Cancer Cytopathology

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

AbstractBackgroundA 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.MethodsIn 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.ResultsAmong 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.ConclusionsPapanicolaou 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.

Hepatocyte nuclear factor 4 alpha immunocytochemistry: A useful marker for detecting endocervical glandular lesions in alcohol‐fixed smears

AbstractBackgroundHepatocyte nuclear factor 4 alpha (HNF4α) contributes to tumorigenesis and cancer progression. This study evaluated the diagnostic potential of HNF4α for detecting endocervical glandular lesions (EGLs), including endocervical adenocarcinomas (ECAs), adenocarcinomas in situ (AIS), and lobular endocervical glandular hyperplasias (LEGH) using alcohol‐fixed cytological smears.MethodsHNF4α expression was immunocytochemically assessed in alcohol‐fixed smears and paired formalin‐fixed paraffin‐embedded tissue specimens obtained from 14 patients with histologically confirmed EGLs: eight papillomavirus‐associated (HPVA) ECAs, one non‐NHPVA ECA, two HPVA AIS, and three patients with LEGHs. Three cases of squamous cell carcinomas (SCCs) and two cases of non‐neoplastic lesions were also analyzed as non‐EGL controls. HNF4α positivity was defined as nuclear staining in one or more cell(s)/slide, regardless of intensity.ResultsHistologically confirmed EGL cases were cytologically diagnosed as four adenocarcinomas, eight atypical glandular cells, one misclassified atypical squamous cells of undetermined significance, and one misclassified SCC, with a sensitivity of 85.7% and specificity of 100%. Strong and diffuse nuclear HNF4α expression was observed in atypical glands in both smears and tissue specimens, whereas non‐neoplastic glands and non‐neoplastic/neoplastic squamous epithelium were HNF4α‐negative. HNF4α expression showed 73.7% concordance between tissue and smear samples. Notably, HNF4α immunocytochemistry demonstrated 100% sensitivity and specificity for detecting EGLs, outperforming cytomorphological or immunohistochemical diagnosis (sensitivity, 71.4%; specificity, 100%).ConclusionsHNF4α is a reliable diagnostic marker when using alcohol‐fixed smears, showing enhanced accuracy for EGLs detection regardless of human papillomavirus status. Immunocytochemical analysis of HNF4α in cervical smears can be used for EGL detection and early diagnosis of cervical cancer.

Disparities in cervical cancer screening in the United States

SOX17 is a highly sensitive and specific marker for metastatic ovarian and endometrial carcinomas in cytology cell block specimens

AbstractBackgroundSOX17 (SRY‐box transcription factor 17) was recently identified as a highly sensitive and specific marker for ovarian and endometrial carcinomas in surgical specimens. In this study, validation of the utility of SOX17 immunohistochemistry (IHC) in diagnosing metastatic gynecologic carcinomas in cytology specimens was sought.MethodsThe study cohort included 84 cases of metastatic carcinomas that included 29 metastatic gynecologic carcinomas (24 ovarian high‐grade serous carcinomas, two endometrial serous carcinomas, one low‐grade serous carcinoma, one ovarian clear cell carcinoma, and one endometrial endometrioid carcinoma) and 55 cases of metastatic nongynecologic carcinomas (10 clear cell renal cell carcinomas, 10 papillary thyroid carcinomas, 11 gastrointestinal adenocarcinomas, 10 breast carcinomas, 10 lung adenocarcinomas, and four urothelial carcinomas). Cytology specimen types included peritoneal fluid (n = 44), pleural fluid (n = 25), and fine‐needle aspiration (n = 15). SOX17 IHC was performed on the cell block sections. The intensity of staining and percent positivity of the tumor cells were evaluated.ResultsSOX17 was highly expressed in all tested metastatic gynecologic carcinomas with diffuse and strong nuclear expression (29 of 29; 100%). SOX17 was negative in other metastatic nongynecologic carcinomas (54 of 55; 98.18%) except for one papillary thyroid carcinoma that showed low positivity (<10%).ConclusionsSOX17 is a highly sensitive (100%) and specific (98.2%) marker for the differential diagnosis of metastatic gynecologic carcinomas in cytology specimens. Therefore, SOX17 IHC should be included in the workup of differential diagnosis of metastatic gynecologic carcinomas in cytology specimens.

Assessment of the efficiency and accuracy of an artificial intelligence assistive system in the diagnosis of Pap cervical atypical glandular cell cytology

Abstract Background A diagnosis of atypical glandular cells (AGC) on Papanicolaou (Pap) slides is rare but has clinically significant findings associated with high‐risk cervical and endometrial lesions. The authors evaluated the efficiency and diagnostic performance of an artificial intelligence (AI)‐assisted platform (Riuqian WSI‐2400; with the registered trademark AICyte) in identifying AGCs on Pap slides. Methods A retrospective analysis of 485 Pap cases was conducted, including 185 cases with AGCs, 50 cases with high‐grade squamous intraepithelial lesions, 50 cases with low‐grade squamous intraepithelial lesions, and 200 negative cases; of these, 264 cases had histologic correlations. An experienced cytopathologist reviewed all slides using conventional microscopy and AICyte. Then, the same cases were evaluated by two other pathologists using the AICyte system. Results The initial study demonstrated a kappa value of 0.744, which indicated strong agreement of the Pap interpretation from the same pathologist between using microscopy and AICyte methods, whereas the average interpretation time was significantly reduced with AICyte (137 vs. 44 seconds). Diagnostic consensus among three pathologists using the AICyte system was strong, with a Kendall W coefficient of 0.802. The AICyte‐pathologist consensus reached an exact match with original interpretations in 95.1% of cases. AICyte‐assisted interpretations demonstrated improved specificity and diagnostic accuracy for glandular lesions compared with original interpretations while maintaining 100% sensitivity and negative predictive value. Conclusions To the authors' knowledge, this is the first study focusing on assessment of AGCs on an artificial intelligence system. The findings demonstrated that the AICyte system offers substantial improvements in efficiency and diagnostic consistency for the interpretation of AGCs and significantly reduces slide reading time. These results support the potential of AI to augment performance, especially in resource‐limited settings or high‐volume screening environments.

Assessment of the efficacy and accuracy of cervical cytology screening with the Hologic Genius Digital Diagnostics System

Abstract Background Medical technologies powered by artificial intelligence are quickly transforming into practical solutions by rapidly leveraging massive amounts of data processed via deep learning algorithms. There is a necessity to validate these innovative tools when integrated into clinical practice. Methods This study evaluated the performance of the Hologic Genius Digital Diagnostics System (HGDDS) with a cohort of 890 previously reviewed and diagnosed ThinPrep Papanicolaou (Pap) tests with the intent to deploy this system for routine clinical use. The study included all diagnostic categories of The Bethesda System, with follow‐up tissue sampling performed within 6 months of abnormal Pap test results to serve as the ground truth. Results The HGDDS demonstrated excellent performance in detecting significant Pap test findings, with close to 100% sensitivity (98.2%–100%) for cases classified as atypical squamous cells of undetermined significance and above within a 95% confidence interval and a high negative predictive value (92.4%–100%). Conclusions The HGDDS streamlined workflow, reduced manual workload, and functioned as a stand‐alone system.

Correlation of different HPV genotype viral loads and cervical lesions: A retrospective analysis of 1585 cases

AbstractBackgroundTo reduce unnecessary examinations and treatments, an effective detection method for differentiating human papillomavirus (HPV)‐positive patients is urgently needed. This study aimed to explore the differences in HPV viral loads across various cervical lesions and identify the optimal cutoff value for high‐grade squamous intraepithelial lesions (HSILs).MethodsThis retrospective study included patients with varying degrees of cervical lesions admitted to a hospital between January 1, 2023, and March 1, 2024. The HPV genotype and viral load were determined using BioPerfectus multiplex real‐time assay. The differences in HPV genotype viral loads among cervical lesion classifications were analyzed to identify the most applicable type of viral load.ResultsThe viral loads of HPV16, HPV31, HPV33, HPV35, and HPV58 were significantly associated with the grade of cervical lesions (p < .05), with the HPV16 group exhibiting the strongest correlation (p < .01). The HPV16 viral load demonstrated good sensitivity (Se) and specificity (Sp) for predicting HSIL (Se = 81.52%, Sp = 64.13%). The three most prevalent HPV genotypes associated with negative, low‐grade squamous intraepithelial lesions (LSILs) and HSILs were HPV16, HPV52, and HPV58. HPV33 exhibited the highest prevalence of HSILs, followed by HPV16.ConclusionsHigh‐risk HPV viral load is associated with cervical lesion classification. HPV16 viral load can effectively differentiate HSIL from LSIL with good Se and Sp.

Analysis of the sensitivity of high‐grade squamous intraepithelial lesion Pap diagnosis and interobserver variability with the Hologic Genius Digital Diagnostics System

AbstractBackgroundArtificial intelligence (AI)–based systems are transforming cytopathology practice. The aim of this study was to evaluate the sensitivity of high‐grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap) diagnosis assisted by the Hologic Genius Digital Diagnostics System (GDDS).MethodsA validation study was performed with 890 ThinPrep Pap tests with the GDDS independently. From this set, a subset of 183 cases originally interpreted as HSIL confirmed histologically were included in this study. The sensitivity for detecting HSIL by three cytopathologists was calculated.ResultsMost HSIL cases were classified as atypical glandular cell/atypical squamous cell–high grade not excluded (AGC/ASC‐H) and above by all cytopathologists. Of these cases, 11.5% were classified as low‐grade squamous intraepithelial lesion (LSIL) by pathologist A (P‐A), 6% by pathologist B (P‐B), and 5.5% by pathologist C (P‐C); 3.8%, 2.7%, and 1.6% of these cases were classified as atypical squamous cell of unknown significance (ASC‐US) by P‐A, P‐B, and P‐C, respectively. The sensitivity for detection of cervical intraepithelial neoplasia 2 and above (CIN2+) lesions was 100% if ASC‐US and above (ASC‐US+) abnormalities were counted among all three pathologists. The sensitivity for detection of CIN2+ lesions was 84.7%, 91.3%, and 92.9% by P‐A, P‐B, and P‐C, respectively, for ASC‐H and above abnormalities. The Kendall W coefficient was 0.722, which indicated strong agreement between all pathologists.ConclusionsNew‐generation AI‐assisted Pap test screening systems such as the GDDS have the potential to transform cytology practice. In this study, the GDDS aided in interpreting HSIL in ThinPrep Pap tests, with good sensitivity and agreement between the pathologists who interacted with this system.

Health disparities in cervical cancer: Prevalence of high‐risk HPV and cytologic diagnoses according to race

BackgroundIn the United States, the rate of cervical cancer is disproportionally higher in Hispanic and Black women compared with White women. In the current study, the authors compared human papillomavirus (HPV) testing and cytology results among Black and White women over a 24‐month period. They then assessed the rates in young women in 2011 compared with 2017 according to race.MethodsThe authors searched the gynecologic cytology case files for Black and White women treated at Johns Hopkins Hospital across all ages for a period of 24 months (2017‐2019) and compared HPV results and cytologic interpretations. They then compared results among Black and White cohorts of young women (aged 21‐29 years) in 2011 versus 2017.ResultsA total of 26,302 specimens from January 2017 to January 2019, including 11,676 Black women and 14,626 White women, were reviewed. The most common HPV genotype(s) detected were non–HPV‐16 and/or HPV‐18 (non‐16/18) high‐risk HPV (hrHPV) (84% of positive results). Non‐16/18 hrHPV was more common in Black women (1309 women; 15%) compared with White women (1075 women; 9%). Non‐16/18 hrHPV was more commonly observed in association with atypical squamous cells, cannot rule out high‐grade squamous intraepithelial lesion and/or high‐grade squamous intraepithelial lesion (ASC‐H/HSIL) in HPV‐positive Black women compared with White women (P = .007). Black women were found to have higher rates of HPV‐positive Papanicolaou results and high‐grade lesions, including carcinoma (P < .01). In the 2011 cohort, young Black women were found to have a higher rate of ASC‐H/HSIL (P = .003) compared with White women. However, the difference was not noted in the 2017 cohort. There was a decrease in ASC‐H/HSIL in 2017 compared with 2011, with a lower incidence of ASC‐H/HSIL noted among Black women in 2017.ConclusionsBlack women appear to have a higher incidence of higher grade lesions, but the difference between Black and White cohorts was not found to be significant in young women in more recent years.

AICyte‐alone capabilities as an independent screener for triaging cervical cytology using a 50% negative cutoff value

AbstractBackgroundAICyte has previously demonstrated a potential role in cervical cytology screening for reducing the workload by using a 50% negative cutoff value. The aim of the current study is to evaluate this hypothesis.MethodsThe authors used the Ruiqian WSI‐2400 (with the registered trademark AICyte) to evaluate a collection of 163,848 original cervical cytology cases from 2018 to 2023 that were collected from four different hospital systems in China. A breakdown of cases included 46,060 from Shenzhen, 67,472 from Zhengzhou, 25,667 from Shijiazhuang, and 24,649 from Jinan. These collected cases were evaluated using the AICyte system, and the data collected were statistically compared with the original interpretative results.ResultsIn 98.80% of all artificial intelligence cases that were designated as not needing further review, the corresponding original diagnosis was also determined to be negative. For any cases that were designated atypical squamous cells, cannot exclude high‐grade squamous intraepithelial lesion or higher, the sensitivity and negative predictive value were 90.77% and 98.80%, respectively. The sensitivity and negative predictive value were greater in cases designated as low‐grade squamous intraepithelial lesion or higher at 98.92% and 99.94%, respectively. Of the 49 low‐grade squamous intraepithelial lesion or higher that were designed by AICyte as not needing further review, the cytohistologic correlation revealed eight cases of cervical intraepithelial neoplasia 1 and 18 negative cases; and the remaining cases were without histologic follow‐up. In practice, AICyte used at a 50% negative cutoff value could reduce the anticipated workload if a protocol were implemented to label cases that qualified within the negative cutoff value as not needing further review, thereby finalizing the case as negative for intraepithelial lesions and malignancy.ConclusionsFor pathologic practices that do not have cytotechnologists or in which the workflow is sought to be optimized, the artificial intelligence system AICyte alone to be an independent screening tool by using a 50% negative cutoff value, which is a potential assistive method for cervical cancer screening.

RNA extended interventional nucleic acid longitudinal study: Clinical performance of Aptima messenger RNA HPV testing in cervical cancer screening with a 9‐year follow‐up

AbstractBackgroundThere is a need for additional longitudinal studies with the Aptima messenger RNA human papillomavirus test (AHPV) to support the safety of extended screening intervals. RNA‐based extended interventional nucleic acid (REINA) provides relevant information on the clinical performance of AHPV.MethodsThis is a longitudinal prospective analysis of 1538 participants after AHPV and liquid‐based cytology (LBC) co‐test complemented with REINA interventional protocol with a second co‐test 4 years after negative screening on 2000 women. Diagnostic accuracy and cumulative risks for CIN2+ up to 9 years were calculated for all test combinations.ResultsSensitivity and specificity for CIN2+ were 96.9% and 88.0% for AHPV and 72.3% and 92.0% for LBC. Negative predictive value (NPV) and positive predictive value (PPV) of AHPV were 99.9% and 23.6%. The 5‐ and 9‐year risks of AHPV‐negative women were 0.4% and 1.0% (CIN2+) and 0.3% and 0.7% (CIN3+), a 73% and 64% lower risk than with negative LBC (p ≤ .002). REINA participants with an AHPV‐positive result at second co‐test after a negative AHPV in first round had a significantly lower 5‐year risk of CIN2+ (11.1%) than AHPV‐positive women with unknown HPV history (29.5%).ConclusionsCurrently, this constitutes the longest European longitudinal study with AHPV testing in screening population. It reveals 99.9% NPV and a significant protective effect of a previous negative test 5 years after a new HPV infection. These findings support the safety of Aptima for screening intervals beyond 5 years. The risk of disease is lower 9 years after a negative AHPV test than 3 years after a negative LBC. High specificity and PPV of Aptima may benefit controlling overtreatment and colposcopy referrals.

Cytologic features of sex cord‐stromal tumors in women

BackgroundGynecologic sex cord‐stromal tumors (SCSTs) arise from sex cords of the embryonic gonad and may display malignant behavior. We describe the cytomorphologic features of SCSTs in females, including adult and juvenile granulosa cell tumors (AGCTs and JGCTs), Sertoli‐Leydig cell tumors (SLCTs), and steroid cell tumors (SCTs).MethodsWe retrieved available cytology slides from females with a histologic diagnosis of sex cord‐stromal tumor between 2009 and 2020 from institutional archives and reviewed their cytoarchitectural features.ResultsThere were 25, 2, 2, and 1 cytology specimens from 19, 2, 2, and 1 patients (aged 7‐90 years, median 57 years) with AGCT, JGCT, SLCT, and SCT, respectively. Features common to all SCSTs included 3‐dimensional groups, rosettes, rare papillary fragments, abundant single cells and naked nuclei. Rosettes and a streaming appearance of cell groups were only seen in AGCTs, which also rarely featured eosinophilic hyaline globules and metachromatic stroma. AGCTs exhibited high nuclear:cytoplasmic (N:C) ratios, with mild nuclear pleomorphism, uniform nuclei with finely granular chromatin, nuclear grooves and small nucleoli; in contrast, other SCSTs lacked rosettes and nuclear grooves and had generally lower N:C ratios, greater nuclear pleomorphism, coarse chromatin and more abundant cytoplasm. Mitotic figures, necrosis, and inflammation were rarely identified.ConclusionsAGCTs show cytomorphologic features that are distinct from those of other SCSTs. Careful evaluation of the cytological features and ancillary studies (eg, immunochemistry for FOXL2, inhibin and calretinin, or sequencing for FOXL2 mutations) can aid in the accurate diagnosis of these tumors.

Validation of BRCA testing on cytologic samples of high‐grade serous carcinoma

BackgroundTesting for BRCA1/2 gene alterations in patients with high‐grade serous carcinoma (HGSC) is a critical determinant of treatment eligibility for poly(adenosine diphosphate‐ribose) polymerase inhibitors in addition to providing vital information for genetic counselling. Many patients present with effusions necessitating therapeutic drainage, and this makes cytologic specimens (CySs) the initial diagnostic material for HGSC, often before histologic sampling. Initiating somatic BRCA testing on a CyS allows the BRCA status to be determined sooner, and this affects clinical management.MethodsRetrospectively, 8 cases of formalin‐fixed, paraffin‐embedded (FFPE) CySs of peritoneal or pleural fluid from patients with HGSC and known BRCA1/2 alterations previously established by the testing of FFPE surgical specimens (SpSs) underwent next‐generation sequencing (NGS). Prospectively, 11 cases of peritoneal or pleural fluid from patients with HGSC but an unknown BRCA1/2 status underwent NGS with fresh, alcohol‐fixed, and FFPE CySs, and they were compared with subsequent NGS on 4 SpSs.ResultsCySs yielded high‐quantity and high‐quality DNA for NGS analysis when sufficient tumor cellularity was present. Fresh, alcohol‐fixed, and FFPE CySs were all suitable for NGS and provided identical NGS results. SpS and CyS BRCA testing was concordant in 10 of 12 cases. The 2 discordant cases showed low tumor cellularity and quality in the CyS and the SpS, respectively.ConclusionEffusion CySs of HGSC are excellent sources for NGS testing for BRCA1/2 genetic alterations when sufficient tumor cellularity is present. Fresh, alcohol‐fixed, and FFPE CySs are equivalent for NGS of BRCA1/2. NGS testing of HGSC CySs demonstrates good concordance with SpSs for the BRCA1/2 status.

Molecular analysis of ascitic fluid cytology reflects genetic changes of malignancies of the ovary equivalent to surgically resected specimens

BACKGROUNDThe objective of this study was to identify the clinical utility of genomic analysis of ascitic fluid cytology (AC) in patients with epithelial ovarian cancer.METHODSTargeted next‐generation sequencing was used to analyze 66 samples from 33 patients who had ovarian (n = 23), fallopian tube (n = 2), and peritoneal (n = 8) carcinoma, and the concordance rate of molecular profiles was compared between surgically resected, formalin‐fixed, paraffin‐embedded (FFPE) tissues and AC samples.RESULTSIn total, 159 mutations were identified (54 oncogenic mutations and 105 nononcogenic mutations) in 66 DNA samples (33 FFPE tissues and 33 AC samples) from 33 patients. Of the 159 mutations, 57 (35.8%) were shared between surgically resected FFPE tissues and AC samples. However, the concordance rate of the molecular profiles between the 2 was significantly higher for oncogenic mutations compared with nononcogenic mutations (85.1% vs 10.5%; P < .01). Indeed, the AC samples covered all oncogenic mutations (n = 46) that were detected in surgically resected specimens and identified additional mutations (n = 8).CONCLUSIONSThe current results indicated that genomic analysis of AC can identify all of the genetic changes associated with epithelial ovarian cancer to understand tumor characteristics without interventional surgery or biopsy and may play an important role in developing personalized precision medicine.

Cytology‐based screening for anal intraepithelial neoplasia in women with a history of cervical intraepithelial neoplasia or cancer

BackgroundHigh‐risk human papillomavirus (HPV) has been identified in the pathogenesis of anal cancer. The purpose of this study was to assess the prevalence of abnormal anal cytology and HPV in women aged ≥40 years who have a history of high‐grade cervical squamous intraepithelial lesion (SIL) or cancer and to estimate the prevalence of anal intraepithelial neoplasia (AIN) using cytology as the primary screening modality.MethodsWomen who had a history of high‐grade cervical SIL or cancer and were ≥40 years of age were included in this prospective study. Anal cytology with HPV‐DNA testing was performed. All patients with abnormal anal cytology were referred for high‐resolution anoscopy (HRA), and abnormal lesions were biopsied and treated if pathologically confirmed. Abnormal anal cytology correlated with HPV status, HRA findings, and clinical and demographic characteristics.ResultsA total of 317 women completed the study. Of these, 96 (30.3%) had abnormal anal cytology (high‐grade SIL, 12.5%; low‐grade SIL, 19.8%; atypical squamous cells, cannot exclude high‐grade SIL, 6.3%; atypical squamous cells of undetermined significance, 61.5%) and 101 (31.9%) were HPV‐DNA–positive. There was a significant association between abnormal cytology results and the presence of high‐risk HPV. Of the 96 patients with abnormal cytology, 30 (31.3%) had biopsy‐proven AIN on HRA, representing 9.5% of the total patient cohort; of these, 10 (33.3%) had low‐grade AIN and 20 (66.7%) had high‐grade AIN. Older age and smoking were significant risk factors for abnormal anal cytology.ConclusionWomen aged ≥40 years with a history of high‐grade cervical SIL or cancer have a high rate of AIN. Screening for anal cancer may therefore be considered in this patient population. The optimal screening approach should be addressed in future studies.

Atypical squamous cells of undetermined significance cervical cytology in the Chinese population: Age‐stratified reporting rates, high‐risk HPV testing, and immediate histologic correlation results

BackgroundThe US American Society of Colposcopy and Cervical Pathology guidelines for cervical cancer screening have been largely adopted worldwide. Pooled high‐risk human papillomavirus (hrHPV) testing has been routinely used to risk‐stratify women who have atypical squamous cells of undetermined significance (ASC‐US) cytology. However, it has been reported that there are distinguished differences in the distribution of hrHPV genotypes between the Chinese and American populations.MethodsThe objective of this study was to analyze the age‐stratified reporting rates, hrHPV‐positive rates, and genotyping by different cytology preparation methods and hrHPV testing assays, along with the immediate histopathologic correlation of ASC‐US cytology, in the Chinese population.ResultsThe ASC‐US reporting rate of 1,597,136 Papanicolaou (Pap) tests was 4.2%, and the overall hrHPV‐positive rate was 48.7% in the ASC‐US cases. In total, 25,338 women with ASC‐US Pap tests had immediate histologic follow‐up, and the detection rate for cervical intraepithelial neoplasia 2 and higher lesions (CIN2+) was 7.1%, including 0.6% carcinomas. Among the women who underwent hrHPV testing, CIN2+ lesions were identified in 657 of 6154 (10.7%) who had hrHPV‐positive results and in only 1.5% those who had hrHPV‐negative results. Further genotyping analysis revealed that HPV types 16 and/or 18 were commonly identified genotypes among the Chinese women who had ASC‐US cytology.ConclusionsThis large‐scale study demonstrated that the hrHPV‐positive rate, the CIN2+ detection rate, and the distribution of hrHPV genotypes in Chinese women with ASC‐US cytology were essentially consistent with those from the American population, further supporting that the current and newly released 2019 American Society of Colposcopy and Cervical Pathology guidelines should be applicable to the Chinese population.

Immediate histologic correlation in women with atypical squamous cells of undetermined significance cytology and positive high‐risk HPV: A retrospective review of 6000 cases in a large academic women's hospital

BackgroundPrevious studies of the histologic correlation in women who have atypical squamous cells of undetermined significance cytology (ASC‐US) and are positive for high‐risk human papillomavirus (hrHPV+) have predominantly utilized the Hybrid Capture 2 (HC2) test, whereas the use of other US Food and Drug Administration (FDA)‐approved methods is relatively limited.MethodsCases of ASC‐US/hrHPV+ that were tested using HC2, Cervista, or Aptima were retrieved, and the immediate histologic correlations were analyzed.ResultsOverall, 53.9% (n = 3238) of women with ASC‐US/hrHPV+ had immediate histologic correlation. The detection rates for grade 1 cervical intraepithelial neoplasia (CIN1) were similar among the 3 methods (37.1%‐41.8%), while the overall detection rates for grade 2 CIN or higher (CIN2+) were much lower (5.1%‐9.0%). CIN2+ detection rates were similar among different age groups for HC2 testing, whereas for Cervista and Aptima testing, detection rates were highest in the youngest group (age <25 years) and decreased with age. Statistical analyses revealed that the CIN2+ detection rate was significantly higher in younger women who were tested with Cervista.ConclusionThese hrHPV testing methods revealed low CIN2+ detection rates in women with ASC‐US/hrHPV+ but demonstrated different patterns when using age‐stratified analyses. The high rate of CIN2+ detection in women aged <25 years by the Cervista and Aptima testing platforms, but not the HC2 platform, suggest that continual investigation of FDA‐approved clinical hrHPV testing—especially large‐scale, long‐term, prospective studies—is needed to evaluate the best options for management of ASC‐US/hrHPV+ in this age group.

Cytomorphologic findings of cervical Pap smears from female‐to‐male transgender patients on testosterone therapy

BackgroundThe cervical cancer screening recommendation for transgender female‐to‐male (FTM) patients is the same as that for cisgender females. A lack of literature on testosterone‐induced changes in cervical cytology in these patients may result in interpretation errors, especially without a proper clinical history. The aim of this study was to delineate the Papanicolaou (Pap) test findings in this patient population.MethodsA pathology laboratory information system was used to obtain a cohort of FTM transgender patients on testosterone therapy (2009‐2019). A cohort of age‐matched, atrophic, control cisgender female patients (postpartum or menopausal) was selected. A retrospective review of the cytomorphologic findings on cervical Pap smears, pertinent follow‐up, and human papillomavirus (HPV) test results was performed.ResultsFourteen transgender patients (age range, 21‐64 years; mean age, 42.5 years) receiving testosterone therapy with 17 Pap smears were identified. One of the 5 available HPV tests was positive for HPV, and 4 were negative. A Pap smear review revealed the following: negative for intraepithelial lesion (NILM; 82.4%), unsatisfactory (5.9%), atypical squamous cells of undetermined significance (ASCUS; 5.9%), and low‐grade squamous intraepithelial lesion (5.9%). The Pap smears of the atrophic cisgender cohort (102 patients) revealed the following: NILM (92.5%), unsatisfactory (0.9%), ASCUS (5.6%), and high‐grade squamous intraepithelial lesion (0.9%). The difference between the rates of epithelial cell abnormality in the 2 cohorts was not statistically significant. Although atrophy was noted in both groups, cytomorphologic findings of transitional cell metaplasia (TCM; 88.2%) and “small cells” (82.4%) were characteristic of the testosterone‐treated transgender cohort. Histologic correlates of TCM and small cells were noted in hysterectomy specimens from 6 patients.ConclusionsSmall cells and TCM are common cytomorphologic findings in Pap smears of testosterone‐treated transgender (FTM) patients. On the basis of histologic follow‐up, small cells most likely represent atrophic parabasal cells of cervical‐vaginal epithelium.

Volunteering at CerviCusco in Peru

Risk stratification for cervical neoplasia using extended high‐risk HPV genotyping in women with ASC‐US cytology: A large retrospective study from China

BackgroundExtended high‐risk human papillomavirus (hrHPV) genotype testing (hrHPVGT) has emerged as a new strategy to help optimize the efficiency of hrHPV triage.MethodsWomen with an atypical squamous cells of undetermined significance (ASC‐US) cervical Papanicolaou test result who underwent hrHPVGT between October 2017 and May 2021 at the Obstetrics and Gynecology Hospital of Fudan University in Shanghai, China, were studied. For hrHPVGT, a proprietary multiplex real‐time polymerase chain reaction assay was used. hrHPVGT and viral load test results in selected patients were correlated with histopathologic follow‐up findings available within 6 months.ResultsIn total, 17,235 women with ASC‐US cytology who had hrHPVGT results were identified in the Obstetrics and Gynecology Hospital of Fudan University database. The hrHPV‐positive rate was 61.8%, and the most prevalent hrHPV genotypes were type 52 (HPV52) (16%), HPV16 (11.3%), HPV58 (10.2%), and HPV53 (8.4%). Single hrHPV genotypes were detected in 65.9% of women with hrHPV‐positive results, and multiple genotypes were detected in 34.1%. Histopathologic cervical findings within 6 months were available in 5627 hrHPV‐positive women and 2223 hrHPV‐negative women. High‐grade cervical intraepithelial lesions or cervical cancer (cervical intraepithelial neoplasia 2 or greater [CIN2+]) were identified in 7.5% of hrHPV‐positive women who had ASC‐US cytology and in 0.9% of hrHPV‐negative women who had ASC‐US cytology. The greatest risk for CIN2+ was in single hrHPV genotype infections with HPV16 (21.1%), HPV33 (15.2%), HPV82 (10%), and HPV18 (9.9%). hrHPVGT for genotypes HPV16, HPV33, HPV82, HPV18, HPV31, HPV45, HPV58, and HPV52 identified 95% of CIN2+ cases with 90.8% sensitivity, 53.8% specificity, a positive predictive value of 10.2%, and a negative predictive value of 99%. A significantly increased viral load was associated only with women who had HPV16‐related CIN2+.ConclusionshrHPVGT for women who have ASC‐US cytology allows for risk stratification capable of optimizing the efficiency of triage for hrHPV‐positive women.

Cervical cytology screening facilitated by an artificial intelligence microscope: A preliminary study

BACKGROUNDCervical cytology screening is usually laborious with a heavy workload and poor diagnostic consistency. The authors have developed an artificial intelligence (AI) microscope that can provide onsite diagnostic assistance for cervical cytology screening in real time.METHODSA total of 2167 cervical cytology slides were selected from a cohort of 10,601 cases from Shenzhen Maternity and Child Healthcare Hospital, and the training data set consisted of 42,073 abnormal cervical epithelial cells. The recognition results of an AI technique were presented in a microscope eyepiece by an augmented reality technique. Potentially abnormal cells were highlighted with binary classification results in a 10× field of view (FOV) and with multiclassification results according to the Bethesda system in 20× and 40× FOVs. In addition, 486 slides were selected for the reader study to evaluate the performance of the AI microscope.RESULTSIn the reader study, which compared manual reading with AI assistance, the sensitivities for the detection of low‐grade squamous intraepithelial lesions and high‐grade squamous intraepithelial lesions were significantly improved from 0.837 to 0.923 (P < .001) and from 0.830 to 0.917 (P < .01), respectively; the κ score for atypical squamous cells of undetermined significance (ASCUS) was improved from 0.581 to 0.637; the averaged pairwise κ of consistency for multiclassification was improved from 0.649 to 0.706; the averaged pairwise κ of consistency for binary classification was improved from 0.720 to 0.798; and the averaged pairwise κ of ASCUS was improved from 0.557 to 0.639.CONCLUSIONSThe results of this study show that an AI microscope can provide real‐time assistance for cervical cytology screening and improve the efficiency and accuracy of cervical cytology diagnosis.

Clinical evaluation of p16INK4a immunocytology in cervical cancer screening: A population‐based cross‐sectional study from rural China

BackgroundCervical cancer screening with cytology suffers from low sensitivity, whereas the efficiency of human papillomavirus (HPV)‐based screening is limited by low specificity. The authors evaluated a novel p16INK4a immunocytology approach in cervical cancer screening compared with HPV‐based and cytology‐based screening.MethodsIn total, 2112 women aged 49 to 69 years from Shanxi, China were screened from March to July 2019. HPV testing, liquid‐based cytology (LBC), and p16INK4a immunocytology were performed on samples from all women. Any positive result triggered a referral to colposcopy with biopsy, if indicated. Screening performance for detecting cervical intraepithelial neoplasia grade 2 and 3 or worse (CIN2+/CIN3+) was evaluated using multiple algorithms.Resultsp16INK4a had a lower positive rate (10.0%) than LBC abnormality (vs 12.1%; P = .004) and a high‐risk HPV positivity (21.4%; P < .001). For the detection of CIN3+, the relative sensitivity of p16INK4a compared with HPV and LBC was 0.93 (95% CI, 0.82‐1.07) and 1.12 (95% CI, 0.95‐1.32), respectively. The specificity of p16INK4a was significantly higher than that for HPV and LBC, with a relative specificity of 1.13 (95% CI, 1.11‐1.16) and 1.02 (95% CI, 1.01‐1.04), respectively. In addition, p16INK4a alone yielded a clinical performance very similar to that of the current mainstream strategy of using HPV16/18 with reflex cytology (ASC‐US+, atypical squamous cells of undetermined significance or worse). The immediate risk of CIN3+ was 14.6% if p16INK4a results were positive and 0.2% if p16INK4a results were negative.ConclusionsWith minimal colposcopy referrals, p16INK4a screening demonstrated promising utility for risk stratification and yielded a better balance between sensitivity and specificity compared with HPV and LBC primary screening. Moreover, with accuracy and efficiency similar to what is achieved using mainstream cotest algorithms, p16 may simplify the screening practice. More evidence will be required before clinical recommendation.

Aptima HPV messenger RNA testing and histopathologic follow‐up in women with HSIL cytology: A study emphasizing additional review of HPV‐negative cases

BackgroundHigh‐risk human papillomavirus (hrHPV) messenger RNA (mRNA) testing, the Food and Drug Administration–approved testing platform since 2013, has been increasing as a cervical screening alternative to hrHPV DNA testing methods. This study reports the largest routine clinical follow‐up study reported to date of hrHPV mRNA cotesting and histopathologic follow‐up results for women with high‐grade squamous intraepithelial lesion (HSIL) cytology results.MethodsHSIL Papanicolaou test results for women cotested with Aptima hrHPV mRNA testing between June 2015 and November 2020 were analyzed along with recorded histopathologic follow‐up results within 6 months of screening.ResultsAptima hrHPV mRNA–positive results were reported for 95.2% of the cotested HSIL cytology cases (905 of 951). Histopathologic cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was diagnosed on follow‐up in 538 of 701 hrHPV mRNA–positive cases (76.8%) and in 15 of 36 hrHPV mRNA–negative cases (41.7%). Additional reviews of the hrHPV mRNA–negative HSIL cases showed variable interpretations, and confirmatory blinded‐review interpretations of HSIL or atypical squamous cells, cannot exclude high‐grade squamous intraepithelial lesion were more likely in cases with histopathologic CIN2+ (77.5% [93 of 120]) than those with cervical intraepithelial neoplasia grade 1 or negative findings (63.1% [101 of 160]; P < .01).ConclusionsThis large routine‐clinical‐practice study confirms the previously reported high sensitivity of hrHPV mRNA testing for the detection of high‐grade cervical dysplasia and cervical cancers. The blinded‐review findings indicate that additional cytology review may be helpful for confirming an interpretation of HSIL in daily practice, especially for hrHPV‐negative HSIL cases.

On the new (version 9) American Joint Committee on Cancer tumor, node, metastasis staging for cervical cancer—A commentary

Recently, the American Joint Committee on Cancer (AJCC), in conjunction with the International Union Against Cancer, released an update of their TNM staging for cervical cancer (version 9). Not only does the new version allow for better alignment with the International Federation of Obstetrics and Gynecology (FIGO) system, but there are also important changes that serve to better allow for integration of parameters that clinicians need for management planning and prognosis. These changes are herein outlined in this concise commentary.

Never stop wondering: When cells become PAP‐art on the slides

AbstractThe project named Victoria’s cells was created to train health care personnel, especially in low‐income countries. This innovative approach is designed to associate benign and malignant cellular images and/or patterns with a range of shapes and color shades to evoke animals, common objects, and colorful aquariums. The project makes use of familiar images to capture the viewer’s interest as an aid for cytological interpretation. Cervicovaginal cytology is processed with conventional and liquid‐based cytology. The images are visually compelling to highlight the importance of studying cells and their diagnostic significance. Infectious diseases as well as malignant cells are thereby easily recognized. The pictures are organized into different sections, including Victoria’s zoo, Victoria’s fantasy, and malignant mockery. Branching mycelia resemble a starfish; squamous metaplasia recalls a sea turtle’s shell. Among others, different patterns of endometrial, endocervical, and squamous cells can resemble fish tanks populated by cells with the shapes of pufferfish, anglerfish, whales, scorpions, and garfish. The sea transitions to the earth, with a sly cat, a little elephant, a dog, and a koala. Other cellular preparations resemble a gymnast, a geisha, and a plunging diver as well as hummingbirds, a heron, a water lily, and a peony. The malignant mockery section is composed of squamous intraepithelial lesion patterns that resemble monsters, eyes, a foul tongue, eagles, and feathers. In conclusion, the recognition of visual images can make the study of cytology simpler and more enjoyable and serve the final objectives of prevention and cure.

Utility of p16/Ki67 double immunocytochemistry for detection of cervical adenocarcinoma

BackgroundAlthough the incidence of cervical adenocarcinoma has consistently increased, especially among young women, there is no established best means for screening. This study evaluated the screening efficacy of CINtec PLUS (CINtec; p16/Ki67 double immunocytochemistry) expression in cervical glandular cells.MethodsCervical cytology was examined using abnormal glandular cells. The CINtec status of 100 samples with corresponding surgically resected specimens and 11 samples that exhibited negative results for intraepithelial lesion or malignancy at follow‐up was analyzed. Additionally, 31 negative samples containing benign glandular cells were included.ResultsOf the 142 samples, CINtec status was diffusely positive in 74, focally positive in 24, and negative in 44. The 74 diffusely positive samples included 70 adenocarcinomas (62 cervical, seven uterine, and one ovarian) and four cases of high‐grade cervical intraepithelial neoplasia. The 24 focally positive samples included 15 adenocarcinomas (seven cervical, seven uterine, and one fallopian tube) and nine without malignancy. The 44 negative samples included nine adenocarcinomas (five uterine and four cervical) and 35 without malignancy. The sensitivity, specificity, positive predictive value, and negative predictive value of the CINtec diffusely or focally positive cases for cervical adenocarcinomas were 94.5%, 58.0%, 70.4%, and 90.9%, respectively. In CINtec diffusely positive cases, the respective values were 84.9%, 82.6%, 83.8%, and 83.8%, and in women aged ≤39 years the values were 90.6%, 89.5%, 93.5%, and 85.0%, respectively.ConclusionsCINtec may support efficient detection of cervical adenocarcinomas.

The clinical utility of extended high‐risk HPV genotyping in risk‐stratifying women with L‐SIL cytology: A retrospective study of 8726 cases

BACKGROUNDThe value of extended high‐risk human papillomavirus (hrHPV) genotyping for cervical cancer screening in women with low‐grade squamous intraepithelial lesion (L‐SIL) cytology has been recognized, but few studies have investigated this.METHODSWomen with L‐SIL Papanicolaou results who underwent human papillomavirus (HPV) genotyping between October 2017 and October 2021 at the Obstetrics and Gynecology Hospital of Fudan University were identified. Their HPV results were correlated with immediate histopathologic follow‐up findings.RESULTSIn total, 8726 women who had L‐SIL cytology and extended HPV genotyping results were analyzed. The overall hrHPV‐positive rate was 84% in women with L‐SIL, and the most prevalent hrHPV genotypes were type 52 (HPV52) (20.7%), HPV53 (15.7%), and HPV16 (14.3%). Single and multiple coinfections of hrHPV genotypes were detected in 57.2% and 42.8% of women with positive hrHPV results, respectively. Cervical intraepithelial neoplasia grade ≥2 (CIN2+) was identified in 8.5% of hrHPV‐positive women. The CIN2+ detection rate in women who had multiple hrHPV infections (9.9%) was significantly higher than the rate in those who had infection with a single HPV type (7.2%). The top 5 CIN2+‐associated HPV infections were HPV16 (25.2%), HPV82 (17.8%), HPV33 (16.3%), HPV31 (14.6%), and HPV26 (13.8%). For the composite group with HPV types HPV16, HPV26, HPV82, HPV31, HPV18, HPV33, HPV58, HPV35, HPV52, and HPV51, the risk of CIN2+ was 11.5% and represented 97.1% of all CIN2+ in biopsied, hrHPV‐positive patients. The composite group of 8 remaining HPV genotypes (HPV39, HPV45, HPV53, HPV56, HPV59, HPV66, HPV68, and HPV73) was identified in 29.7% of hrHPV‐positive patients, and the risk of CIN2+ for this composite group was similar to the risk of CIN2+ in hrHPV‐negative patients.CONCLUSIONSThis large retrospective study in a predominantly unvaccinated cohort demonstrated that extended hrHPV genotyping improves genotype‐specific risk stratification in women with L‐SIL.;

Improving the Pap test with artificial intelligence

The cytology community should be excited about the emergence of artificial intelligence–based solutions and embrace these promising technologies. However, there is also a need to determine how best to adopt these tools into routine practice and to monitor their long‐term usefulness.

Scrutinizing high‐risk patients from ASC‐US cytology via a deep learning model

BACKGROUNDAtypical squamous cells of undetermined significance (ASC‐US) is the most frequent but ambiguous abnormal Papanicolaou (Pap) interpretation and is generally triaged by high‐risk human papillomavirus (hrHPV) testing before colposcopy. This study aimed to evaluate the performance of an artificial intelligence (AI)‐based triage system to predict ASC‐US cytology for cervical intraepithelial neoplasia 2+ lesions (CIN2+).METHODSMore than 60,000 images were used to train this proposed deep learning‐based ASC‐US triage system, where both cell‐level and slide‐level information were extracted. In total, 1967 consecutive ASC‐US Paps from 2017 to 2019 were included in this study. Histological follow‐ups were retrieved to compare the triage performance between the AI system and hrHPV in 622 patients with simultaneous hrHPV testing.RESULTSIn the triage of women with ASC‐US cytology for CIN2+, our system attained equivalent sensitivity (92.9%; 95% confidence interval [CI], 75.0%‐98.8%) and higher specificity (49.7%; 95% CI, 45.6%‐53.8%) than hrHPV testing (sensitivity: 89.3%; 95% CI, 70.6%‐97.2%; specificity: 34.3%; 95% CI, 30.6%‐38.3%) without requiring additional patient examination or testing. Additionally, the independence of this system from hrHPV testing (κ = 0.138) indicated that these 2 different methods could be used to triage ASC‐US as an alternative way.CONCLUSIONThis de novo deep learning‐based system can triage ASC‐US cytology for CIN2+ with a performance superior to hrHPV testing and without incurring additional expenses.;

Cytohistologic immunohistochemical correlation of epithelial tubo‐ovarian neoplasms: Can cell blocks substitute for tissue?

BackgroundCytologic specimens often represent the initial diagnostic material for tubo‐ovarian neoplasms resulting from therapeutic paracentesis for patients presenting with high‐volume ascites. However, subtyping and immunohistochemical (IHC) characterization, which have implications in preoperative management and downstream ancillary testing, are not routinely performed in many institutions. This study aims to perform cytohistologic correlation of commonly used IHC stains to establish their reliability in peritoneal fluids/washing specimens.MethodsA retrospective search of the laboratory information systems was performed to identify peritoneal fluid/washing specimens involved by borderline or malignant epithelial tubo‐ovarian neoplasms and concurrent/subsequent surgical resection specimens. Cell blocks and tissue were stained for PAX8, WT‐1, p53, p16, Napsin‐A, estrogen receptor, and progesterone receptor, and staining between cytological and surgical specimens was compared.ResultsA total of 56 case pairs were included, with the following final diagnoses on histological examination: 37 high‐grade serous carcinomas, eight clear cell carcinomas, one endometrioid adenocarcinoma, two low‐grade serous carcinomas, and eight serous borderline tumors. There was perfect cytohistologic correlation for PAX8 (Lin’s concordance correlation coefficient [LINCCC] = 1.00) and WT‐1 (LINCCC = 1.00), substantial/good correlation for p53 (LINCCC = 0.96), p16 (LINCCC = 0.93), napsin‐A (LINCCC = 0.91) and ER (LINCCC = 0.77), and moderate correlation for PR (LINCCC = 0.54).ConclusionsImmunohistochemical correlation between peritoneal fluid and surgical resection specimens for tubo‐ovarian neoplasms is high. Common subtypes of tubo‐ovarian carcinomas can be reliably distinguished on fluids using IHC.

Evaluating the diagnostic accuracy of imprint and scrape cytology for intraoperative risk stratification of ovarian tumors: A systematic review and meta‐analysis

AbstractBackgroundAccurate intraoperative assessment of ovarian tumors is crucial for guiding surgical management. The objective of this systematic review and meta‐analysis was to evaluate the diagnostic accuracy of imprint and scrape cytology for intraoperative risk stratification of ovarian tumors.MethodsA comprehensive literature search was conducted across multiple databases to identify studies that assessed the sensitivity, specificity, positive predictive value, and negative predictive value of imprint and scrape cytology in distinguishing benign and malignant ovarian tumors. Data were pooled using a bivariate random‐effects model. The methodological quality of included studies was assessed using the quality assessment of diagnostic accuracy studies 2 tool.ResultsIn total, 34 studies comprising 3318 ovarian tumors were included in the current review. Analysis indicated that the pooled sensitivity of imprint cytology was 89%, whereas the pooled specificity was 92%. The positive and negative likelihood ratios, calculated using a random‐effects model, were 8.47 (95% confidence interval [CI], 5.27–13.61) and 0.16 (95% CI, 0.12–0.21), respectively. The pooled diagnostic odds ratio was 63.42 (95% CI, 37.5–107.27). For scrape cytology, the pooled sensitivity and specificity were 89% and 97%, respectively. The positive and negative likelihood ratios were 21.05 (95% CI, 12.36–35.84) and 0.14 (95% CI, 0.09–0.22), respectively. The pooled diagnostic odds ratio was 180.46 (95% CI, 88.01–370.03). Both techniques demonstrated high diagnostic accuracy, and scrape cytology was particularly effective in detecting malignancies.ConclusionsImprint and scrape cytology are valuable intraoperative diagnostic tools for ovarian tumor stratification, offering rapid and reliable results. Their integration into surgical decision making may enhance intraoperative management, particularly in resource‐limited settings. Further studies with standardized protocols are needed to refine their clinical utility.

Prognostic significance of pelvic washing cytology in early stage endometrial cancer: A 10‐year matched cohort analysis from a large single institute

Abstract Background Pelvic washing (PW) cytology has been excluded from endometrial cancer staging by the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria, and its prognostic significance in early stage disease remains controversial. In this study, the authors evaluated the clinicopathologic correlates and prognostic impact of positive PW cytology in a large institutional cohort using a matched case–control design. Methods A retrospective case–control cohort was created by reviewing PWs for endometrial cancer from 2013 to 2023 in the authors' pathology database. Cases with positive PW were retrieved from consecutive patients who had FIGO 2009 stage I or II endometrial cancer. The control group was comprised of randomly selected patients with negative PWs who were matched to patients in the positive PW group on patient age, tumor histologic subtype, FIGO grade, and disease stage. Cox proportional hazards models and multivariable logistic regression analyses were used to correlate survival outcomes and to identify predictors of cytologic positivity. Results The cohort included 88 patients who had positive PW cytology and 223 matched controls. Positive PW cytology was independently associated with significantly worse disease‐free survival (hazard ratio, 4.33; p  < .001) and demonstrated borderline significance for overall survival (hazard ratio, 1.67; p  = .05). The presence of free‐floating tumor cells in the fallopian tubes was an independent predictor of positive PW cytology ( p  < .001). Conclusions The current study demonstrates that positive PW cytology is an independent adverse prognostic factor in patients with stage I/II endometrial cancer and suggests that PW cytology status should be considered for accurate risk stratification of patients who have early stage endometrial cancer although it is not part of the current FIGO staging criteria.

The role of cytology in endometrial cancer: Diagnostic and clinical considerations from peritoneal/pelvic washings. Is it still a heated debate?

This editorial explores the diagnostic criteria and clinical implications of cytopathologic samples obtained from peritoneal/pelvic washings in patients with endometrial cancer.

Sensitivity of cervico‐vaginal cytology in endometrial carcinoma: A systematic review and meta‐analysis

Cervico‐vaginal cytology is primarily a cervical cancer screening test. The anatomical continuity of the uterine cavity with the cervix makes the Papanicolaou (Pap) test accessible to evaluate signs of disease shed from the endometrium. Our aim was to determine the sensitivity of routine Pap test in endometrial carcinoma detection and its relationship with clinico‐pathologic factors. We performed a systematic review of studies reporting Pap test results prior to diagnosis of or surgery for endometrial carcinoma between 1990 and 2018 in PubMed or Web of Science. Two independent reviewers extracted data and assessed study quality using an adapted Newcastle‐Ottawa Quality Assessment Scale and Quality Assessment of Diagnostic Accuracy Studies tool. We identified 45 studies including a total of 6599 women with endometrial cancer. Abnormal Pap test results prior to diagnosis of or surgery for endometrial carcinoma were observed in 45% (95% CI, 40%‐50%) of study participants. This percentage was significantly higher among those of non‐endometrioid histology compared with endometrioid subtypes (77% [95% CI, 66%‐87%] vs 44% [95% CI, 34%‐53%], respectively; P heterogeneity <.001). Several clinico‐pathologic factors were related to a higher percentage of abnormal Pap test results, including high‐stage, myometrial invasion >50%, high histological grade, positive peritoneal cytology, presence of lymph node metastasis, cervical involvement, and lymphovascular invasion (P heterogeneity <.05 for all variables). Routine cervical cytology can detect endometrial cancer in almost half of patients, whereas sensitivity is higher among individuals with non‐endometrioid histology or more advanced cancers. This review summarizes the current clinical and prognostic value of cervical cytology in endometrial carcinoma. Recent technological developments using molecular biomarkers may improve accuracy for early cancer detection.

Extended HPV genotyping and dual stain for the triage of primary HPV screen‐positive cases: Practical guidance for the cytopathology laboratory

AbstractBecause of many factors, the landscape of cervical cancer prevention is again at a pivot point within the United States. Primary human papillomavirus (HPV) screening has been recommended as the preferred testing method by the American Cancer Society since 2020. Although primary HPV testing provides high negative predictive value in screening, women who screen positive for HPV need triage using methods that have an optimal balance between sensitivity for precancer and the number of colposcopies required for detection. The triage test ideally should maximize specificity while also reassuring patients who test negative, although it should be acknowledged that no screening or triage test can entirely exclude disease in a screen‐positive patient. While cervical cytology (the Papanicolaou test) triage of primary HPV screen‐positive patients is currently recommended by most screening strategies, additional triage tests, specifically extended HPV genotyping and combined p16/Ki‐67 dual‐stain immunocytochemistry, are now approved by the US Food and Drug Administration and incorporated into cervical cancer screening and management guidelines. Incorporating these triage methods into practice should be achieved by using appropriate validation/verification and implementation steps and, in the case of dual‐stain immunocytochemistry, appropriate cytologist/cytopathologist training. The US Food and Drug Administration approval of vaginal self‐collection in May 2024 is another significant advance for increasing access to screening. These samples can only be tested using primary HPV screening platforms, and guidance for management has been endorsed by the ASCCP's enduring guidelines process. This review discusses issues that warrant consideration before implementation and provides practical guidance for the incorporation of self‐collected specimens and extended genotyping/dual‐stain tests into the workflow of the cytopathology laboratory.

Retrospective analysis of HPV infection: Cotesting and HPV genotyping in cervical cancer screening within a large academic health care system

AbstractBackgroundIn 2019, the American Society for Colposcopy and Cervical Pathology introduced fundamental shifts toward “risk‐based” guidelines, with human papillomavirus (HPV) genotyping as a principal test for investigating squamous intraepithelial lesions. This study aims to provide practice‐based evidence and supplement the updated guidelines by investigating HPV demographic distribution and uncovering the pathological features of high‐grade squamous intraepithelial lesions (HSILs) caused by high‐risk HPV (hrHPV) subtypes.MethodsPatients who underwent Papanicolaou screening and HPV testing in two hospital systems over the course of 4 years were recruited. The cytology results were categorized on the basis of the 2014 Bethesda classification. DNA sequences of 14 types of hrHPV were detected by Aptima test. The histological features of HSILs caused by different subtypes were compared between biopsies and excisions.ResultsA total of 63,709 cases were included. The HPV prevalence was 14.70%, predominantly in the 30 to 39‐year‐old age group, with slightly higher rates observed in African Americans. There was no significant racial distribution difference between HPV 16/18/45 and other types. HPV 16/18/45 infection was directly correlated with the severity of abnormal cytology, although the other subtypes were the major causes of cytological abnormalities. The trend for HPV prevalence was consistent across calendar years, and was associated with 8.77% negative for intraepithelial lesion or malignancy, 30.46% atypical squamous cell of undetermined significance, 64.62% low‐grade squamous intraepithelial lesion, 66.75% atypical squamous cell‐cannot exclude a high‐grade squamous intraepithelial lesion, and 91.80% HSIL. Furthermore, 29.09% of HSILs associated with other subtypes were not detectable on subsequent resections.ConclusionsGiven the HPV demographic distribution and the histological features of HSILs caused by different subtypes, cotesting with reflex HPV genotyping in specific populations, or expanding the subtypes in the primary HPV screening test, should be considered.

Intraoperative peritoneal cytology for cervical gastric‐type adenocarcinoma: Cytopathology and clinical impact

AbstractBackgroundThe objective of this study was to elucidate the frequency and cytologic features of positive peritoneal washing cytology (PWC) in cervical gastric‐type adenocarcinoma (GAS) and to clarify the clinical significance of positive PWC.MethodsThe authors analyzed cases from their institution between 1991 and 2023 in which patients underwent surgery and PWC. The study included 62 patients who had cervical GAS (1991–2023; including seven patients with adenocarcinoma in situ and 26, 15, nine, and five patients with International Federation of Gynecology and Obstetrics 2018 stage I, II, III, and IV disease, respectively) and 100 patients who had usual‐type endocervical adenocarcinoma (2007–2023; including 65, 15, and 20 patients with stage I, II, and III disease, respectively). The frequency of positive PWC results and cytologic features was assessed, and correlations between positive PWC results and clinicopathologic factors were examined, including prognosis, in the GAS group.ResultsPositive PWC results were significantly more frequent in patients who had GAS at 24% (15 of 62 patients) compared with 7% (seven of 100 patients) in those who had usual‐type endocervical adenocarcinoma. The cytologic features of GAS included distinct cellular atypia (enlarged nuclei, nuclear irregularity) and frequent formation of spherical clusters (10 of 15 cases) without the golden‐yellowish mucus commonly seen in cervical smears. A positive PWC result in GAS was significantly correlated with larger tumor size, parametrium invasion, lymph node metastasis, and elevated carbohydrate antigen 19‐9 levels. In patients with stage I GAS, the PWC‐positive group had significantly shorter disease‐free survival and overall survival compared with the PWC‐negative group.ConclusionsPositive PWC findings are frequent in cervical GAS and are associated with pathologic factors indicative of tumor growth and progression. In patients who have stage I GAS, positive PWC results may indicate a poor prognosis, warranting further investigation.

Cytologic features of gynecologic germ cell tumors and carcinomas exhibiting germ cell tumor differentiation

AbstractBackgroundIn this study, the authors sought to describe the cytologic features of primary gynecologic germ cell tumors and carcinomas exhibiting germ cell differentiation because little information currently exists.MethodsAn institutional database search was performed to identify histologically confirmed gynecologic germ cell tumors and carcinomas with germ cell tumor differentiation. Available cytologic material was reviewed by three observers, and morphologic features were recorded in addition to patient age at original diagnosis, primary tumor site, site(s) from which the examined cytologic material was obtained, and the type of examined cytologic preparations.ResultsIn total, 15 cytologic specimens from 12 women (aged 19–82 years) were identified and included touch preparations of core biopsies from various sites (n = 6), fine‐needle biopsies (n = 2), pelvic washings (n = 1), ascitic fluids (n = 4), pelvic cyst fluid (n = 1), and endometrial aspirate (n = 1). Of the 12 patients, seven had primary gynecologic germ cell tumors, four had gynecologic (ovarian and endometrial) tumors exhibiting somatic yolk sac tumor‐like differentiation, and the remaining patient had an intestinal‐type adenocarcinoma arising within an ovarian teratoma. There was morphologic overlap among many of the cases, although cytoplasmic vacuolation/granular cytoplasm was seen in 75% of primary yolk sac tumors or carcinomas with yolk sac tumor differentiation, and dense/squamoid cytoplasm was seen in 100% of teratomatous elements that were sampled.ConclusionsGerm cell tumors and somatic neoplasms exhibiting germ cell tumor differentiation occurring in adult women share some cytologic features and may be difficult to distinguish from one another, although some tumor types showed characteristic cytomorphologic findings.

Homage to Georgios Papanikolaou: A pilgrimage to his birthplace

As a cancer epidemiologist focused on the science of cervical cancer prevention and control, the author journeyed to the home of his hero, Georgios Nikolaou Papanikolaou, whose pioneering contribution of the cervicovaginal cytology test (the Pap test) has saved countless female lives over generations throughout the world, laying the groundwork for one of the most beautiful stories in public health.

Implementing 100% quality control in a cervical cytology workflow using whole slide images and artificial intelligence provided by the Techcyte SureView™ System

AbstractBackgroundRecent advancements in digital pathology have extended into cytopathology. Laboratories screening cervical cytology specimens now choose between limited imaging options and traditional manual microscopy. The Techcyte SureView™ Cervical Cytology System, designed for digital cytopathology, was validated at CorePlus, a pathology laboratory in Puerto Rico, and adopted as a 100% quality control (QC) tool.MethodsThe validation study included 1442 whole slide images (WSIs) from 1273 ThinPrep® and 169 SurePath™ cervical cytology slides, digitized with the 3DHISTECH Panoramic 1000 DX scanner using dry and water immersion scanning profiles. These WSIs were processed by the Techcyte SureView™ system, with a board‐certified cytopathologist reviewing artificial intelligence (AI)‐identified objects of interest and comparing them to traditional light microscopy results.ResultsTechcyte SureView™ with the water immersion scanning profile outperformed both the dry scanning profile and light microscopy in detecting squamous and glandular abnormalities. It achieved 97% accuracy, 82% sensitivity, 99% specificity, 98% negative predictive value, and 86% positive predictive value. Additionally, the review time was rapid. The system has been operational for several months, enhancing accuracy and workflow efficiency.ConclusionsThis study demonstrates that digital cytopathology, particularly through the Techcyte SureView™ system, can improve laboratory workflow and performance. Successful validation led CorePlus to integrate the AI algorithm into their workflow as a 100% QC review tool, resulting in improved accuracy, benefiting both laboratory professionals and patients.

Retrospective analysis of cytology and high‐risk HPV testing in 1067 endocervical adenocarcinomas and precursor lesions

AbstractBackgroundCytology and high‐risk human papilloma virus (hrHPV) cotesting is the mainstay in the detection of cervical carcinoma.MethodsEndocervical adenocarcinoma (EAC) is divided into HPV‐associated adenocarcinoma (HPVA) and HPV‐independent adenocarcinoma (HPVI) by the World Health Organization classification (2020). The detection effect of cotesting is suggested to be different among EAC subtypes and precursors, but has not well‐documented yet. In this study, the authors retrospectively analyzed cotesting among adenocarcinoma in situ (AIS), HPVA, and HPVI. The cohort included 569 AIS and 498 EAC consisting of 371 (74.5%) HPVA, 111 (22.3%) HPVI, and 16 (3.2%) adenocarcinoma, not otherwise specified.ResultsThe authors found that AIS patients were significantly younger than HPVA and HPVI (mean ± SD, years: 40.7 ± 8.6; HPVA, 44.8 ± 9.3; HPVI, 50.0 ± 11.3; p < .001) and had a higher prevalence of concurrent squamous intraepithelial lesions (75.5%, HPVA, 37.2%; HPVI, 12.6%; p < .001). The detection rate of hrHPV test or cytology was substantially higher in AIS and HPVA than in HPVI (97.7% and 90.2% vs. 16.5%, p < .001, or 71.1% and 71.9% vs. 60.7%, p = .042, respectively). Cytology and hrHPV cotesting was superior to a single test in the detection of EAC and AIS. The detection rate of cotesting amounted to 100% in AIS and 94.3% in HPVA but was substantially lower in HPVI (72.2%) (p < .001).ConclusionsThe authors conclude that cytology and hrHPV cotesting can maximize the detection effect for HPVA and AIS but is not optimal for HPVI.

Challenging the concept of “risk of malignancy” in cytology

AbstractSeveral standardized systems for nongynecological cytopathology have been published following the successful implementation of The Bethesda System for Reporting Cervical Cytology. Each of these systems comprises a set of reporting categories accompanied by a risk of malignancy. However, in most cases, these risk of malignancy estimates have not been based on high‐quality evidence and often may not be consider proper “risks” (because they have been estimated based on cross‐sectional studies). This commentary discusses the problems related to the data used to generate these risks. To make nongynecological cytopathology reporting more evidence‐based, large‐scale prospective cohort studies and randomized trials, in addition to high‐quality systematic reviews and meta‐analyses, should be performed.

Efficacy of Cobas HPV testing for predicting grade 2+ cervical intraepithelial neoplasia in a cancer prevention center and a gynecologic oncology clinic: A single‐institution experience

AbstractBackgroundTo evaluate the efficacy of Cobas human papillomavirus (HPV) testing to predict cervical intraepithelial neoplasia of grade 2 or higher (CIN2+), Cobas HPV testing results were correlated with follow‐up biopsy in patients from Cancer Prevention Center (CPC) and Gynecologic Oncology Clinic (GOC) of The University of Texas MD Anderson Cancer Center.MethodsInstitutional data for patients who underwent Cobas HPV and Papanicolaou (Pap) cytology cotesting from 2019 to 2020 were retrospectively reviewed. Surgical follow‐up results were compared with Cobas HPV testing results in two populations.ResultsA total of 2226 patients, including 921 women (mean age, 55.2 years) seen at the CPC and 1305 women (mean age, 49.3 years) seen at the GOC, were included. Specimens from GOC patients had a significantly higher HPV positivity rate than did those from CPC patients (22.9% vs. 10.1%; p < .001). Cobas HPV testing was positive in all seven CPC patients with surgical follow‐up results showing CIN2+. Among 36 GOC patients with CIN2+ lesions, five patients had HPV−/Pap+ testing results. Although only seven CPC patients had CIN2+, Cobas HPV testing showed 100% sensitivity for predicting CIN2+ in this group. Sensitivity for CIN2+ was 86.5% in the GOC group, whereas 13.9% of GOC patients with CIN2+ had negative HPV testing results.ConclusionsCobas HPV testing was highly efficacious for predicting CIN2+ lesions in the low‐risk CPC population, which supports HPV primary screening for cervical cancer in low‐risk populations. For high‐risk patients, especially those with a history of CIN2+/cervical cancer, HPV/Pap cotesting may still be necessary to maintain a high clinical sensitivity for CIN2+.

Cytologic features of undifferentiated and dedifferentiated carcinomas of the endometrium

BackgroundUndifferentiated carcinoma (UC) is a rare, aggressive subtype of endometrial carcinoma. Dedifferentiated carcinomas (DCs) are UCs associated with a component of well differentiated endometrioid carcinoma. The authors sought to describe the morphologic features of UCs and DCs in cytologic specimens.MethodsCytologic specimens from 23 women (aged 46‐86 years; median age, 59 years) were reviewed, including cervicovaginal specimens (n = 7), peritoneal washings (n = 5), touch preparations of core biopsies from various sites (n = 5), fine‐needle biopsies of lymph nodes (n = 3), ascitic fluid (n = 1), pleural fluid (n = 1), and intrauterine fluid (n = 1).ResultsThere were 10 UCs (43%) and 13 DCs (57%). Tumor cells were arranged as single cells (9 UCs, 90%; 12 DCs, 92%) and 3‐dimensional groups (8 UCs, 80%; 11 DCs, 85%). Most cases showed high nuclear‐to‐cytoplasmic ratios. Nuclear molding was observed in 3 UCs (30%) and in 5 DCs (38%). Nuclear chromatin was often coarsely granular 6 UCs, 60%; 9 DCs, 69%). Nucleoli were inconspicuous in some cases (6 UCs, 60%; 8 DCs, 62%) but were appreciable in others. Necrosis was observed in 5 UCs (50%) and in 5 DCs (38%). Most cases exhibited clean backgrounds, and a few showed acute inflammation. Comparison of the cytologic features of UCs and DCs did not reveal any statistically significant differences.ConclusionsUCs and DCs have a spectrum of cytomorphologic appearances that are not pathognomonic, but the presence of some of these (relatively uniform population of predominantly singly dispersed cells with high nuclear‐to‐cytoplasmic ratios and variably conspicuous nucleoli) should prompt consideration of UC and DC in the differential diagnosis.

Correlation of immediate prevalence of cervical precancers and cancers with HPV genotype and age in women with atypical glandular cells cytology: A retrospective analysis of 369 cases

AbstractBackgroundThis study aims to assess the immediate risk of cervical precancers and cancers in women with atypical glandular cells (AGC) cytology, based on high‐risk human papillomavirus (hrHPV) genotypes and age.MethodsA retrospective analysis was conducted on 369 cases of AGC with immediate follow‐up biopsy results, including 299 AGC‐not otherwise specified (NOS) and 70 AGC‐favor neoplastic (FN).ResultsAmong the 369 AGC cases, 127 tested positive for hrHPV (34.4%). The predominant high‐risk type was other 11 genotypes (44.1%), followed by 16+ (29.1%), 18/45+ (26.0%), and 16 and 18/45 double‐positive (0.79%). Precancers and cancers were detected in 30.4% (112 of 369) and 9.8% (36 of 369) of cases, respectively. The HPV‐18/45+ group had notably higher adenocarcinoma in situ and adenocarcinoma (AIS+) prevalence compared to other 11 genotype groups (p < .0001 and p = .001, respectively). The HPV‐16+ group showed significantly higher high‐grade cervical squamous epithelial lesion and squamous cell carcinoma prevalence than other 11 genotype groups (p < .0001 and p = .017, respectively). Using 40‐year cutoff, older women had significantly higher prevalence of abnormal glandular lesion+ lesions (17.6% vs. 7.6%, p = .005) and adenocarcinoma (AC) (12.4% vs. 2.5%, p = .001). Using 50‐year cutoff, older women had higher prevalence of squamous cell carcinoma (SCC) (3.3% vs. 0.4%, p = .042) and AC (15.2% vs. 5.8%, p = .005). Subgroup analysis revealed that AGC‐FN women showed more severe cervical pathology than AGC‐NOS women (p < .001).ConclusionsAGC women have a significantly increased risk of cervical precancerous lesions and cancer. HPV genotyping and patient age factors need to be taken into consideration in the clinical management process of AGC patients.

HPV persistence after cervical surgical excision of high‐grade cervical lesions

Human papillomavirus (HPV) is the primary cause of cervical dysplasia and cervical cancer. Attempts are needed to better categorize patients with HPV in order to provide useful information for prognosticating and appropriately tailoring surveillance.

Cervicovaginal Papanicolaou tests in transgender men: Cytomorphologic alterations, interpretation considerations, and clinical implications

AbstractBackgroundThe transgender population faces unique psychosocial and physical obstacles to cervical cancer screening. Additionally, most individuals undergo masculinizing testosterone hormone therapy, and the physiologic changes can cause cytomorphologic alterations that may mimic lesions. Although the literature on cervicovaginal cytology is growing in this patient population, it is still limited.MethodsThe pathology information system was queried for all Papanicolaou (Pap) tests from transgender men from January 2013 to February 2023. The original diagnostic categories were catalogued. Cases were reviewed to evaluate the cytomorphologic alterations. Clinical data were also sought, including whether the sample was self‐collected. Two comparison groups were established: one was a postpartum atrophic group and the other was an all‐comer group.ResultsA total of 51 cases from 43 individuals were identified, with a mean age of 31 years. Approximately a third of cases (18 of 51; 35%) were self‐collected. The abnormal rate was low, with 5.9% of cases rendered atypical squamous cells of undetermined significance on original review and no lesions identified. The Pap unsatisfactory rate according to original reports was 3.9%. This increased to 13.7% when the cases were rereviewed, which was significantly higher than the all‐comer comparison group. The unsatisfactory rate did not correlate with self‐collection. Atrophy was a prevalent cytomorphologic alteration, with the vast majority of cases (92%) showing at least mild atrophy. Small blue cells and transitional cell metaplasia were seen in many cases (53% and 43%, respectively).ConclusionsThere are clinical and morphologic considerations that are distinct to the transgender patient population. Laboratory personnel and diagnosticians need to be aware of these in order to optimize patient care.

Cytopathological assessment is an accurate method for identifying immunophenotypic features and BRCA1/2 mutations of high‐grade serous carcinoma from ascites

AbstractBackgroundHigh‐grade serous carcinoma (HGSC) is the most common and aggressive type of ovarian cancer, and it is often associated with ascites at presentation. The objective of this study was to evaluate the accuracy of cytopathology to identify immunophenotypic features of HGSC and BRCA1/2 mutations from ascites.MethodsThe study included 45 patients with histologically confirmed primary HGSC and malignant ascites. Immunocytochemistry (ICC) staining for PAX8, WT1, P53, P16, and Ki‐67 was performed on cytospins and cytoblocks prepared from ascites. Next‐generation sequencing (NGS) was used to detect germline/somatic BRCA1/2 mutations in the ascites. Both ICC and NGS results were compared with immunohistochemistry (IHC) and NGS results from tissue blocks of primary tumor. Cronbach α and χ2 statistics, respectively, were used.ResultsICC/IHC results for PAX8, WT1, P53, and P16 showed good reliability between cytospins, cytoblocks, and tissue blocks (α > 0.75), whereas poor reliability and significant differences were observed for Ki‐67 between ascites and tissue blocks (α < 0.26; p < .001 [Kruskal–Wallis]). For germline BRCA1/2 mutations, 100% concordance was confirmed, but only 14% concordance was confirmed for somatic mutations.ConclusionsThese results demonstrate that cytopathology is an accurate method for identifying immunophenotypic features of HGSC and detecting germline BRCA1/2 mutations from ascites. However, further investigation is required for assessing the proliferation activity of HGSC in ascites and for detecting somatic BRCA1/2 mutations.

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American Cancer Society signals transition in cervical cancer screening from cytology to HPV tests

The 2020 American Cancer Society cervical cancer screening guidelines call for a shift to primary human papillomavirus testing every 5 years, with cotesting and cytology alone acceptable where primary testing platforms are not available. Initiation of screening is recommended at the age of 25 years instead of 21 years.

Cytology interpretation after a change to HPV testing in primary cervical screening: Observational study from the English pilot

BACKGROUNDOvercalling of abnormalities has been a concern for using cytology triage after positive high‐risk human papillomavirus (HPV) tests in cervical screening.METHODSThe authors studied the detection of cytological and histological abnormalities at age 24 to 64 years, using data from the English HPV pilot. The pilot compared routine implementation of primary cervical screening based on cytology (N = 931,539), where HPV test results were not available before cytology reporting, with that based on HPV testing (N = 403,269), where cytology was only required after positive HPV tests.RESULTSRevealed HPV positivity was associated with a higher direct referral to colposcopy after any abnormality (adjusted odds ratio [ORadj], 1.16; 95% confidence interval [CI], 1.14‐1.18). Laboratories with higher direct referral referred fewer persistently HPV‐positive women after early recall. The detection of high‐grade cervical intraepithelial neoplasia (CIN2+) after direct referral increased with an ORadj of 1.17 (95% CI, 1.13‐1.20) for informed versus uninformed cytology. Generally, the positive predictive value (PPV) of colposcopy for CIN2+ remained comparable under both conditions of interpreting cytology. In women 50 to 64 years old with high‐grade dyskaryosis, however, the PPV increased from 71% to 83% after revealing HPV positivity (ORadj, 2.05; 95% CI, 1.43‐2.93).CONCLUSIONSQuality‐controlled cervical screening programs can avoid inappropriate overgrading of HPV‐positive cytology.;