P16(INK4a) immunocytochemistry in liquid-based cytology samples in equivocal Pap smears: added value in management of women with equivocal Pap smear

OBJECTIVE: To test whether p1l6(INK4a) immunocytochemistry (ICC) in liquid-based cytology (LBC) is useful with colposcopy in abnormal Pap smears. STUDY DESIGN: A series of 248 women with abnormal Pap smear were analyzed for oncogenic (HR) human papillomavirus (HPV) types using the Hybrid Capture II assay and for p16(INK4a) expression using ICC on cervical samples in PreservCyt liquid media. Colposcopic and loop electrosurgical excision procedure (LEEP) cone biopsy were the gold standard. RESULTS: p16(INK4a) ICC did best as predictor of high-grade squamous intraepithelial lesion, with OR 12.18 (2.72-54.57) (p = 0.0001), showing 88.2% sensitivity (SE), 61.9% specificity (SP), 14.6% positive predictive value (PPV) and 98.6% negative predictive value (NPV). In sorting discrepant cases, p16(INK4a) ICC results in 100% SE and 100% NPV in detecting cervical intraepithelial neoplasia (CIN) 2 lesions among Pap+/biopsy- women. In atypical squamous cells undetermined significance (ASCUS) cytology, adding p16(INK4a) ICC improves specificity of colposcopy from 27.3% to 81.8% and PPV from 42.8% to 71.4%. Best performance is obtained with p16(INK4a) ICC and colposcopy: 83.3% SE, 81.8% SP, 71.4% PPV and 90.0% NPV. CONCLUSION p16(INK4a) is useful in sorting clinically relevant discrepant cases, and p16(INK4a) ICC significantly improves SP and PPV of colposcopy in management of ASCUS cytology.     

Outcomes of women with atypical squamous cells of undetermined significance and high-risk human papillomavirus DNA

OBJECTIVE: To study the risk of high-grade squamous intraepithelial lesion (HSIL) and cervical intraepithelial neoplasia (CIN) 2 or 3 in women with human papillomavirus (HPV)-positive atypical squamous cells of undetermined significance (ASCUS) cytology over a 2-year period using the 2001 Bethesda System and ThinPrep Paps. STUDY DESIGN: In 2002, 846 patients with ThinPrep cervical cytology having an ASCUS interpretation and positive for high-risk HPV DNA were identified. A cohort of 514 (60.8%) patients with follow-up by repeat cytology, cervical biopsy or both was included in the study. Patient age was 12-81 years, with a median of 25 years. RESULTS: There were 291 women (56.6%) with negative status by cytology, HPV testing or biopsy with a median interval of 8.5 months, and an additional 174 patients (33.9%) had persistent ASCUS, positive HPV DNA or low-grade SIL/CIN 1. Finally, 49 patients (9.5%) had CIN 2 or 3, with a median interval of 8.5 months. CONCLUSION: Our study suggests that HSIL or CIN 2 or 3 will be detected in 1 in 10 women with HPV-positive index ASCUS cervical cytology at initial colposcopy or within a 2-year follow-up period.     

A human papillomavirus testing system in women with abnormal Pap results: a comparison study with follow-up biopsies

OBJECTIVE: To evaluate the efficacy of INFORM HPV using the SurePath collection method in women whose Pap tests indicated abnormal results. STUDY DESIGN: Ninety-two women from the gynecology clinics at The University of Texas M.D. Anderson Cancer Center who had Pap tests and underwent follow-up biopsies were selected for the study. This included 51 women with atypical squamous cells of undetermined significance (ASCUS), 23 women with low-grade squamous intraepithelial lesion (LSIL), 15 women with high-grade squamous intraepithelial lesion (HSIL) and 3 women with negative Pap results. The INFORM HPV, an in situ hybridization assay, testing for oncogenic types of HPV was performed, and the results were compared with follow-up biopsies. RESULTS: The positive rate of the INFORM HPV increased with higher grades of cytology diagnoses. The sensitivity of the INFORM HPV testing for predicting high-grade cervical intraepithelial neoplasia (CIN 2/3) also increased with higher grades of cytology diagnoses. A negative predictive value (NPV) of 94.9% and a specificity of 80.4% for predicting CIN 2/3 were observed in the ASCUS group. CONCLUSION: Using SurePath Pap specimens, the INFORM HPV lacks sufficient sensitivity and NPV for predicting CIN 2/3 in women with ASCUS. Therefore, use of the test as a triage tool is limited.     

Conventional Pap smear and liquid-based cytology as screening tools in low-resource settings in Latin America: experience of the Latin American screening study

OBJECTIVE: To evaluate the performance of the conventional Pap test and liquid-based cytology (LBC) in an ongoing multicenter trial testing optional screening tools (cytology, screening colposcopy, visual inspection with acetic acid, visual inspection with Lugol's Iodine, cervicography and Hybrid Capture II [HCII] (Digene Brazil, S?o Paulo, Brazil) conventional and self-sampling), for cervical cancer in Brazil and Argentina. STUDY DESIGN: A cohort of 12,107 women attending four clinics (Campinas, S?o Paulo, Porto Alegre, Buenos Aires) were randomized into the 8 diagnostic arms. Women testing positive with any of the tests were referred for colposcopy, and cervical biopsies were used as the gold standard to assess performance characteristics of the diagnostic tests. Conventional Pap smears were sampled by all clinics (n = 10,240), and LBC (Autocyte PREP, [TriPath Imaging, Burlington, North Carolina, U.S.A.], n=320, and DNA-Citoliq [Digene Brazil], n =1,346) was performed by 1 of the clinics. RESULTS: Conventional Pap smears showed no squamous intraepithelial lesions (normal) in 8,946 (87.4%) and LBC in 1,373 (82.4%). Using high grade squamous intraepithelial lesions (HSIL) as the cutoff, Pap smears predicted high grade (cervical intraepithelial neoplasia [CIN] 3) with OR 63.0 (95% CI, 36.90-107.70), standard error (SE) 59%, SP 97.8%, positive predictive value (PPV) 68.1% and negative predictive value (NPV) 96.7%. The same figures for Autocyte PREP were: OR 9.0 (95% CI, 2.43-33.24), sensitivity (SE) 33.3%, specificity (SP) 100%, PPV 100% and negative PV (NPV) 88.8%. DNA-Citoliq detected CIN 3 as follows: OR 11.8 (95% CI 2.60-53.26), SE 40.0%, SP 94.6%, PPV 40.0% and NPV 94.6%. Lowering the cutoff to low grade squamous intraepithelial lesions increased SE and NPV but compromised SP and PPV. The detection rates for high grade lesions after an atypical squamous cells of undetermined significance diagnosis were similar with the 3 techniques. In our settings, the 3 methods of cervical cytology were slightly different in performance. The conventional Pap smear had the highest SE, while Autocyte PREP had 100% SP and PPV in detecting CIN3 with the HSIL cutoff. All 3 tests had lower SE but higher SP as compared to HCII.     

HPV E6/E7 mRNA testing is more specific than cytology in post-colposcopy follow-up of women with negative cervical biopsy

Background

In Norway, women with negative or low-grade cervical biopsies (normal/CIN1) are followed up after six months in order to decide on further follow-up or recall for screening at three-year intervals. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures whereas a low risk of high-grade disease among triage negative women assures safety.

Materials and Methods

At the University Hospital of North Norway, cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in post-colposcopy follow-up of women with negative or low-grade biopsy. In this study, women with negative biopsy after high grade cytology (ASC-H/HSIL) and/or positive HPV mRNA test in the period 2005–2009 were included (n = 520). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as study endpoint.

Results

Of 520 women with negative or low-grade biopsy, 124 women (23.8%) had CIN2+ in follow-up biopsy. The sensitivity and specificity of the HPV mRNA test were 89.1% (95% CI, 80.1–98.1) and 92.5% (95% CI, 88.2–96.7), respectively. The ratios of sensitivity, specificity and PPV of HPV mRNA testing compared to repeat cytology for finding CIN2+ was 1.05 (95% CI: 0.92–1.21), 1.21 (95% CI: 1.12–1.32), and 1.49 (95% CI: 1.20–1.86), respectively. The PPV of mRNA was 77.3% (95% CI, 59.8–94.8) in women aged 40 or older.

Conclusion

Women with negative cervical biopsy require follow-up before resumption of routine screening. Post-colposcopy HPV mRNA testing was as sensitive but more specific than post-colposcopy cytology. In addition, the HPV mRNA test showed higher PPV. A positive mRNA test post-colposcopy could justify treatment in women above 40 years.     

Genital human papillomavirus testing by in situ hybridization in liquid atypical cytologic materials and follow-up biopsies

OBJECTIVE: To describe cases of HPV testing by DNA in situ hybridization performed on atypical cervicovaginal samples collected by a liquidsed method that were negative for HPV DNA on cytology but revealed cervical intraepithelial neoplasia on follow-up biopsies. STUDY DESIGN: Three hundred ninety-five consecutive SurePath atypical squamous cells of undetermined significance (ASC-US) cytologic samples from asymptomatic, reproductive-age women were tested for human papillomaviruses (HPVs) by the in situ hybridization (ISH) method (Ventana Inform HPV Test, Tucson, Arizona, U.S.A). One hundred (25%) cases underwent follow-up colposcopic biopsy within 3 months of cytology. All the tests (cytology, ISH, histology) were independently evaluated without knowledge of the other tests. RESULTS: One hundred twenty-two (33%) cytologic samples were positive for HPVs. Of a total of 100 (HPV positive and negative) follow-up biopsies, 55 were positive for cervical intraepithelial neoplasia (CIN). Fourteen cases of biopsy-proven CIN tested negative for all HPV types in the prior cytologic samples. Retesting of the 14 CIN tissues by ISH was negative in 10, positive for HPV in 2 and inconclusive in 2. CONCLUSION: There is a small but significant (14%) false negative rate with HPV testing by the Ventana ISH method. Clinically suspicious cases should be followed even if an HPV test is negative.     

Combined Pap smear, cervicography and HPV DNA testing in the detection of cervical intraepithelial neoplasia and cancer

OBJECTIVE: The sensitivity of the Pap smear (PAP) continues to be the subject of debate. During the past several years, cervicography (CER) and HPV DNA testing have been suggested as optional tools in the screening of cervical cancer precursors. STUDY DESIGN: The performance characteristics of PAP, CER and HPV DNA testing (hybrid capture test [HCT]) in all potential combinations were evaluated in a series of 1,030 women (aged 16-70, median, 33), subjected to colposcopy (COLPO) as the reference tool. RESULTS: Of the 992 evaluable cases, 402/992 (41%) had positive COLPO (i.e., an abnormal transformation zone). Of them, 298 women underwent directed punch biopsy, while of the COLPO negative patients, 18/93 positive by at least one of the three tests had endocervical curettage. Of the 402 COLPO positive women, 146 (36%) remained negative on all tests, whereas 256 (64%) had at least one positive test. There were 84 cervical intraepithelial neoplasia (CIN) 2 and 3 lesions and 6 invasive carcinomas. Of the former, 10 were detected by PAP alone, 4 by CER alone and 3 by HCT alone. Three of the 6 carcinomas were HCT negative. The predictive value (PPV) of a positive test was 45% for PAP, 51% for CER and 48% for HCT. The combinations of PAP with CER (for PAP negative cases) and PAP with HCT were more sensitive for CIN 2 and 3 (95% and 94%, respectively) as compared with PAP alone but were associated with a significant decrease in specificity (44% and 46% vs. 57%, respectively). However, both combinations retained a PPV (43%) similar to that of PAP alone (45%). CONCLUSION: The potential combinations of PAP with CER and with HCT were more sensitive in detecting CIN 2 and 3 as compared with PAP alone and retained a PPV similar to that of PAP.     

A thin-layer,liquid-based pap test for mass screening in an area of China with a high incidence of cervical carcinoma. A cross-sectional,comparative study

OBJECTIVE: To confirm the accuracy of the ThinPrep Pap Test (Cytyc Corp., Boxborough, Massachusetts, U.S.A.) on the basis of histologic diagnosis by biopsy and the detection of human papillomavirus (HPV) DNA in mass screening. STUDY DESIGN: A total of 1,997 women residing in Xiangyuan County, Shanxi Province, P.R.C., an area with a high incidence of cervical carcinoma, were enrolled in this study. We collected exfoliative cervical samples from all subjects into a liquid buffer (Preserv-Cyt [Cytyc]) and utilized for both cytologic screening using the ThinPrep Pap Test and HPV DNA testing. Subsequent colposcopic biopsies were taken on all subjects. All the tests were performed in an independent and blinded fashion. We compared the ThinPrep Pap test with colposcopic biopsy and HPV test. RESULTS: High grade squamous intraepithelial lesions (HSIL) (CIN 2/3) were identified in 74 (3.7%) of 1,993 women adequately assessed, and there were 12 cases of squamous cell carcinoma (SCC). The false negative rate of ThinPrep cytology was 3.2% for biopsy-confirmed CIN 3 and 9.3% for CIN 2. Twenty-seven (87%) of the 31 women with biopsy-confirmed CIN 3 and 12 (100%) of 12 with biopsy-confirmed SCC had a diagnosis of either HSIL or greater abnormalities on ThinPrep cytology. In addition, the HPV DNA detection rates offered a good correlation between cytology and biopsy. CONCLUSION: The ThinPrep Pap performed extremely well in this primary screening trial. We found a good correlation between ThinPrep cytology and colposcopic biopsy on detection of HSIL and SCC; cervical specimens collected in ThinPrep liquid buffer serve as a direct test for HPV as well.     

The role of cervical cytology and colposcopy in detecting cervical glandular neoplasia

Objective:  To determine the role of cervical cytology and colposcopy in the management of endocervical neoplasia.
Setting:  Colposcopy unit and cytology laboratory in a teaching hospital.
Sample:  Group 1 included 184 smears showing endocervical glandular neoplasia from 129 patients and group 2 included 101 patients with histology showing endocervical abnormalities in a 6-year period (1993–1998). Follow-up of 6–11 years to 2004 was available.
Methods:  Group 1 were identified from the cytology computer records. Group 2 were identified from histology records on the cytology database and a record of histology cases kept for audit purposes. The clinical records were examined retrospectively.
Results:  The positive predictive value (PPV) of abnormal endocervical cells in smears was 81.1% for significant glandular/squamous [cervical glandular intraepithelial neoplasia (CGIN)/cervical intraepithelial neoplasia grade2 (CIN2 or worse)] lesions. The PPV of colposcopy was 93.5% for significant glandular/squamous lesions of the cervix. The postcolposcopy probability of a significant lesion when colposcopy was normal was 87.5%. The sensitivity of colposcopy in detecting endocervical lesions was 9.8%. The sensitivity of cervical smears in detecting a significant endocervical abnormality (CGIN or worse) was 66.3%. The false negative rate for cytology of endocervical glandular lesions was 4.0%.
Conclusions:  Endocervical glandular neoplasia detected on cytology is predictive of significant cervical pathology even when colposcopy is normal, which supports excisional biopsy in the primary assessment of these smears. The high concomitant squamous abnormality rate justifies the use of colposcopy to direct biopsies from the ectocervix. Cervical cytology is the only current screening method for cervical glandular abnormalities but sensitivity is poor.     

Evaluation of a cervical cancer screening program based on HPV testing and LLETZ excision in a low resource setting

We conducted studies in Vanuatu to evaluate potential screening and treatment strategies to assist with control of cervical cancer. In a pilot study of 496 women, visual inspection and cytology were evaluated as screening tests for detection of CIN 2 or worse (CIN2+), observed in 21 of 206 subjects biopsied on the basis of abnormal visual inspection or cytology. Sensitivity of visual inspection with Lugol's Iodine for detection of CIN2+ on biopsy was 0.63, specificity was 0.32, and the positive predictive value was 0.09. For HSIL cytology, sensitivity was 0.99, specificity was 0.77, and the positive predictive value was 0.88. HSIL cytology was significantly more sensitive and had a significantly higher PPV for CIN 2+ than visual inspection (p<0.01). In a further study of 514 women, we compared testing for HR HPV and cytology as predictors of biopsy proven CIN 2+. Sensitivity of HSIL cytology for CIN2+ as established by loop excision of the cervix was 0.81, specificity was 0.94, and positive predictive value was 0.48. Sensitivity of a positive test for HR HPV for detection of CIN2+ was non-significantly different from cytology at 0.81, specificity was 0.94, and positive predictive value was 0.42. Combining the two tests gave a significantly lower sensitivity of 0.63, a specificity of 0.98, and a positive predictive value of 0.68. For women over 30 in a low resource setting without access to cytology, a single locally conducted test for high risk HPV with effective intervention could reduce cervical cancer risk as effectively as intervention based on cytology conducted in an accredited laboratory.     

Role of urinary NMP-22 combined with urine cytology in follow-up surveillance of recurring superficial bladder urothelial carcinoma

OBJECTIVE: To determine efficacy and utility of NMP-22 in follow-up of bladder urothelial carcinoma (UC) and compare NMP-22 as a single evaluating test vs combination with cytology. STUDY DESIGN: Ninety-four consecutive urine cytology samples of bladder UC were identified. Patients received follow-up urine cytology, NMP-22 testing and cystoscopy with surgical biopsy. RESULTS: NMP-22 specificity was 100%, sensitivity 45%, positive predictive value (PPV) 100% and negative predictive value (NPV) 87%. NMP-22 showed lower sensitivity for high-grade lesions and higher for low-grade lesions. Cytologic diagnosis had a high inconclusive rate; when regarded as positive, it resulted in 75% sensitivity, 58% specificity, 33% PPV and 89% NPV. NMP-22 correctly classified 60% of false negative cases diagnosed by cytology with low-grade UC and clarified 27 inconclusive cytologic diagnoses. NMP-22 misclassified 9 cases as false negative, all with high-grade UC; all were correctly identified on cytology as true positive. Combined interpretation showed 90% sensitivity, 92% specificity, 75% PPV and 98% NPV. CONCLUSION: NMP-22 complements cytology by its higher sensitivity for low-grade lesions; its values are not affected by bacillus Calmette Guérin therapy changes, which are limiting in cytology. Combined interpretation of NMP-22 and cytology shows promise as an effective, noninvasive method for surveillance of UC.     

TCT、HPV检测在宫颈锥切术后复发中的预测价值

目的:评估薄层液基细胞学检查(thinprep cytologic test,TCT)和人乳头瘤病毒(human papillomavirus,HPV)检测在宫颈锥切术后复发中的预测价值。方法:随访531例病理诊断为子宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)Ⅱ-Ⅲ级接受宫颈锥切术的患者,分别于术后3、6个月及术后每6-12月随访1次,以TCT及HPV检测作为随访的检测指标,若二者有一项异常,行阴道镜下活组织检查,病理证实存在子颈上皮内瘤变Ⅰ-Ⅲ级者视为复发。采用敏感度、特异度、阳性预测值、阴性预测值表示TCT、HPV检测性能。结果:531例患者中10%(54例)的患者出现不同级别的病变复发。TCT在术后预测病变复发的灵敏度77%,特异度72%;HPV在术后预测病变复发的灵敏度95%,特异度60%,TCT联合HPV预测病变复发的灵敏度100%,特异性80%。术后HPV负荷量100 RLU/PC者较HPV负荷量100 RLU/PC者而言术后病变复发的风险增高,差别有统计学意义(P0.01),术后HPV负荷量100 RLU/PC是锥切术后病变复发的高危因素。结论:使用细胞学联合HPV检测是有效的预测宫颈锥切术后病变复发的方法,术后高HPV负荷量与病变复发相关,并可对术后复发高风险人群进行分流,临床需严密随访。     

Triage of women with low-grade cervical lesions--HPV mRNA testing versus repeat cytology

Background

In Norway, women with low-grade squamous intraepithelial lesions (LSIL) are followed up after six months in order to decide whether they should undergo further follow-up or be referred back to the screening interval of three years. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures.

Materials and Methods

At the University Hospital of North Norway, repeat cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in triage of women with ASC-US and LSIL. In this study, women with LSIL cytology in the period 2005–2008 were included (n = 522). Two triage methods were evaluated in two separate groups: repeat cytology only (n = 225) and HPV mRNA testing in addition to repeat cytology (n = 297). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as the study endpoint.

Results

Of 522 women with LSIL, 207 had biopsies and 125 of them had CIN2+. The sensitivity and specificity of repeat cytology (ASC-US or worse) were 85.7% (95% confidence interval (CI): 72.1, 92.2) and 54.4 % (95% CI: 46.9, 61.9), respectively. The sensitivity and specificity of the HPV mRNA test were 94.2% (95% CI: 88.7, 99.7) and 86.0% (95% CI: 81.5, 90.5), respectively. The PPV of repeat cytology was 38.4% (95% CI: 29.9, 46.9) compared to 67.0% (95% CI: 57.7, 76.4) of the HPV mRNA test.

Conclusion

HPV mRNA testing was more sensitive and specific than repeat cytology in triage of women with LSIL cytology. In addition, the HPV mRNA test showed higher PPV. These data indicate that the HPV mRNA test is a better triage test for women with LSIL than repeat cytology.     

Outcomes of cervical liquid-based cytology suggesting a glandular abnormality

Objective: To ascertain the positive predictive value of both ?glandular neoplasia (national standard code 6) and borderline change (national standard code 8) in glandular cells in liquid‐based cervical cytology specimens in Cardiff and Vale NHS Trust and to outline the histological outcomes of these cases. Method: Eighty‐nine liquid‐based (Surepath?) cervical cytology cases were retrospectively identified from a 2‐year period (January 2005 to December 2006) and correlated with histopathological diagnoses. Results: Initial punch biopsy histology revealed 18 cases (21%) of cervical glandular intraepithelial neoplasia (CGIN). A further nine cases (10%) of CGIN were identified following local excision or hysterectomy. Ten cases of invasive malignancy were identified: four endocervical adenocarcinomas (all node negative, TNM stage T1b1), five endometrial adenocarcinomas and one squamous cell carcinoma. There were 10 with high‐grade cervical intraepithelial neoplasia (CIN) alone. Women diagnosed with endometrial malignancy presented later with an average age of 64.6 years compared with 34.9 years for endocervical lesions. Taking high‐grade CIN or worse as a positive outcome, the overall positive predictive value (PPV) of glandular abnormalities on cytology (both code 6 and 8) was 58.1% [95% confidence interval (CI) 47.8, 68.4]. PPV for borderline change in glandular cells alone was 24.1% (95% CI 8.5, 39.6) and for ?glandular neoplasia alone 75.4% (95% CI 64.3, 86.5). Conclusion: With our interpretation of the classification, women with cytological diagnoses of glandular neoplasia of the cervix should initially be investigated by local resection rather than punch biopsy, and those with borderline change in glandular cells with repeat cytology.     

Primary Screening for Cervical Cancer Based on High-Risk Human Papillomavirus (HPV) Detection and HPV 16 and HPV 18 Genotyping,in Comparison to Cytology

Objectives

The objective of the present study is to assess the performance of a high-risk human papillomavirus (HR-HPV) DNA test with individual HPV-16/HPV-18 genotyping as a method for primary cervical cancer screening compared with liquid-based cytology (LBC) in a population of Greek women taking part in routine cervical cancer screening.

Methods

The study, conducted by the “HEllenic Real life Multicentric cErvical Screening” (HERMES) study group, involved the recruitment of 4,009 women, aged 25–55, who took part in routine cervical screening at nine Gynecology Departments in Greece. At first visit cervical specimens were collected for LBC and HPV testing using the Roche Cobas 4800 system. Women found positive for either cytology or HPV were referred for colposcopy, whereas women negative for both tests will be retested after three years. The study is ongoing and the results of the first screening round are reported herein.

Results

Valid results for cytology and HPV testing were obtained for 3,993 women. The overall prevalence of HR-HPV was 12.7%, of HPV-16 2.7% and of HPV-18 1.4%. Of those referred for colposcopy, cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was detected in 41 women (1.07%). At the threshold of CIN2+, cytology [atypical squamous cells of undetermined significance (ASC-US) or worse] and HPV testing showed a sensitivity of 53.7% and 100% respectively, without change between age groups. Cytology and HPV testing showed specificity of 96.8% and 90.3% respectively, which was increased in older women (≥30) in comparison to younger ones (25–29). Genotyping for HPV16/18 had similar accuracy to cytology for the detection of CIN2+ (sensitivity: 58.5%; specificity 97.5%) as well as for triage to colposcopy (sensitivity: 58.5% vs 53.7% for cytology).

Conclusion

HPV testing has much better sensitivity than cytology to identify high-grade cervical lesions with slightly lower specificity. HPV testing with individual HPV-16/HPV-18 genotyping could represent a more accurate methodology for primary cervical cancer screening in comparison to liquid-based cytology, especially in older women.     

Can human papillomavirus DNA testing of self-collected vaginal samples compare with physician-collected cervical samples and cytology for cervical cancer screening in developing countries?

Background: To determine human papillomavirus (HPV) types by polymerase chain reaction (PCR)-reverse line blot assay and examine the concordance between HPV by Hybrid Capture 2 (HC2) and PCR on self-collected vaginal and physician-collected cervical samples and cytology. Methods: This was a cross-sectional study of 546 sexually active women aged ≥30 years with persistent vaginal discharge, intermenstrual or postcoital bleeding or an unhealthy cervix. Participants self-collected vaginal samples (HPV-S) and physicians collected cervical samples for conventional Pap smear and HPV DNA (HPV-P) testing and performed colposcopy, with directed biopsy, if indicated. HPV testing and genotyping was done by HC2 and PCR reverse line blot assay. Concordance between HC2 and PCR results of self- and physician-collected samples was determined using a Kappa statistic (κ) and Chi-square test. Results: Complete data were available for 512 sets with 98% of women providing a satisfactory self-sample. PCR detected oncogenic HPV in 12.3% of self- and 13.0% of physician-collected samples. Overall, there was 93.8% agreement between physician-collected and self-samples (κ = 76.31%, 95% confidence interval [CI]: 64.97–82.29%, p = 0.04)—complete concordance in 473 cases (57 positive, 416 negative), partial concordance in seven pairs and discordance in 32 pairs. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of self-sampling for detection of cervical intraepithelial neoplasia (CIN)2+ disease were 82.5%, 93.6%, 52.4% and 98.4%, respectively; for physician-sampling they were 87.5%, 93.2%, 52.2% and 98.9%, respectively; and for cytology they were 77.5%, 87.3%, 34.1% and 97.9%, respectively. Concordance between HC2 and PCR was 90.9% for self-samples (κ = 63.7%, 95% CI: 55.2–72.2%) and 95.3% for physician-collected samples (κ = 80.4%, 95% CI: 71.8–89.0%). Conclusions: Self-HPV sampling compares favourably with physician-sampling and cytology. A rapid, affordable, HPV self-test kit can be used as the primary method of cervical cancer screening in low-resource situations.     

Exploratory analysis of quantitative histopathology of cervical intraepithelial neoplasia: objectivity, reproducibility, malignancy-associated changes, and human papillomavirus.

BACKGROUND: As part of a project to evaluate emerging optical technologies for cervical neoplasia, our group is performing quantitative histopathological analyses of biopsy specimens from 1,190 patients. Objectives in the interim analysis are (a) quantitatively assessing progression of the neoplastic process of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesions (SIL), (b) detecting malignancy-associated changes (MACs), and (c) phenotypically measuring human papillomavirus (HPV) detected by DNA testing. METHODS: The diagnostic region of interest (ROI) from immediately adjacent sections were imaged, and the basal lamina and surface of the superficial layer were delimited. Nonoverlapping quantitatively stained nuclei were selected from 1,190 samples with histopathological characteristics of normal (929), koilocytosis (130), CIN 1 (40), CIN 2 (23), and CIN 3/carcinoma in situ (CIS) (68). A fully automatic procedure located and recorded the center of every nucleus in the region of interest (ROI). We used linear discriminant analysis to assess the changes between normal and CIN 3/CIS. RESULTS: Scores computed from the cell-by cell features and the clinical grade of CIN/SIL were highly correlated, as were those of the architectural features and the clinical grade of CIN/SIL. We found even higher correlations between a combination of cell-by-cell and architectural scores, and clinical grade. Using these scores, we found MACs in the normal biopsy specimens from patients with high-grade CIN/SIL. Furthermore, the same scores correlated with the molecular detection of HPV. CONCLUSIONS: Quantitative histopathology can be used in large clinical trials as an objective and reproducible measure of CIN/SIL. Detectable phenotypic changes correlate well with CIN/SIL neoplastic progression. It can also be used to infer the presence of CIN/SIL (MACs) and molecular changes associated with increased risk of cancer development (high-risk HPV).     

Borderline nuclear change,high‐grade dyskaryosis not excluded: current concepts and impact on clinical practice

S. S. Hoo, A. Patel, H. Buist, K. Galaal, J. D. Hemming and R. Naik Borderline nuclear change, high‐grade dyskaryosis not excluded: current concepts and impact on clinical practice Objective: Borderline nuclear change, high‐grade dyskaryosis not excluded (B/HG) is a subcategory of the borderline category recommended by the British Society for Clinical Cytology as warranting direct referral to colposcopy. This subcategory is equivalent to the Bethesda category of atypical squamous cells, cannot exclude high‐grade squamous intraepithelial lesion (ASC‐H). The purpose of this study was to determine the validity and accuracy of using B/HG to identify potential cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+). Methods: Data were collected from the hospital pathology database for borderline, B/HG and high‐grade cytology (moderate dyskaryosis and above), and their respective histological and colposcopic outcomes. SPSS was used for data analysis. Results: Of the 84 799 total cytology samples screened between July 2006 and December 2009, 5225 (6.1%) were reported as borderline, 309 (0.4%) as B/HG and 1222 (1.4%) as high‐grade cytology. Thus, B/HG comprised 5.9% of the overall borderline category, in keeping with national guidelines (<10%). CIN2+ was confirmed in 86.6% of high‐grade, 40.8% of B/HG and 3.0% of borderline cytology. Of 309 women reported with B/HG cytology, 239 had colposcopy. Colposcopic appearances showed a positive predictive value (PPV) of 71.8% for detecting CIN2+ and a negative predictive value of 60.7%. Conclusions: The B/HG category was associated with a significantly higher incidence of CIN2+ compared with borderline cytology as a whole. This refining performance justifies its existence. Colposcopic appearances had a high PPV for detecting CIN2+. Therefore, colposcopy is recommended in patients with B/HG cytology and treatment should be offered if high‐grade colposcopic changes are seen.