biopsy in AIS patients was associated with a significantly greater risk of disease persistence or recurrence. The posttreatment surveillance by cytology and adjunct hrHPV would be an ideal strategy in predicting AIS persistence and recurrence, which will warrant further treatments.

Cervical Stenosis: Previously Unrecognized Cause of False-Negative Human Papillomavirus Tests in Women Developing Cervical Cancer.

OBJECTIVES: Cervical stenosis can jeopardize adequate posttreatment cytologic follow-up of patients treated for high-grade cervical intraepithelial lesions. An impact on human papillomavirus (HPV) testing has not been described. MATERIALS AND METHODS: We describe 2 patients with cervical stenosis, followed by cytology and HPV co-testing after excisions of high-grade cervical intraepithelial lesions. Each had 1 or more co-test "double-negative" results. Hysterectomies revealed unexpected cervical carcinomas. RESULTS: In case 1, an 80-year-old woman with complete cervical stenosis and earlier high-grade squamous dysplasia presented with abdominal pain, nausea, and an enlarged uterus. Attempted endometrial biopsy was unsuccessful. Cytology and HPV tests 9 months earlier were negative. Hysterectomy revealed a cervical squamous carcinoma. In case 2, a 40-year-old woman followed conservatively after excision of endocervical adenocarcinoma in situ had 5 follow-up cytology and HPV co-tests. All were HPV negative. Elective hysterectomy revealed cervical adenocarcinoma. Both carcinomas tested HPV positive. CONCLUSIONS: Cervical stenosis in women developing cervical cancer can cause misleading sampling and false-negative HPV test results.

Serine/threonine kinases 31(STK31) may be a novel cellular target gene for the HPV16 oncogene E7 with potential as a DNA hypomethylation biomarker in cervical cancer.

BACKGROUND: Cervical cancer (CC) is a leading cause of mortality in females, especially in developing countries. The two viral oncoproteins E6 and E7 mediate the oncogenic activities of high-risk human papillomavirus (hrHPV), and hrHPV, especially HPV16 or/and HPV18 (HPV16/18) play critical roles in CC through different pathways. STK31 gene of which the expression has been proven to be regulated by the methylation status of its promoter, is one of the novel cancer/testis (CT) genes and plays important roles in human cancers. Reasearches have indicated that viral infection is correlated to the methylation statuses of some genes. Herein, we detected methylation status of the STK31 gene in cervical tumors and explored its interaction with HPV16 or/and HPV18 (HPV16/18) infection. METHODS: Bisulfite genomic sequencing PCR (BGS) combined with TA clone, methylation-specific PCR (MSP) were used to analyze methylation statuses of the STK31 gene promoter/exon 1 region in HPV16/18-positive, HPV-negative CC cell lines; ectopically expressed HPV16 E6, -E7, and -E6/E7 CC cells; normal cervical tissues and cervical tumor tissues of different stages. The mRNA and protein expressions of STK31 were detected by RT-PCR and western blotting. RESULTS: The STK31 gene promoter/exon 1 was hypomethylated in the HPV16/18-positive cell lines HeLa, SiHa and CaSki, and the mRNA and protein expression were detected. In contrast, the STK31 gene exhibited hypermethylation and silenced expression in the HPV-negative CC cells C33A and HT-3. Compared with the primary HPV-negative CC cell lines, the STK31 methylation was downregulated, and STK31 expression was induced in the HPV16E7/E67 transfected cells. The methylation statuses and expressions of STK31 were verified in the cervical tumor samples at different stages. Additionally, chemotherapy treatment may influence STK31 expression by regulating its methylation status. CONCLUSIONS: STK31 may be a novel cellular target gene for the HPV16 oncogeneE7. The HPV16 oncogene E7 may affect STK31 expression through a methylation-mediated mechanism. The aberrant methylation of the STK31 promoter/exon 1 region may be a precursor of human cervical carcinogenesis and a potential DNA aberrant methylation biomarker of conditions ranging from precancerous disease to invasive cancer.

Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.

BACKGROUND: Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors. METHODS: We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays. RESULTS: DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity. CONCLUSIONS: Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).

Point-Counterpoint: Cervical Cancer Screening Should Be Done by Primary Human Papillomavirus Testing with Genotyping and Reflex Cytology for Women over the Age of 25 Years.

Screening for cervical cancer with cytology testing has been very effective in reducing cervical cancer in the United States. For decades, the approach was an annual Pap test. In 2000, the Hybrid Capture 2 human papillomavirus (HPV) test was approved by the U.S. Food and Drug Administration (FDA) for screening women who have atypical squamous cells of underdetermined significance (ASCUS) detected by Pap test to determine the need for colposcopy. In 2003, the FDA approved expanding the use of the test to include screening performed in conjunction with a Pap test for women over the age of 30 years, referred to as "cotesting." Cotesting allows women to extend the testing interval to 3 years if both tests have negative results. In April of 2014, the FDA approved the use of an HPV test (the cobas HPV test) for primary cervical cancer screening for women over the age of 25 years, without the need for a concomitant Pap test. The approval recommended either colposcopy or a Pap test for patients with specific high-risk HPV types detected by the HPV test. This was based on the results of the ATHENA trial, which included more than 40,000 women. Reaction to this decision has been mixed. Supporters point to the fact that the primary-screening algorithm found more disease (cervical intraepithelial neoplasia 3 or worse [CIN3+]) and also found it earlier than did cytology or cotesting. Moreover, the positive predictive value and positive-likelihood ratio of the primary-screening algorithm were higher than those of cytology. Opponents of the decision prefer cotesting, as this approach detects more disease than the HPV test alone. In addition, the performance of this new algorithm has not been assessed in routine clinical use. Professional organizations will need to develop guidelines that incorporate this testing algorithm. In this Point-Counterpoint, Dr. Stoler explains why he favors the primary-screening algorithm, while Drs. Austin and Zhao explain why they prefer the cotesting approach to screening for cervical cancer.

Genotypic analysis and latent membrane protein 1 expression of Epstein-Barr virus in extranodal NK/T-cell lymphoma from Northern Chinese patients.

As the most common NK/T-cell lymphoma in Asian countries, extranodal NK/T-cell lymphoma, nasal type (ENKTL), has unique clinical features and a strong association with Epstein-Barr virus (EBV). In order to gain a preliminary understanding of the relationship between ENKTL and EBV, we performed genotypic analysis of EBV and investigated LMP1 expression in extranodal NK/T-cell lymphoma. Our study shows that ENKTL is an EBV-associated malignancy and that A, C and F are the predominant EBV genotypes in northern China. LMP1 expression is stronger in extranasal sites than nasal sites, and the expression level is strongly correlated to ENKTL and may play an important role in the development of ENKTL.

Comprehensive overview of genotype distribution and prevalence of human papillomavirus in cervical lesions.

Across cervical squamous and glandular lesions, a spectrum of human papillomavirus (HPV) genotypes has been identified. This review aims to provide a comprehensive summary detailing the distribution and profile of HPV genotypes detected in cervical lesions, leveraging insights from histological and cytological findings. High-risk HPV (HR-HPV) genotypes exhibit varying degrees of oncogenic potential, with HPV16 and HPV18 identified as the most prevalent and oncogenic types. The distribution of HR-HPV genotypes varies among different degrees of the cervical lesions and varies between squamous and glandular neoplasia. HPV16 is predominantly associated with severe lesions (precancers and carcinomas), while HPV18 demonstrates a significantly higher prevalence in endocervical as compared with squamous neoplasia. The distribution of HR-HPV in severe squamous lesions is complex, involving many HR-HPV genotypes in addition to HPV16, while the distribution of HR-HPV genotypes in endocervical glandular lesions is mainly limited in HPV18 and HPV16. Large datasets from China have identified the three most common HR-HPV genotypes in this population as stratified by diagnostic category: HPV52, HPV16, HPV58 in histologically negative cases and cervical intraepithelial neoplasia 1 (CIN1); HPV16, HPV52, HPV58 in CIN2/3; HPV16, HPV58, HPV52 or HPV18 in squamous cell carcinoma (SCC); HPV16, HPV18 and HPV52 in endocervical adenocarcinoma in situ (AIS), invasive adenocarcinoma, as well as mixed squamous and glandular lesions. HPV33 is the fourth most common HPV type in CIN2/3 and SCC, while HPV45 occurs more commonly in AIS and adenocarcinoma, compared with squamous lesions. The prevalence and distribution of multiple HR-HPV coinfections vary across different cervical diseases. The clinical significance and pathogenesis of these multiple HR-HPV infections remain uncertain, although recent two large studies demonstrate that multiple HR-HPV infections are not associated with cumulatively higher risk of high-grade cervical squamous lesion development, suggesting competitive and/or cooperative interactions among HPV genotypes. Extensive HPV genotyping aids in risk assessment and optimising clinical approaches for women with mild abnormalities in Pap cytology. Women with atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) Pap test results and with the infection of some HR-HPV genotypes carry a very low risk of high-grade cervical lesions. HPV genotyping can allow for risk stratification and triage optimisation for these HR-HPV-positive women. Women with atypical glandular cell (AGC) Pap test results showed a specific HPV genotyping pattern and extended HPV genotyping may be helpful for the clinical management of AGCs. Continual advancements in clinical guidelines integrating extended genotyping would increase diagnostic accuracy and refine strategies in clinical management.

Genotype profile of HPV in ASC-H cytology and histologic follow-up-prevalence, distribution, and risk: A retrospective study of 1414 cases.

BACKGROUND: A cytologic diagnosis of atypical squamous cells, cannot exclude high-grade squamous lesion (ASC-H) poses a disproportionately high risk of cervical cancer development. The objective of this study was to analyze type-specific risks by mapping human papillomavirus (HPV) genotypes in ASC-H cytology. METHODS: In total, 1,048,581 Papanicolaou tests that had ASC-H cytology were retrieved. Concurrent HPV genotyping using proprietary multiplex real-time (MRT) and polymerase chain reaction (PCR) HPV tests and histologic follow-up findings were analyzed. RESULTS: Among 1678 patients who had ASC-H findings (0.16%), 1414 (84.3%) underwent concurrent HPV genotyping (MRT, 857; HPV PCR test, 557). The overall high-risk HPV (hrHPV)-positive rate was 84.4%. Of the 857 MRT cases, 63.9% were infected with a single hrHPV, and 24.4% had multiple genotypes. The most prevalent HPV types were HPV16/52/58/33/31. Lesions that were identified as cervical intraepithelial neoplasia 2 or worse (CIN2+) were detected in 498 of 906 cases (55.0%), including 81 cervical carcinomas (8.9%). The risk of CIN2+ for the composite group of HPV16/52/58/33/31-positive cases was 62.7%, representing 90.7% (264 of 291) of total CIN2+ lesions in ASC-H/hrHPV-positive cases by MRT. CIN2+ lesions were detected in 108 of 142 (76.1%) HPV16-positive and/or HPV18-positive women by the PCR the HPV test. Among 128 hrHPV-negative ASC-H cases by both methods, CIN2+ lesions were identified in 21 of 128 (16.4%), including five cervical carcinomas (3.9%). The sensitivity, specificity, positive predictive value, and negative predictive value for patients in the composite group with HPV16/52/58/33/31 were 88.0%, 40.8%, 62.7%, and 75.0%, respectively. CONCLUSIONS: Papanicolaou tests classified as ASC-H are associated with a high CIN2+ rate and warrant colposcopy, regardless of HPV status. The extent to which the risk-stratification provided by comprehensive HPV genotyping can inform the management of ASC-H cytology remains to be explored.

Characteristics and utility of high-resolution optical coherence microscopy images of endocervical canal lesions.

OBJECTIVES: To investigate optical coherence microscopy (OCM) imaging features and the application value of these high-resolution images for identifying endocervical canal lesions (ECLs), which is a clinical dilemma in cervical cancer screening programs. METHODS: In total, 520 OCM images were obtained by scanning the cervical canal lesions with an ultra-high-resolution OCM system (204 specimens from 73 patients). The OCM morphologic characteristics of ECLs were observed and summarized, and then 3 researchers performed a diagnostic test of OCM images of cervical canal lesions. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, 95% confidence interval of each parameter, and interinvestigator agreement (κ) were calculated. RESULTS: Normal endocervix, cysts, squamous metaplasia, high-grade squamous intraepithelial lesions involving glands, and invasive carcinoma had distinct OCM characteristics, which correlated well with corresponding H&E histologic sections. The accuracy, sensitivity, and specificity of the 3 researchers were 90.6%, 89.3% (95% CI, 86.5%-91.7%) and 91.6% (95% CI, 89.2%-93.5%), respectively. The positive predictive value was 90.1% (95% CI, 87.3%-92.4%), and the negative predictive value was 90.9% (95% CI, 88.5%-92.9%), with almost perfect agreement (κ = 0.874). CONCLUSIONS: The application of the OCM system in cervical canal lesions is feasible and could help improve detection of occult ECLs in cervical cancer screening programs. This study lays the foundation for further research on OCM in cervical canal lesions in vivo, which also has a potential impact on projecting pathologic evaluation beyond what is currently possible, perhaps globally.

Implementation of Digital Image Analysis in Assessment of Ki67 Index in Breast Cancer.

The clinical utility of the proliferation marker Ki67 in breast cancer treatment and prognosis is an active area of research. Studies have suggested that differences in pre-analytic and analytic factors contribute to low analytical validity of the assay, with scoring methods accounting for a large proportion of this variability. Use of standard scoring methods is limited, in part due to the time intensive nature of such reporting protocols. Therefore, use of digital image analysis tools may help to both standardize reporting and improve workflow. In this study, digital image analysis was utilized to quantify Ki67 indices in 280 breast biopsy and resection specimens during routine clinical practice. The supervised Ki67 indices were then assessed for agreement with a manual count of 500 tumor cells. Agreement was excellent, with an intraclass correlation coefficient of 0.96 for the pathologist-supervised analysis. This study illustrates an example of a rapid, accurate workflow for implementation of digital image analysis in Ki67 scoring in breast cancer.

Epstein-Barr virus gene polymorphism in different parts of the same nasopharyngeal carcinoma patient.

In most previous studies, comparisons of Epstein-Barr virus (EBV) gene polymorphisms and genotypes were made between strains from tumors and normal throat washings (TWs) from different individuals. However, it remains controversial whether different EBV subtypes are present in different parts of the same NPC patient. In order to address this question, in this study, we compared the genotypes in sets of paired throat washings (TW) and paraffin-embedded tissues of 20 patients with nasopharyngeal carcinoma (NPC), and we found the same genotype in throat washings (TWs) and tumor cells from the same individual in most cases. The subtypes of EBER and EBNA1 genes were furthermore sequenced, and identical EBV strains were identified in tumor tissues and TWs. In conclusion, different sites of the same individual are infected by the same EBV strains, except for a few differences in occasional cases, suggesting that the EBV subtype detected in throat washings is a reasonable guide to the subtype present in the carcinoma tissue.

Long-term follow-up results from women with cervical adenocarcinoma in situ treated by conization: an experience from a large academic women's hospital.

OBJECTIVES: Cervical adenocarcinoma in situ (AIS) is the precursor to adenocarcinoma, and early management will often prevent the occurrence of invasive adenocarcinoma. Conservative treatment with conization has been proposed for the initial treatment for cervical AIS. To evaluate the risk of residual/recurrent disease after conization, we investigated the long-term follow-up results for patients with cervical AIS treated by conization. MATERIALS AND METHODS: One hundred thirty-six patients with a biopsy diagnosis of cervical AIS followed by conization were followed up with cytologic, histologic, and human papillomavirus testing. RESULTS: The rate of residual AIS in the following hysterectomy was significantly increased in patients with positive margins on the conization (48.6%, 17/35) compared to patients with negative margins (0/30). No significant disease was identified in patients treated by hysterectomy as primary treatment. More importantly, only 2 patients with conization as primary management had adenocarcinoma or focal AIS, respectively, during a long-term follow-up period (mean, 45 mo). However, one of them had positive margin on the conization and did not proceed to further treatment. The other one had negative margin on the conization but only had focal AIS on the hysterectomy. Human papillomavirus-positive rate showed no significant difference between patients treated by conization and patients treated by hysterectomy during the long-term follow-up. CONCLUSIONS: Therefore, if a negative resection margin is achieved, conservative management with conization and careful surveillance is suitable for patients with cervical AIS and desire for future childbearing.

Updates in Cervical Cancer Screening Guidelines, The Bethesda System for Reporting Cervical Cytology, and Clinical Management Recommendations.

Over the past decades, cervical cancer has been a worldwide public health problem. Population-based early cancer risk detection and prevention approaches, including vaccination, cytology screening and human papilloma virus (HPV) detection, with the aligned clinical management, have formed a well-rounded high-quality implementation system for cervical cancer control, and revolutionarily improved the quality of life of women: (1) the success of cervical cancer screening practices, (2) standardization of The Bethesda system for reporting cervicovaginal cytology, (3) improvement in the understanding of HPV pathogenesis in cervical cancer, and (4) the development of appropriate management approaches have significantly decreased the disease burden of cervical cancer worldwide. This scoping review aimed to understand the evolvement of cervical cancer screening and management guidelines, describe the Bethesda cervical cytology reporting system, and HPV vaccines and tests, and highlight the key information of present policies and practices.