Correlation of High-Risk HPV Genotypes with Pap Test Findings: A Retrospective Study in Eastern Province, Saudi Arabia.

INTRODUCTION: High-risk human papillomavirus (HR HPV) is found to be responsible for 4.5% of cancer in general, primarily cervical cancer. We aim here to highlight the prevalence and genotypes of HR HPV and correlate its association with Pap tests' results, which are still not well known in the Eastern Province of Saudi Arabia. METHODS: Over 7 years (2013-2019), the results of 164 Saudi women coinvestigated for HR HPV along with Pap tests were collected from the archive of King Fahd University Hospital. Only women who had atypical squamous cells of undetermined significance (ASCUS) on the Pap test and those at elevated risk of infection were cotested for HR HPV; otherwise, the Pap test was the only screening modality for cervical cancer. Data were organized and statistically analyzed using IBM SPSS v26. RESULTS: Out of 164 Saudi women, 14.5% (n = 24/164) showed positive results for HR HPV (8 patients had HPV16 and 2 had both HPV16 and HPV18/45, while the remaining 14 had other HR HPV); among them, 41.5% (n = 10/24) had an abnormal Pap test (5 ASCUS and 5 LSIL), while 58.5% (n = 14/24) had a negative Pap test. On the other hand, 21% (n = 35/164) of patients, in the study, had an abnormal Pap test (24 ASCUS, 8 low-grade squamous intraepithelial lesion [LSIL], and 3 atypical glandular cell [AGC]). In 80% (n = 19/24) of ASCUS cases, HR HPV was not detected; however, 20% (n = 5/24) were positive for other HR HPV. Concerning LSIL cases, 62.5% (n = 5/8) were positive for HR HPV (1 case showed HPV16 and HPV18/45, 2 cases showed HPV16, and 2 cases showed other HR HPV), while in the remaining 37.5% (n = 3/8) LSIL cases, HR HPV was negative; similarly, all AGC cases were negative for HR HPV. Statistical analysis showed a significant correlation between HPV status and Pap test findings (p value <0.001). DISCUSSION/CONCLUSION: HR HPV frequency and genotype distribution, in this study, might reflect a different regional infection pattern. The high association of HR HPV with negative cytology emphasizes the need to add the HR HPV test to screening modalities of cervix cancer.

Cytological, Colposcopic and Pathohistological Correlation of HSIL and ASC H Findings.

INTRODUCTION: Cervical cancer can be successfully prevented by timely detection of changes that precede it such as atypical (ASC-H) and high grade squamous lesions (HSIL). AIM: To investigate the correlation between Pap smear and colposcopy in the detection of premalignant and malignant cervical lesions based on a pathohistological finding. METHODS: In a retrospective study 118 patients with HSIL and ASC-H findings were examined. A Pap smear, colposcopic examination and cervical canal biopsy were performed. The study was conducted at the Gynecological Center "Dr Mahira Jahic" Tuzla and the Clinical Center Tuzla, Department of Gynecology and Obstetrics. RESULTS: 1049 abnormal Pap tests were analyzed, ASCUS in 51,8% (N-544), LSIL 32,1% (N-337), HSIL 7,7% (N-81) and ASC-H 3,5% (N-37), AGC 4,8% (N-51). The mean age of the subjects with the abnormal Pap test was 46.33 ± 3.2. The age of patients with ASCUS lesion was 38,6 , LSIL 41,0, ASC-H was 47,3 , HSIL (CIN II and CIN III) 45,8 , while patients with CIS were 51,2 years. Pathological histology HSIL confirmed a high grade lesion in 67,7% (CIN II, CIN III and CIS) (N-55), in 32% (N-26) a lower grade CIN I in 18,5% and chronic cervicitis in 13,5% (N-11). In ASC-H lesion pathohistological HSIL was found in 13,5% (N-5), CIN I 13,5% (N-5) and chronic cervicitis 48,6 % (N-18). Abnormal colposcopic imaging with HSIL lesion was found in 72,9% (N-69), in 8,6% (N-7) was unsatisfactory and in 18,5% (N-15) the colposcopic finding was normal. In ASC-H lesions, abnormal colposcopic imaging was found in 40,5% (N-15), unsatisfactory findings in 10,8% (N-4), and normal findings in 48,6% (N-18). CONCLUSION: Colposcopy has proven to be better method than cytology with an accuracy of 72,9% in high-grade lesion such as HSIL and ASC-H.

Morphometric analysis of atypical glandular cells correctly classifies normal, reactive, and atypical cells in cervical smears.

The 2014 Bethesda System diagnostic criteria for atypical glandular cells (AGC) aid in the classification of atypical cells in cervical cytology. Anyway, AGC diagnosis remains challenging, due to low frequencies of this finding (approximately 0.5%-1% of Pap test results), abundance of AGC mimics, and significant interobserver variability. We developed an algorithm based on nuclear areas parameter that can help to differentiate AGC from Normal and Reactive glandular cells. Nuclear areas and perimeters were measured on 16 Pap smears with AGC and 18 with Reactive glandular cells of women aged between 30 and 77. Glandular cells from nonpathological Pap smears were used as controls. For each case, the means, medians, standard deviations, and the minimum and maximum values of both nuclear areas and perimeters of the cells of interest were calculated. The nuclear area analysis showed a 100% specificity in discriminating Normal from Altered cells (either Reactive or AGC), whereas the nuclear perimeter analysis showed a lower specificity (87.5%). Both nuclear area and perimeter variability analysis resulted in high specificity values in distinguishing Reactive cells from AGC. Therefore, a stepwise two-step algorithm using nuclear areas to discriminate Normal from Altered cells, and nuclear area variability to distinguish Reactive from AGC, allowed us to reliably classify the cells into these three categories. The morphometric analysis of nuclear area is a valuable and reliable aid in AGC diagnosis and standardization, easily integrable into common automatic algorithms.

Prognostic and diagnostic validity of p16/Ki-67, HPV E6/E7 mRNA, and HPV DNA in women with ASCUS: a follow-up study.

BACKGROUND: We evaluated the prognostic and diagnostic ability of p16/Ki-67 immunocytochemistry, HPV E6/E7 mRNA testing and HPV DNA assay in triaging ASCUS to find a way to manage cervical lesions more effectively. METHODS: We conducted a prospective study through follow-up. The detection methods of the three factors: p16/Ki-67 immunocytochemistry conducted by using the CINtec® Plus Kit, E6/E7 mRNA testing by QuantiVirus®HPV E6/E7 mRNA assay and DNA by Hybrid Capture 2 assay. RESULTS: One hundred three women with ASCUS satisfied requirements and completed the entire follow-up process. All CIN2+ occurred in women who were mRNA positive at baseline, none in mRNA negative. 100% (6/6) patients with CIN2+ were HPV DNA assay positive, 100% (6/6) were HPV E6/E7 mRNA testing positive and 50.0% (3/6) were p16/Ki-67 immunocytochemistry positive. The risk ratio of E6/E7 mRNA test was 57.306 (95% CI 0.077-42,400.545). For endpoint of CIN2+, the sensitivity between HPV DNA assay and HPV E6/E7 mRNA testing is no statistical difference, but statistical difference exists between HPV E6/E7 mRNA testing vs. p16/Ki-67 immunocytochemistry (χ2 = 5.718, P = 0.023) and HPV DNA assay vs. p16/Ki-67 immunocytochemistry (χ2 = 5.718, P = 0.023). The specificity of E6/E7 mRNA testing, p16/Ki-67 and DNA assay in triaging ASCUS was 44.33, 75.26 and 11.34% respectively and is all statistical difference (χ2 = 26.277, P < 0.001(HPV DNA assay vs. HPV E6/E7 mRNA testing), χ2 = 19.297, P < 0.001(HPV E6/E7 mRNA testing vs. p16/Ki-67 immunocytochemistry), χ2 = 80.707, P < 0.001(HPV DNA assay vs. p16/Ki-67 immunocytochemistry). The expression level of 2097.09 copies/ml was the optimal cut-off value for HPV E6/E7 mRNA testing to diagnose CIN2+, the sensitivity and specificity was 61.1 and 68.2%. CONCLUSIONS: High expression of HPV E6/E7 mRNA could be a good candidate as a diagnostic biomarker to triage ASCUS superseding HPV DNA. p16/Ki-67 immunocytochemistry is suggested to be a good tool to triage ASCUS, but it reduced the sensitivity of diagnosis when improves the diagnostic specificity.

Prevalence of cervical cancer and pre-cancerous lesions among unscreened Women in Kumasi, Ghana.

Ghana does not have a universal population-based cervical cancer screening program and there is very limited information about the distribution of cervical epithelial cell lesions. This study provides evidence that a moderately high prevalence of cervical cancer and precancerous lesions exists among unscreened women in Kumasi.The prevalence of cervical epithelial cell abnormalities among a cross-section of women attending cervical cancer screening for the first time in a suburb of Ghana from 2011 to 2014 was studied. Cervical smears were prepared and examined independently by 2 cytotechnologists and confirmed by a pathologist. Cervical lesions were classified according to the Bethesda System for cervical cytology 2001.Out of the 592 women for whom a Pap smear was available for evaluation, 555 (93.8%) were negative for intraepithelial lesion or malignancy. Eight women (1.4%) showed atypical squamous cells of undetermined significance (ASCUS), 9 (1.4%) low-grade squamous intraepithelial lesions, and 2 (0.3%) high-grade squamous intraepithelial lesions. A total of 15 (2.5%) smears were unsatisfactory for cervical cytology. Additionally, 3 women (0.5%) had squamous cell carcinoma, giving an overall rate of 3.7% for epithelial cell abnormalities.Cervical cancer and precursor epithelial cell abnormalities are common among women in Kumasi for a disease that can be prevented by early detection through routine screening and management. This study provides adequate background data to recommend the implementation of cervical cancer screening in all eligible women in Ghana.

Performance of HPV16/18 in Triage of Cytological Atypical Squamous Cells of Undetermined Significance.

CONTEXT: Human papillomavirus (HPV) testing is widely used in cervical cancer screening in women; however, its efficiency in triaging women with atypical squamous cells of undetermined significance (ASC-US) needs to be validated. OBJECTIVE: To evaluate the performance of HPV16/18 in the triage of women with ASC-US. METHODS: Women presenting for routine cervical cancer screening had cervical specimens collected, with which both liquid-based cytology (LBC) and hrHPVs were examined; those with ASC-US cytology underwent colposcopy. HPV16/18 and 12 other types were tested with domestic hybridization capture and chemiluminescence signal amplification (DH3). Performance characteristics of HPV test (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for identification of cervical intraepithelium neoplasma (CIN) grade 2 or worse (CIN2+), and CIN grade 3 or worse (CIN3+)) were determined using standard statistical tests. RESULTS: 317 women with ASC-US were eligible for the study. HrHPV prevalence was 15.77% (50/317); HPV16/18 prevalence was 3.61% (20/317). Sensitivity and specificity of HPV16/18 for detection of CIN 2+ were 64.71% and 97% and 64.29% and 96.37% for detection of CIN 3+, respectively. The positive predictive values (PPVs) and negative predictive values (NPVs) of HPV16/18 were 55.00% and 97.98% for CIN2+ and 45.00% and 98.32% for CIN3+, respectively. CONCLUSION: HPV16/18 can be considered as an effective method to triage women with ASC-US as its good clinical performance. TRIAL REGISTRATION: This trial is registered with Henan Cancer Hospital Medical Ethics Committee on July 5, 2016 (http://www.anti-cancer.com.cn), with registry no.: 2016037.

Risks of cervical intraepithelial neoplasia grade 3 or invasive cancers in ASCUS women with different management: a population-based cohort study.

OBJECTIVE: To investigate the progression risk of atypical squamous cells of undetermined significance (ASCUS) with different clinical managements. METHODS: Women with their first diagnosis of ASCUS cytology were retrieved from the national cervical cancer screening database and linked to the national health insurance research database to identify the management of these women. The incidences of developing cervical intraepithelial neoplasia grade 3 and invasive cervical cancer (CIN3+) were calculated, and the hazard ratios (HRs) were estimated using a Cox proportional hazards model. This study was approved by the Research Ethics Committee of the National Taiwan University Hospital and is registered at ClinicalTrials.gov (Identifier: NCT02063152). RESULTS: There were total 69,741 women included. Various management strategies including colposcopy, cervical biopsies and/or endocervical curettage, and cryotherapy, failed to reduce the risk of subsequent CIN3+ compared with repeat cervical smears. Loop electrosurgical excision procedure/conization significantly decreased risk of subsequent CIN3+ lesions (HR=0.22; 95% confidence interval [CI]=0.07-0.68; p=0.010). Women in their 40s-50s had an approximately 30% risk reduction compared to other age groups. Women with a previous screening history >5 years from the present ASCUS diagnosis were at increased risk for CIN3+ (HR=1.24; 95% CI=1.03-1.49; p=0.020). CONCLUSION: In women of first-time ASCUS cytology, a program of repeat cytology can be an acceptable clinical option in low-resource settings. Caution should be taken especially in women with remote cervical screening history more than 5 years.

Hallazgos no neoplásicos y anormalidades celulares epiteliales en citología cervical / Non Neoplastic Findings and Epithelial Cell Abnormalities in Cervical Cytology

Introducción: el examen citológico de Papanicolaou tiene como objetivo el diagnóstico de lesiones precancerosas o cancerosas del cuello uterino, una evaluación hormonal y de flora bacteriana. Objetivos: determinar la proporción de hallazgos no neoplásicos y las anormalidades epiteliales escamosas y glandulares remitidos al área de Citología del Hospital Nacional Docente Madre Niño San Bartolomé. Métodos: se diseñó una investigación de tipo analítico-correlacional prospectiva de corte transversal en todos los frotices referidos de cinco redes y microredes de salud. El procesamiento citológico se realizó en conformidad con los requerimientos internacionales para citología. La interpretación citológica se realizó según el Sistema Bethesda. Resultados: de 72 644 extendidos cérvicouterinos evaluados mediante sistema de calidad del Sistema Bethesda, la proporción de resultados con alteraciones cérvico-uterinas (prevalencia 6,5 por ciento; IC: 95 por ciento: 6,32 por ciento, 6,68 por ciento), negativos posevaluación y Hallazgos no neoplásicos fue de 4724 (6,5 por ciento), 35 318 (51,7 por ciento) y 32 602 (48,2 por ciento) muestras, respectivamente (p< 0,005). La probabilidad posprueba fue de 89,3 por ciento (IC: 95 por ciento: 87,1 por ciento a 91,1 por ciento; likelihood ratio LR > 10) y se estableció una correlación directa significativa entre los hallazgos/NLIM y las edades de los pacientes (rho= 0,477; p< 0,005). Además, 46,53 por ciento de estos hallazgos corresponden a flora sugestiva de vaginosis bacteriana, 22,5 por ciento a cambios reactivos asociados a inflamación y 21 por ciento a metaplasia escamosa. La asociación más frecuente fue la metaplasia escamosa, vaginosis bacteriana e inflamación severa 5,5 por ciento (1495 resultados). Conclusiones: la proporción de hallazgos no neoplásicos fue considerable y las anormalidades epiteliales escamosas y glandulares estuvieron sobre el promedio estándar(AU)

Introduction: The Pap test aims at diagnosing precancerous or cancerous lesions of the cervix, hormonal evaluation, and bacterial flora. Objectives: Determine the proportion of non-neoplastic findings, squamous and glandular epithelial abnormalities referred to the district ofHospital Nacional Docente Madre Niño San Bartolome. Methods: A prospective, analytical, correlational, cross-sectional research was designedfor all vaginal smear which were referred from five health networks and micro-networks. Cytological processing was carried out in accordance with applicable international requirements. Cytologic interpretation was performed according to Bethesda System. Results: Out of 72,644 cervical smears evaluated by Bethesda quality system, the proportion of results with cervical uterine disorders (prevalence 6.5 percent CI 95 percent: 6.32 percent, 6.68 percent) were 4724 (6.5 percent) samples, negative posevaluación was 35318 (51.7 percent) samples, and nonneoplastic findings 32 602 (48.2 percent) samples, (p< 0.005). Posttest probability was 89.3 percent (CI 95 percent: 87.1 percent to 91.1 percent; likelihood ratio LR > 10) and a significant direct correlation was established between the findings/nLiM and ages of patients (rho= 0.477; p< 0.005). Moreover, 46.53 percent of NIM flora suggestive corresponds to bacterial vaginosis (BV), 22.5 percent to reactive changes associated with inflammation and squamous metaplasia 21 percent (MET). The most frequent association was MET, VB, and severe inflammation 5.5 percent (1495 results). Conclusions: The proportion of non-neoplastic findings was considerable; squamous and glandular epithelial abnormalities were above average standard(AU)

Association of Human Papillomavirus 31 DNA Load with Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3.

The association between human papillomavirus 31 (HPV31) DNA loads and the risk of cervical intraepithelial neoplasia grades 2 and 3 (CIN2-3) was evaluated among women enrolled in the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) triage study (ALTS), who were monitored semiannually over 2 years and who had HPV31 infections detected at ≥1 visit. HPV31 DNA loads in the first HPV31-positive samples and in a random set of the last positive samples from women with ≥2 HPV31-positive visits were measured by a real-time PCR assay. CIN2-3 was histologically confirmed at the same time as the first detection of HPV31 for 88 (16.6%) of 530 women. After adjustment for HPV31 lineages, coinfection with other oncogenic types, and the timing of the first positive detection, the odds ratio (OR) per 1-log-unit increase in viral loads for the risk of a concurrent diagnosis of CIN2-3 was 1.5 (95% confidence interval [CI], 1.2 to 1.9). Of 373 women without CIN2-3 at the first positive visit who had ≥1 later visit, 44 had subsequent diagnoses of CIN2-3. The initial viral loads were associated with CIN2-3 diagnosed within 6 months after the first positive visit (adjusted OR, 1.5 [95% CI, 1.0 to 2.4]) but were unrelated to CIN2-3 diagnosed later. For a random set of 49 women who were tested for viral loads at the first and last positive visits, changes in viral loads were upward and downward among women with and without follow-up CIN2-3 diagnoses, respectively, although the difference was not statistically significant. Results suggest that HPV31 DNA load levels at the first positive visit signal a short-term but not long-term risk of CIN2-3.

Comparative analysis of cervical cytology screening methods and staining protocols for detection rate and accurate interpretation of ASC-H: Data from a high-volume laboratory in Turkey.

BACKGROUND: This study evaluated the effectiveness of the ThinPrep(®) Imaging System (TIS) and ThinPrep(®) Pap Stain (TPPS). A comparative analysis was conducted to determine the detection rates of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H), the ASC:squamous intraepithelial lesion (SIL) ratio, biopsy follow-up for ASC-H in terms of the screening method used (manual screening [MS] vs. TIS screening [TISS]) and the staining protocol (regular Pap stain [RPS] vs. TPPS). METHODS: This study was performed over two periods. The RPS period included manually screened slides, whereas the TPPS period included TIS + manually screened slides. All data from the study periods were compared using statistical analysis. RESULTS: The detection rate of ASC-H was significantly higher during the TPPS period than during the RPS period (0.49% vs. 0.23%); this finding is in contrast to the insignificant difference between the screening method periods. The positive predictive value (PPV) of ASC-H cytodiagnosis for cervical intraepithelial neoplasia of grade 2 or more severe histologies was significantly different between manually screened and TIS slides (22.10% vs. 38.55%), in contrast to an insignificant difference between RPS and TPPS periods (37.14% vs. 29.77%). CONCLUSION: Implementation of the TIS did not change the ASC-H detection rates appreciably. However, the new technology improved PPV for ASC-H cytodiagnosis and enabled the detection of true disease. Our laboratory statistics indicate that the TPPS is not a superior staining protocol and did not increase our diagnostic accuracy for ASC-H compared with RPS.

Impact of Possibly Oncogenic High-Risk Human Papillomavirus (HPV) Types in Triage for ASC-US Cervical Cytology Results.

OBJECTIVE: Current guidelines recommend including 13 or 14 high-risk human papillomavirus (HPV) types for triage of atypical squamous cells of undetermined significance (ASC-US) cervical cytology; however, at least 13 additional types are considered possibly oncogenic. We evaluated the effect of including possibly oncogenic HPV types in the test panel. METHODS: Outcomes for all women 30 years or older with ASC-US and positive HPV testing who underwent colposcopic biopsy at University of Washington Medical Center-affiliated clinics between 2010 and 2011 were reviewed. We compared biopsy results between cases that were HPV positive for 1 or more of 13 possibly oncogenic types only (26/53/55/62/64/67/69/71/73/82/83/84/IS39) versus 1 or more of the 14 established high-risk types (16/18/31/33/35/39/45/51/52/56/58/59/66/68). We used the Fisher exact test to compare cervical intraepithelial neoplasia grade 2 or higher (CIN2+) diagnoses between HPV risk groups. RESULTS: Three hundred twenty-six ASC-US HPV-positive cervical cytology results were identified, with 170 that were linked to subsequent cervical biopsy results. Among 51 cases positive for possibly oncogenic types only, 31 (61%) had no neoplasia, 20 (39%) had CIN1, and none had CIN2+. Among 119 controls positive for at least one established high-risk type, 64 (53%) had no neoplasia, 42 (35%) had CIN1, and 13 (11%) had CIN2+ (p = .01 for the comparison of CIN2+ diagnoses between groups). CONCLUSIONS: The inclusion of possibly oncogenic types in the HPV test panel led to an additional 51 colposcopy biopsies (33% increase), with no additional cases of CIN 2+. Our results suggest that including possibly oncogenic HPV types increases the number of colposcopy biopsies with minimal improvements in detection of CIN2 +.

Razão ASC/SIL como indicador de qualidade em Citotecnologia / The ASC/SIL Ratio as a Quality Indicator in Cytotechnology

Introdução: A razão entre células escamosas atípicas (ASC) e lesão intraepitelial escamosa (SIL) entre os citotecnologistas é um dos indicadores de qualidade no processo de trabalho de rastreamento colpocitológico e, de acordo com a literatura, seu índice não deve ser superior a três. Objetivo: Avaliar a razão ASC/SIL da Seção Integrada de Tecnologia em Citopatologia do Instituto Nacional de Câncer José Alencar Gomes da Silva (SITEC/INCA) como indicador de desempenho e qualidade entre citotecnologistas. Método: Análise retrospectiva e quantitativa da razão ASC/SIL. As informações foram extraídas do sistema informatizado da SITEC/INCA, instituição de referência em citopatologia oncológica, no período de julho de 2013 até junho de 2014. A amostra está representada por 35 citotecnologistas que participaram da rotina de primeira leitura de exames colpocitológicos, obtendo um total de 7.585 ASC e 3.829 SIL. Os dados obtidos para análise foram organizados em tabelas utilizando-se o programa Microsoft Excel 2010. Resultado: A média da razão ASC/SIL entre os citotecnologistas no período analisado foi de 2,2% e a mediana 1,9%. Conclusão: Os resultados demonstram que a razão ASC/SIL entre os citotecnologistas é um importante dado no Monitoramento Interno da Qualidade (MIQ) permitindo um planejamento adequado de educação permanente e que os profissionais tenham dados para reflexão sobre a qualidade do processo de trabalho.