Risk of cervical high-grade squamous intraepithelial neoplasia in cytologic negative and persistently high-risk human papillomavirus positive patients according to genotypes: a retrospective single center analysis.

In January 2020, a different cervical cancer screening program started in Germany. Women above the age of 35 are recommended to have a combined HPV and cytology swab every three years. Showing persistent high-risk human papillomavirus (hrHPV), cytologic negative cervical samples at baseline and after 12 months, patients are referred to colposcopy. Entailing considerable additional workload due to the required colposcopies, we analyzed the risk of high-grade cervical intraepithelial neoplasia (CIN 3) in cytologic negative and persistent hrHPV women according to their hrHPV genotypes.Methods In this single center retrospective study, patients with persistent hrHPV, cytology negative cervical samples from our certified Colposcopy Unit in 2020 and 2021 were analyzed. Patient demographics, hrHPV types, biopsy rates and histological reports were collected.Results During the study, 69 patients were enrolled. Most frequent hrHPV genotypes were: hrHPV other 72.5%; HPV 16, 20.3% and HPV 18, 7.2%. Colposcopy showed no or minor changes in 92.7% and major changes in 7.2%. CIN 3 was found in 7 patients (10.1%). Prevalence of CIN 3 by hrHPV genotypes was 27.3% for HPV16, 20.0% for HPV18 and 7.1% for HPVO. A statistically significant dependency between hrHPV and cervical intraepithelial neoplasia was demonstrated (p = 0.048).Conclusion Within this single center study of persistent hrHPV, cytologic negative samples, patients with HPV 16 were more likely to have high-grade disease compared to other hrHPV subtypes. Larger prospective randomized trials are needed to substantiate our results and obtain adjusted cervical cancer screening time intervals according to the hrHPV genotypes.

Retrospective analysis of negative cytology results correlated with a positive high-risk in the human papillomavirus result and subsequent results of patients over a period of three years.

This research paper evaluates the efficacy of co-testing in precluding cervical cancer, with a particular focus on distinguishable outcomes of the human papillomavirus (HPV) vs. cytology tests. A retrospective review of 5948 patients, who tested positive for high-risk HPV but showed negative cytologic findings, revealed that 15.006% tested positive in subsequent screenings. A comparative analysis of various commercial HPV tests highlighted the precision of mRNA-based HPV testing by Aptima (Hologic) in reducing the likelihood of false-negative cytology. The paper challenges the conviction that a negative cytology alone suffices advocating for a condensed testing interval in instances of positive HPV outcomes, thereby facilitating earlier intervention and optimal preventive care. These findings unveil an exigency for reconsidering preventive strategies based on test outcomes.

Immediate histopathologic correlation in Turkish population with negative cytology and high-risk human papillomavirus positivity: A retrospective analysis of high-risk human papillomavirus genotype and stratified by age.

INTRODUCTION: According to the American Society of Colposcopy and Cervical Pathology (ASCCP) recommendations, regardless of age, women with high-risk infections other than human papillomavirus 16/18 positivity (other hrHPV) and negative cytology should not be referred directly to colposcopy. Several studies compared detection rates of ≥high-grade squamous intraepithelial lesion (HSIL) between HPV 16/18 ± 45, and other hrHPV types on colposcopic biopsy. METHODS: We designed a retrospective study to determine the presence of ≥HSIL in colposcopic biopsy in women with negative cytology and hrHPV positivity during the years 2016-2022. RESULTS: HPV 16/18/45 had a PPV of 43.8%, while other hrHPV types had a PPV of 29.1% for a tissue diagnosis of ≥HSIL. For a tissue diagnosis of ≥HSIL detection, there was no statistically significant difference between the PPV of other hrHPV and HPV 16/18/45 in patients ≥30. There were only two cases with a tissue diagnosis of ≥HSIL in the other hrHPV group of women under 30 years of age. CONCLUSION: We suggested that the follow-up recommendations of ASCCP for patients above the age of 30 with negative cytology and other hrHPV positivity may not be fully applicable to countries like Turkey with a different healthcare environment. Referring to patients ≥30 who had other hrHPV positivity and negative cytology to direct colposcopy may be clinically beneficial, particularly in populations where a colposcopic examination is easy and inexpensive.

Reasons for truly negative cytology reports preceding the diagnoses of invasive cervical cancer-Results of a false-negative cytology audit in Polish Cervical Cancer Screening Programme.

BACKGROUND: False-negative (FN) results in cervical cancer (CC) screening pose significant risk for participants and should be audited. The aim of the study was to analyse the results of audit of FN slides collected in 2010-2013 in Polish Cervical Cancer Screening Program (CCSP) and to seek for risk factors of obtaining true-negative result (TN; not containing abnormal cells as confirmed in audit) before CC diagnosis. METHODS: Screening database was merged with National Cancer Registry to identify negative slides preceding histologically confirmed CC diagnosis up to 42 months. Two blinding slides were randomly assigned per each FN. The whole set was reassessed independently by three pathologists with 30 years of experience in cytology evaluation. Final audit result was established in the case of ≥2 coherent reports. Agreement rates and kappa (κ) coefficients were calculated. Logistic analysis of risk factors for obtaining TN result was performed. RESULTS: Of 374 included FNs, 204 were considered abnormal (54.6%) and 91 were confirmed negative for intraepithelial neoplasia (24.3%). Agreement between experts was moderate for FNs (κ = 0.266) and fair for blinding slides (κ = 0.142) when grouping abnormal slides. Adenocarcinoma diagnosis elevated the risk of TN result (OR = 3.83); detection of macroscopic changes on the cervix and smoking lowered the risk (OR = 0.39, OR = 0.40 respectively). CONCLUSIONS: Misinterpretation was the main reason for FN cytology in the CCSP which indicated the need of further personnel training to increase screening quality. Rather low agreement between auditors requires further insight. A standardised process of auditors' selection should be planned to increase audit quality.

Prevalence of higher-grade dysplasia in persistently high-risk human papillomavirus positive, cytology negative women after introduction of the new cervical cancer screening in Germany.

PURPOSE: According to the recently implemented organized cervical cancer screening program in Germany, women older than 35 years with negative cytology but persistent high-risk human papilloma virus (hrHPV) infection > 12 months should be referred to colposcopy for further evaluation. This study aimed to present and dissect colposcopic and histopathological findings with particular focus on associated hrHPV genotypes. METHODS: This study is a retrospective analysis of clinical data from 89 hrHPV positive patients with normal cytology who underwent colposcopic examination at a certified dysplasia outpatient clinic in Germany in 2021. RESULTS: While 38 (43%) women had a normal colposcopic finding, 45 (51%) had minor and 6 (7%) major changes. Thirty-one (35%) of the women were HPV 16 and/or HPV 18 positive and 58 (65%) women were positive for other hrHPV only. Among patients who underwent colposcopy with biopsies (in case of an abnormal finding or type 3 transformation zone, n = 68), eight (12%) had cervical intraepithelial neoplasia (CIN) 3 and six (9%) had CIN 2. The proportion of women diagnosed with CIN 3 varied among different hrHPV genotypes (HPV 16: 11%, HPV 18: 33%, HPV 31: 27%, HPV 33: 33%, HPV 52: 33%). CONCLUSION: Persistently hrHPV positive women with negative cytology are at increased risk of being diagnosed with CIN 3. As CIN 3 prevalence seems to differ with regard to hrHPV strain, immediate HPV genotyping for risk stratification and subsequent early referral for colposcopy might constitute a feasible strategy.

Clinical Management of Atypical Endometrial Cells of Undetermined Significance Followed by Negative Cytology.

INTRODUCTION: In Japan, endometrial cytology is widely performed to evaluate the status of the endometrium in women with suspected endometrial cancer. A new classification system for endometrial cytology has recently been used: the Yokohama system, based on a descriptive reporting format. This study aimed to clarify the triage for patients with atypical endometrial cells of undetermined significance (ATEC-US) when followed by negative endometrial cytology. METHODS: We enrolled patients diagnosed with ATEC-US at the Cancer Institute Hospital between January 2016 and December 2017, based on the following inclusion criteria: (1) ATEC-US diagnosed by office endometrial cytology, with or without office endometrial biopsy; (2) follow-up endometrial cytology was performed 3-6 months after initial sampling, with a negative result for malignancy; and (3) no prior history of conservative treatment with progestin for endometrial cancer or atypical endometrial hyperplasia (ATEC-A). Among eligible patients, we analyzed those later diagnosed by endometrial biopsy with ATEC-A or carcinoma. RESULTS: Among 187 patients, 65 met the inclusion criteria. Forty-two patients (64.6%) were observed for more than 24 months. Two patients (3.1%) developed ATEC-A during a median observation time of 26.5 months; the times to diagnosis were 32 months and 22 months. DISCUSSION/CONCLUSION: No patient developed ATEC-A or worse within 1 year. For patients with ATEC-US, if negative cytology is obtained at the next examination, a close follow-up is not necessary.

Human Papillomavirus (HPV) 16 and 18/45 Genotyping-Directed Follow-up of Women With Messenger RNA HPV-Positive, Cytology-Negative Cervical Screening Test Results.

OBJECTIVES: In this study, we sought to correlate genotype test results for human papillomavirus (HPV) types 16, 18, and 45 with histopathologic follow-up diagnoses in patients with messenger RNA (mRNA) high-risk HPV-positive, cytology-negative results. METHODS: We identified 1,157 patients with mRNA HPV-positive, cytology-negative cervical screening test results between June 2015 and June 2018. Reflex HPV 16/18/45 genotype results were documented in 1,018 women aged 30 years or older, 318 of whom had follow-up within 18 months. RESULTS: Histopathologic findings of cervical intraepithelial neoplasia 2 or worse (CIN2+) were diagnosed in 14 of 122 (11.5%) patients positive for HPV 16/18/45 vs in seven of 196 (3.6%) HPV 16/18/45-negative patients. Three patients with high-risk HPV-positive, cytology-negative cervical screening test results were diagnosed with stage I cervical adenocarcinomas following early colposcopic referral and biopsy after HPV 16/18/45-positive genotype results. CONCLUSIONS: Immediate reflex HPV 16/18/45 genotyping of mRNA HPV-positive, cytology-negative patients led to early colposcopic referral and histopathologic diagnoses of three difficult-to-detect, low-stage, cervical adenocarcinomas and significantly increased overall early detection of CIN2+ lesions.

Prevalence of HPV-16/18 genotypes and immediate histopathologic correlation results in a Chinese population with negative cytology and positive high-risk HPV testing.

BACKGROUND: The objective of this study was to examine the prevalence of human papillomavirus 16/18 (HPV-16/18) genotypes and immediate histopathologic correlations in a Chinese population with negative cytology and positive high-risk human papillomavirus (hrHPV) testing. METHODS: Patients who had documented negative cytology with immediate follow-up (within the 6 months after negative for intraepithelial lesion or malignancy Papanicolaou [Pap] testing), including a histopathologic examination and/or hrHPV testing, between 2011 and 2018 were included, and the data were analyzed. RESULTS: Among 1,424,182 Pap tests, 1,333,453 (93.6%) were interpreted as negative cytology. Although conventional Pap smears had the highest reporting rate, cervical intraepithelial neoplasia 2 and higher (CIN-2+) lesions were detected significantly more with liquid-based cytology preparations (2.1%) than the conventional method (1.4%; P < .01). The overall hrHPV-positive rate was 14.9% (25,507 of 171,273) in the women with negative cytology. Among the 18,423 cytology-negative, HPV-positive cases tested with the Cobas assay, the overall HPV-16/18 prevalence was 24.7%, with 17.9% being HPV-16-positive, 6.2% being HPV-18-positive, and 0.6% being positive for both HPV-16 and HPV-18. The immediate histopathologic examination was documented for 21,796 women with cotesting results, including 8915 HPV-positive cases and 12,881 HPV-negative cases. CIN-2+ lesions were diagnosed in 15.2% of the HPV-16-positive cases; this rate was significantly higher than the rates seen in the HPV-18-positive cases (4.8%) and the cases positive for 1 of the other 12 types of HPV (3.0%). CONCLUSIONS: This is by far the largest routine clinical practice report of HPV-16/18 genotyping and histopathologic examination in negative-cytology women and the first report of such an investigation in the Chinese population. This study indicates enhanced risk stratification with HPV-16/18 genotype testing in HPV-positive, cytology-negative women in the Chinese population.

High-Risk Types of Human Papilloma Virus DNA Testing in Women with False Negative Cytology.

OBJECTIVE: To determine whether high-risk types of human papilloma virus (hrHPV) DNA testing is reliable for selection patients in need of further investigation with colposcopy in women with increased risk of high-grade cervical lesions as a result of false negative cytology. The secondary objective was to compare the sensitivity of hrHPV testing on self-collected versus physician-collected samples for the detection of histological high-grade cervical intraepithelial neoplasia (CIN2+). METHODS: Sixty-three patients identified with a missed abnormality following the re-evaluation of benign cervical cytology were included. A patient-collected and a physician-collected sample for HPV, colposcopy and cervical specimen collection for histology and cytology were performed. RESULTS: The sensitivity of hrHPV testing of physician-collected samples for CIN2+ was 100% (95% CI 82.7-100), and the negative predictive value (NPV) was 100% (95% CI 93.3-100). The sensitivity of the self-sampling device to identify CIN2+ was 84.6% (95% CI 59.1-96.7), and the NPV was 94.4% (95% CI 83.4-98.8). The differences in the sensitivity and NPV between the 2 methods were non-significant. The agreement between the 2 methods regarding the HPV results was good, with a kappa value of 0.74 (95% CI 0.57-0.91). CONCLUSION: The current findings indicate that physician-collected samples for hrHPV DNA testing may be used as triage for the colposcopy of women with false negative cytology.

Underestimated risk of cancer in solitary thyroid nodules ≥3 cm reported as benign.

BACKGROUND: The study aims to assess the risk of cancer in solitary thyroid nodules ≥30 mm in size reported as Bethesda II, and its implications. METHOD: The clinical records of 202 patients, who underwent thyroid lobectomy for solitary nodules measuring ≥30 mm, reported as Bethesda II on preoperative FNAC between Jan 2015 and Apr 2016 were reviewed. Data collected included nodule size and consistency, and final histopathology results. The risk of cancer and the recommended management according to ATA guidelines were the outcomes of interest. Comparisons were then made between two size categories: (30-40 mm; n = 72; C1) and (>40 mm; n = 130; C2), and two nodule consistencies. RESULTS: Mean nodule size was 43.2 mm (range 30-92). Ninety-five percent were solid and 5% were predominantly cystic. The risk of cancer was 22.8% (46/202) with no size threshold, or graded increase in risk observed. Based on biologic behavior, 50% of cancers were considered clinically significant. Accordingly, the risk of cancer for which surgery is recommended was 11.4% (23/202). The risk of cancer requiring total thyroidectomy was 9.4% and was influenced by nodule size (19 vs. 60% in C1 and C2, respectively; p = 0.01). Predominantly cystic nodules had a greater risk of malignancy compared to predominantly solid nodules even after adjusting for size (40 vs. 9.9%; p = 0.01 and 40 vs. 12.5%; p = 0.02, respectively). CONCLUSION: The risk of malignancy in Bethesda II solitary nodules ≥30 mm is considerable implying a need for changing the way these are approached and refining cytopathology reporting.

Prevalencia del virus del papiloma humano en mujeres con citología negativa / Prevalence of Human Papillomavirus Infection in Women with Negative Cytology

Introducción: la infección persistente por los subtipos oncogénicos del virus del papiloma humano es la causa principal del desarrollo del cáncer cérvico-uterino. Las mujeres que presentan citología normal pueden estar infectadas por subtipos de alto riesgo carcinogénico. Objetivo: brindar información actualizada existente en la literatura científica internacional acerca de la prevalencia de la infección por el virus del papiloma humano a nivel mundial y de la importancia de la detección temprana de estos virus en mujeres con citología negativa. Método: se realizó una revisión de los estudios desarrollados a nivel global y para esto se utilizaron las bases de datos PubMed, MedLine, BioMed Central y SciELO. Resultados: la prevalencia de la infección por los subtipos de alto riesgo del virus del papiloma humano en las mujeres con citología normal fue del 10 - 12 por ciento, con algunas diferencias entre países. El mayor pico de frecuencia de esta infección viral se localizó en jóvenes menores de 25 años y, en algunas regiones geográficas, se observó un segundo pico en mayores de 49 años. Los cinco subtipos oncogénicos más frecuentes de estos virus fueron 16, 18, 31, 52 y 58 con ciertas variaciones a nivel global. Conclusiones: el diagnóstico precoz de la infección por el virus del papiloma humano, especialmente los genotipos de alto riesgo, es un factor importante para una mejor prevención del cáncer cérvico-uterino(AU)

Introduction: Persistent infection with the oncogenic subtypes of human papillomavirus is the leading cause of cervical cancer. Women with normal cytology may be infected with subtypes of high carcinogenic risk. Objective: Provide updated information on the prevalence of human papillomavirus infection worldwide and the importance of their early detection in women with negative cytology. Methods: A review of the studies developed at a global level was carried out and PubMed, MedLine, BioMed Central, and SciELO databases were used. Results: The prevalence of infection with high - risk subtypes of human papillomavirus in women with normal cytology was 10 - 12 percent, with some differences between countries. The highest peak of frequency of this viral infection was located in young women under 25 years old and, in some geographic regions a second peak could be observed in those older than 49 years. The five most frequent oncogenic subtypes of these viruses were 16, 18, 31, 52 and 58 with certain variations globally. Conclusions: Early diagnosis of human papillomavirus infection, especially high-risk genotypes, is an important factor for better prevention of cervical-uterine cancer(AU)

Prevalencia del virus del papiloma humano en mujeres con citología negativa / Prevalence of Human Papillomavirus Infection in Women with Negative Cytology

Introducción: la infección persistente por los subtipos oncogénicos del virus del papiloma humano es la causa principal del desarrollo del cáncer cérvico-uterino. Las mujeres que presentan citología normal pueden estar infectadas por subtipos de alto riesgo carcinogénico. Objetivo: brindar información actualizada existente en la literatura científica internacional acerca de la prevalencia de la infección por el virus del papiloma humano a nivel mundial y de la importancia de la detección temprana de estos virus en mujeres con citología negativa. Método: se realizó una revisión de los estudios desarrollados a nivel global y para esto se utilizaron las bases de datos PubMed, MedLine, BioMed Central y SciELO. Resultados: la prevalencia de la infección por los subtipos de alto riesgo del virus del papiloma humano en las mujeres con citología normal fue del 10 - 12 por ciento, con algunas diferencias entre países. El mayor pico de frecuencia de esta infección viral se localizó en jóvenes menores de 25 años y, en algunas regiones geográficas, se observó un segundo pico en mayores de 49 años. Los cinco subtipos oncogénicos más frecuentes de estos virus fueron 16, 18, 31, 52 y 58 con ciertas variaciones a nivel global. Conclusiones: el diagnóstico precoz de la infección por el virus del papiloma humano, especialmente los genotipos de alto riesgo, es un factor importante para una mejor prevención del cáncer cérvico-uterino(AU)

Introduction: Persistent infection with the oncogenic subtypes of human papillomavirus is the leading cause of cervical cancer. Women with normal cytology may be infected with subtypes of high carcinogenic risk. Objective: Provide updated information on the prevalence of human papillomavirus infection worldwide and the importance of their early detection in women with negative cytology. Methods: A review of the studies developed at a global level was carried out and PubMed, MedLine, BioMed Central, and SciELO databases were used. Results: The prevalence of infection with high - risk subtypes of human papillomavirus in women with normal cytology was 10 - 12 percent, with some differences between countries. The highest peak of frequency of this viral infection was located in young women under 25 years old and, in some geographic regions a second peak could be observed in those older than 49 years. The five most frequent oncogenic subtypes of these viruses were 16, 18, 31, 52 and 58 with certain variations globally. Conclusions: Early diagnosis of human papillomavirus infection, especially high-risk genotypes, is an important factor for better prevention of cervical-uterine cancer(AU)