Meta-analysis of the accuracy of p16 or p16/Ki-67 immunocytochemistry versus HPV testing for the detection of CIN2+/CIN3+ in triage of women with minor abnormal cytology.

BACKGROUND: Women with atypical squamous cells of undetermined significance (ASC-US) can be triaged accurately with a high-risk human papillomavirus (hrHPV) test to identify those who need a referral. However, the triage of low-grade squamous intraepithelial lesion (LSIL) with hrHPV testing has very low specificity. Overexpression of p16, with or without Ki-67, indicates neoplastic transformation of human papillomavirus-infected cervical cells and may more accurately predict underlying cervical intraepithelial neoplasia of grade 3 or worse (CIN3+). METHODS: A literature search was conducted in 3 bibliographic databases. Studies were selected if they included women with ASC-US or LSIL who were triaged with dual staining (p16/Ki-67) and/or p16 staining and, if available, with a comparator hrHPV test to detect cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or CIN3+. RESULTS: Thirty-eight studies were eligible. The sensitivity of p16 staining for CIN3+ was significantly lower than that of hrHPV DNA testing (ratio for ASC-US, 0.87; 95% confidence interval [CI], 0.78-0.97; ratio for LSIL, 0.86; 95% CI, 0.80-0.93). In contrast, the specificity of p16 staining was substantially higher with relative specificities of 1.60 (95% CI, 1.35-1.88) and 2.29 (95% CI, 2.05-2.56) for ASC-US and LSIL respectively. Dual staining was as sensitive as hrHPV DNA testing but was more specific (ratio for ASC-US, 1.65; 95% CI, 1.42-1.92; ratio for LSIL, 2.45; 95% CI, 2.17-2.77). CONCLUSIONS: This meta-analysis confirms that p16 staining and p16/Ki-67 staining are more specific for CIN2+/CIN3+ than hrHPV DNA testing. Although p16 staining is less sensitive for CIN3+ than hrHPV DNA testing, dual staining has similar sensitivity.

Portable Pocket colposcopy performs comparably to standard-of-care clinical colposcopy using acetic acid and Lugol's iodine as contrast mediators: an investigational study in Peru.

OBJECTIVE: Our goal was to develop a tele-colposcopy platform for primary-care clinics to improve screening sensitivity and access. Specifically, we developed a low-cost, portable Pocket colposcope and evaluated its performance in a tertiary healthcare centre in Peru. DESIGN AND SETTING: Images of the cervix were captured with a standard-of-care and Pocket colposcope at la Liga Contra el Cáncer in Lima, Peru. POPULATION: Two hundred Peruvian women with abnormal cytology and/or human papillomavirus positivity were enrolled. METHODS: Images were collected using acetic acid and Lugol's iodine as contrast agents. Biopsies were taken as per standard-of-care procedures. MAIN OUTCOME MEASURES: After passing quality review, images from 129 women were sent to four physicians who provided a diagnosis for each image. RESULTS: Physician interpretation of images from the two colposcopes agreed 83.1% of the time. The average sensitivity and specificity of physician interpretation compared with pathology was similar for the Pocket (sensitivity = 71.2%, specificity = 57.5%) and standard-of-care (sensitivity = 79.8%, specificity = 56.6%) colposcopes. When compared with a previous study where only acetic acid was applied to the cervix, results indicated that adding Lugol's iodine as a secondary contrast agent improved the percent agreement between colposcopes for all pathological categories by up to 8.9% and the sensitivity and specificity of physician interpretation compared with pathology by over 6.0 and 9.0%, respectively. CONCLUSIONS: The Pocket colposcope performance was similar to that of a standard-of-care colposcope when used to identify precancerous and cancerous lesions using acetic acid and Lugol's iodine during colposcopy examinations in Peru. TWEETABLE ABSTRACT: The Pocket colposcope performance was similar to that of a standard-of-care colposcope when identifying cervical lesions.

Assessing the detection of human papillomavirus late mRNA in liquid base cytology samples for risk stratification of cervical disease.

Molecular human papillomavirus (HPV) testing is an important and developing tool for cervical disease management. However there is a requirement to develop new HPV tests that can differentiate between clinically significant and benign, clinically insignificant infection. Evidence would indicate that clinically significant infection is linked to an abortive HPV replication cycle. In particular the later stages of the replication cycle (i.e., production of late messenger (m) RNAs and proteins) appear compromised. Compared to current DNA-based tests which indicate only presence or absence of virus, detecting virus mRNAs by reverse transcriptase PCR (RT-PCR) may give a more refined insight into viral activity and by implication, clinical relevance. A novel quantitative (q)RT-PCR assay was developed for the detection of mRNAs produced late in the viral replication cycle. Initially this was validated on HPV-containing cell lines before being applied to a panel of 223 clinical cervical samples representing the cervical disease spectrum (normal to high grade). Samples were also tested by a commercial assay which detects expression of early HPV E6/E7 oncoprotein mRNAs. Late mRNAs were found in samples associated with no, low and high grade disease and did not risk-stratify HPV infection. The data reveal hidden complexities within the virus replication cycle and associated lesion development. This suggests that future mRNA tests for cervical disease may require quantitative detection of specific novel viral mRNAs.

Incidence of genital warts in adolescents and young adults in an integrated health care delivery system in the United States before human papillomavirus vaccine recommendations.

BACKGROUND: Information on genital wart incidence in adolescents and young adults before human papillomavirus (HPV) vaccination is important for understanding the impact of the vaccine on the epidemiology of this early outcome of HPV infection. METHODS: The study population included 11- to 29-year-old enrollees of Northern California Kaiser Permanente between July 1, 2000, and July 1, 2005, before the availability of the HPV vaccine. We identified genital warts with an algorithm combining genital wart-specific International Classification of Diseases, Ninth Revision, Clinical Modification codes (078.10, 078.11, and 078.19) with physician-recorded anatomic locations. We calculated sex- and age-specific incidence rates of genital warts and described the specific anatomic location of presentation, as well as recurrences of genital warts. RESULTS: We identified 1,682 cases of genital warts among 181,264 individuals. The incidence rate was highest among women (6.3/1000 person-years) and men (2.9/1000 person-years) aged 20 to 24 years old. Among women (n = 96,792), 63.4% of the 1240 incident genital wart cases occurred on the vulva and 21.1% on the cervix. Among men (n = 84,472), 91.6% of the 442 incident genital wart cases did not have a specific anatomic location recorded. Most people with an incident genital wart diagnosis (87.2%) did not have a recurrence during the observation period. CONCLUSIONS: Our study found that the incidence of genital warts was highest among persons aged 20 to 24 years using a unique method to identify the location of the wart. Information on incidence of genital warts before vaccine use provides baseline data that can be used to measure HPV vaccine impact.

2011 colposcopic terminology of the International Federation for Cervical Pathology and Colposcopy.

New colposcopy terminology was prepared by the Nomenclature Committee of the International Federation of Cervical Pathology and Colposcopy after a critical review of previous terminologies, online discussions, and discussion with national colposcopy societies and individual colposcopists. This document has been expanded to include terminology of both the cervix and vagina. The popular terms "satisfactory colposcopy" and "unsatisfactory colposcopy" have been replaced. The colposcopic examination should be assessed for three variables: 1) adequate or inadequate, with the reason given; 2) squamocolumnar junction visibility; and 3) transformation zone type. Other additions were the localization of the lesion to either inside or outside the transformation zone and determinants of size as well as location of cervical lesions. Two new signs were included in the terminology-the "inner border sign" and "ridge sign." The following definitions have been added: congenital transformation zone, polyp (ectocervical or endocervical), stenosis, congenital anomaly, and posttreatment consequence. In addition, the terminology includes standardization of cervical excision treatment types and cervical excision specimen dimensions. The International Federation of Cervical Pathology and Colposcopy recommends that the 2011 terminology replace all others and be implemented for diagnosis, treatment, and research.

Evaluation of the FocalPoint GS system performance in an Italian population-based screening of cervical abnormalities.

OBJECTIVE: To evaluate the FocalPoint Location-Guided Screening (FPGS) performance in computer-assisted primary screening of Papanicolaou-stained cervicovaginal smears. STUDY DESIGN: A total of 37,306 routine consecutive conventional Pap slides were prospectively processed on the FPGS. Each slid designated by the instrument as Review was reported according to results obtained using a GS Review Station. Subsequently, all slides under went conventional manual rapid screening and reported results were compared. RESULTS: Of the slides initially submitted to the FPGS, 34,004 (91.15%) were qualified for scanning. Within these slides, the system classified 7,399 (21.8%) as needing No Further Review and ranked to Review the remaining 26,605 (78.2%). Of the 418 cellular abnormalities found, 409 were classified for Review by FPGS and 9 minor grade lesions were classified in the "No Further Review" population. Overall, 352 (86%) of atypical squamous cell (ASC)+ were ranked in high-score quintiles, including 96 (94%) of the 102 high-grade squamous intraepithelial lesion (HSIL) or worse. Location-guided software identified cellular abnormalities, in the automatically selected fields of view, in 378 (92%) of the ranked abnormal slides, showing a sensitivity > 95% on SILs. CONCLUSION: Slide ranking and location-guided screening features are of value in detecting and triaging abnormal smears.

Error reduction and risk management in cytopathology.

Currently, tort reform is not a major priority in either the Congress of the United States or in state legislatures. Thus, it is fortunate that medical negligence claims against pathologists are relatively infrequent, at 8.3% per year per 100 insured pathologists (data from the Doctors' Company, 2000-2003). However, claims for "missed" cervical cytology specimens rank third, behind those for alleged misinterpretation of breast biopsies and pigmented skin lesions. The severity of cervical cytology errors is high, at almost $700,000 per claim, surpassed only by those concerning melanoma. There are common threads that appear consistently in the analysis of slides from allegedly misdiagnosed cervical cytology cases, including small-cell variants of high-grade squamous intraepithelial neoplasia (HGSIL), present in small numbers; hyperchromatic crowded cell groups; atypical squamous cells of undetermined significance (ASCUS); smears taken during menses; other bloody smears, particularly with degenerative features or excessive inflammation; others showing atypical repair; and unsatisfactory samples. It is important for pathologists to spend time with cytotechnologists to emphasize the patterns of abnormal smears at low microscopic magnification and those backgrounds featuring blood and inflammation which require particular attention. Managing the "look-back" requirement of the Clinical Laboratory Amendments of 1988 (CLIA88) is also crucial; the need to issue amended reports as a consequence of that provision is quite rare. Procedures for administrating and reporting retrospective reviews under the CLIA88 should be clearly outlined in a peer-reviewed procedure document in each laboratory. They should be reviewed and approved by risk managers or insurance carriers, and documented in such a manner that one obtains maximal protection from legal discovery. Consumer education is particularly important in maintaining laboratory performance and reducing risk from error in cytology. Periodic feedback to clinicians on the quality of their smear preparations, the use of ancillary techniques (eg, human papillomavirus testing), and discussion of reporting terminology are important. Moreover, one should stress the need for pertinent clinical history that is often required to initiate quality control measures for evaluation and reporting of cervical cytology specimens. The incidence of cervical cancer in the United States, at only 9700 new cases per year, is low, emphasizing the need for clinical vigilance, attention to unexplained symptoms and signs, and biopsies of any cervical abnormality. These and other efforts may assist in reducing the risk of litigation attached to allegedly false-negative gynecologic and nongynecologic cytology samples.

Internal Federation for Cervical Pathology and Colposcopy nomenclature and treatment for cervical preinvasive disease.

OBJECTIVE: To examine the effects of IFCPC transformation zone type and treatment modality on outcome from excisional treatments for cervical pre-invasive disease at an inner city colposcopy department. MATERIALS AND METHODS: All patients treated within the colposcopy department for whom age, treatment modality, resection margin status at histology and six-month cytologic data was available. RESULTS: Transformation zone type is affected by patient age. Change in accessibility of the transformation zone to examiantion by colposcopy affected cytologic outcome. There was no obvious effect of treatment modality to explain this change in outcome. CONCLUSIONS: Transformation zone type is an important determinant of excisional treatment outcome for cervical disease. This needs to be considered when comparing therapeutic success.

The natural history of type-specific human papillomavirus infections in female university students.

Little is known about the average duration of type-specific human papillomavirus (HPV) infections and their patterns of persistence. The objectives of this study were to evaluate the rate of acquisition and clearance of specific HPV types in young women. Female university students (n = 621) in Montreal were followed for 24 months at 6-month intervals. At each visit, a cervical specimen was collected. HPV DNA was detected using the MY09/MY11 PCR protocol followed by typing for 27 HPV genotypes by a line blot assay. The Kaplan-Meier technique was used to estimate the cumulative probability of acquiring or clearing a HPV infection considering types individually or in high-risk (HR) or low-risk (LR) groups defined by oncogenic potential. Incidence rates were 14.0 cases/1000 women-months (95% confidence interval, 11.4-16.3) and 12.4 cases/1000 women-months (95% confidence interval, 10.4-14.8) for acquiring HR and LR HPV infections, respectively. The 24-month cumulative rates of acquisition were highest for HPV-16 (12%), HPV-51, and HPV-84 (8%). Of the incident infections, HPV-16 was the most persistent (mean duration, 18.3 months), followed by HPV-31 and HPV-53 (14.6 and 14.8 months, respectively). HPV-6 and HPV-84 had the shortest mean duration time (<10 months) The mean durations of incident, same-type LR or HR HPV infections were 13.4 months and 16.3 months, respectively. Whereas the majority of episodes with a type-specific HPV infection cleared within 2 years, there were many women who were either reinfected with a new HPV genotype or presumably experienced reactivation of their initial infection.

Histologic follow-up of atypical endocervical cells. Liquid-based, thin-layer preparation vs. conventional Pap smear.

OBJECTIVE: To review the histologic findings in patients diagnosed with "atypical glandular cells of uncertain significance, endocervical cell type" (AGUS-EC) by ThinPrep Pap Test (TPPT) or conventional Pap smear (CPS) and to evaluate the clinical value of subclassifying AGUS-EC as "favor reactive" or "favor neoplastic." STUDY DESIGN: All TPPT and CPS diagnosed as AGUS-EC (favor reactive, unspecified and favor neoplastic) from January 1998 through December 1999 and all available histologic follow-up (defined as endocervical curettage, cervical biopsy, cervical conization or hysterectomy obtained within six months of the time of an AGUS-EC diagnosis) were obtained from a computerized database. RESULTS: AGUS-EC was diagnosed in 0.77% of CPS (683 of 88,825) and 0.59% of TPPT (183 of 30,968) (P = NS). There was no statistically significant difference in any of the follow-up histologic diagnoses between the CPS and TPPT groups. The majority of the follow-up biopsies demonstrated benign processes in both groups. Patients with a diagnosis of AGUS-EC "favor neoplastic" had a greater proportion of true glandular pathology as compared with AGUS-EC "unspecified" or "favor reactive" (P < .001). None of the patients with a diagnosis of AGUS-EC "favor reactive" were found to have true glandular pathology; however, a minority of them proved to have squamous pathology. CONCLUSION: In this study there was no difference in CPS and TPPT in regard to the specificity of a diagnosis of AGUS-EC for true glandular pathology. Subclassifying AGUS-EC as "favor reactive" or "favor neoplastic" may provide valuable information for directing patient follow-up.

Relevance of the rates of PCNA, Ki-67 and p53 expression according to the epithelial compartment in cervical lesions.

In order to assess further biological evidence for similarities among the "diagnostic classes" of cervical lesions, which are now a matter of international discussion in the search for a uniform classification, the purpose of this study was to characterize the immunoexpression of cell proliferation markers (proliferating cell nuclear antigen, PCNA and Ki-67) and protein p53. Each marker was individually quantified in basal, intermediate, and superficial epithelial compartments presenting chronic cervicitis (CC) accompanied by the cytopathic effects of infection by human papillomavirus (CCHPV) or not (CC), as well as in cervical intraepithelial neoplasia (CIN) grades I, II, and III. A total of 100 patients were evaluated and the positive nuclei were counted separately, including all extensions of the available epithelium. The percentage of PCNA- and Ki-67-positive cells increased with increasing grade of the cervical lesions, although PCNA immunoreactivity was always greater than the immunoreactivity observed with Ki-67 antigen. The immunoexpression of p53 protein was found to be weak, with no remarkable behavior in any specific "diagnostic class". The differences in cell proliferation markers found herein further emphasize the progressive loss of epithelial layer organization in the course of the development of preneoplastic changes in cervical squamous epithelium. Furthermore, difficulties in morphologically distinguishing "borderline lesions" persist when cell cycle markers are studied, further supporting the suggestion to consider the lesions of CCHPV and CIN I together as only one diagnostic class. Conversely, the different immune profile found between CIN II and III further supports the validity of the subdivision of CIN into three groups.

Revisäo das alteraçöes citomorfológicas da infecçäo pelo vírus do papiloma humano em citologia cervicovaginal / Cytological effects of human papillomavirus infection in cervical smears: a review article

Os autores revisam os principais critérios propostos pela literatura para o diagnóstico da infecçäo pelo vírus do papiloma humano (HPV) em esfregaçös cervicovaginais. A evoluçäo do conhecimento sobre as lesöes pré-malignas escamosas do colo uterino, os diferentes tipos de hpv e a interligaçäo entre estas entidades resultaram em diversas mdificaçöes no conceito e na nomenclatura cito-histológica destas lesöes. No decorrer deste artigo de revisäo, estas informaçöes säo equacionadas, e validade da aplicaçäo de critérios para o diagnóstico indireto do HPV pelo citopatologista é discutida

ThinPrep Pap Test promotes detection of glandular lesions of the endocervix.

The objectives of this study were to evaluate 1) the detection rate of atypical glandular cells of undetermined significance of endocervical cell type (AGUS-EC) and 2) the correlation between AGUS-EC on cytology and biopsy results using the conventional Papanicolaou (Pap) smear test vs. the ThinPrep Pap test (TPPT). Cervical-vaginal samples processed by the conventional Pap smear for 11 mo in 1996-1997 were identified, as were TPPTs collected for the same interval in 1997-1998. Biopsy results were compared after a 9-mo follow-up for both groups. There were 112 AGUS-EC cases from 82,754 conventional Pap smears (detection rate, 0.14%) compared with 58 cases from 82,252 TPPTs (detection rate, 0.07%) (P < 0.01). Biopsies were available in 72 of 112 patients from the conventional Pap smear group and 35 of 58 patients from the TPPT groups. Five dysplastic glandular lesions/ AIS were diagnosed by biopsy in the 35 patients (14.3%)from the TPPT group, compared with 2 of the 72 patients (2.8%) from the conventional Pap smear group (P < 0.05). There were no statistically significant differences between other follow-up diagnoses for the two methods. The use of TPPT resulted in fewer cases of AGUS-EC and better correlation with histology. The TPPT appears to be as sensitive as and more specific than the conventional Pap smear for detection of endocervical glandular lesions.

[Value and limits of cytology in the diagnosis of cervico-vaginal lesions at the Mahajanga University Hospital Center: 465 cases]. / Apports et limites de la cytologie dans le diagnostic des lésions cervico-vaginales au Centre Hospitalier Universitaire de Mahajanga: à propos de 465 cas.

Cervix neoplasms are the most frequent of female neoplasms in Madagascar. The authors reported a prospective study carried out at the Hospital Center of the University of Mahajanga for ten months (January-October 1993). 500 patients were investigated. 465 results of cervix and vaginal smears were considered. The Bethesda group classification was used to interpret lesions. 333 specific pathological lesions were listed. Bacterial infections and trichomoniasis were their principal causes. 4 cases were presumed as human papillomavirus condylomata. 39 SIL low-grade and 24 SIL high-grade were detected. 5 cervix neoplasms were diagnosed. Only few patients had consultation to perform cervix and vaginal smears because these exams are expensive. It may be an explication to the chronicity of lesions, a favourising factor of cancer. The role of viruses, especially human papillomavirus, in the development of cervix neoplasms is mentioned. The authors conclude that the low number of cervix neoplasms they founded is misleading. Cervix neoplasms are the first female cancers in Madagascar. A systematic surveillance of all female genitalia diseases must be programed. While its settling, cervix neoplasms control must be centred on Information--Education--Communication.