Living with uncertainty: Equivocal Pap test results and the evolution of ASC terminology

Communication of equivocal findings and their significance has been a significant challenge related to Pap testing throughout its history. Terminology to report these findings has changed considerably to accommodate the changes in understanding of cervical neoplasia, and to accommodate new management strategies, tests, and technologies. This article reviews the evolution of terminology for equivocal Pap test findings from the original Papanicolaou classification to the current the Bethesda System 2001 atypical squamous cells terminology, the implication and use of these terms, and the changing landscape of cervical neoplasia screening, which prompted these terminology changes. Emerging issues related to improving risk stratification through the introduction of additional terms and the impact of human papillomavirus testing may alter terminology of equivocal findings in the future. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

Role for HPV testing in ASCUS: a cytologic-histologic correlation

Human papilloma virus (HPV) Hybrid Capture II testing was introduced at our institution in mid-April, 2001. Relatively little data exists on the histologic follow-up of "high-risk HPV-positive ASCUS" patients without a previous abnormal Pap result. The results of the cytologic-histologic correlation of 50 patients over an 11-mo period are presented. Our results indicate that significant lesions may be discovered in patients of the "high-risk HPV-positive ASCUS" category who have no previous abnormal Pap history. Of the 50 patients presented in this study, histologic follow-up demonstrated evidence of squamous carcinoma in one patient (2%), high-grade squamous intraepithelial lesion (HSIL) in eight patients (16%), and low-grade squamous intraepithelial lesion (LSIL) in 19 patients (38%). The other 22 (44%) showed chronic cervicitis, reactive changes, or no pathologic changes. These findings suggest a more aggressive clinical approach may be warranted in the management of new onset ASCUS positive for high risk HPV.     

Influence of specimen adequacy on the diagnosis of ASCUS

The impact of specimen adequacy on the diagnosis of cervical cytology is not fully understood. Virtually, the greatest impact of smear quality limitation factors is on the diagnosis of atypical squamous cells of undetermined significance (ASCUS) because this category is more susceptible to interpretation mistake due to its criteria subjectivity. This study aims to evaluate the impact of smear quality impairing factors on the diagnosis of ASCUS. The 1,507 cases of ASCUS studied were obtained from the Cervical Cancer Screening Program of Paraná (CCSPP). The cases were reviewed by expert cytopathologists and the results were correlated to the specimen adequacy. The results showed that the presence of obscuring blood impairs the correct diagnosis and leads the pathologist to overdiagnose negative smears as ASCUS. The presence of adequate endocervical sampling contributes to a higher rate of correct ASCUS diagnoses but did not influence the pathologist to over- or underestimate the cytological findings.     

意义不明确的不典型鳞状细胞中检测高危型HPV的价值

目的探讨在意义不明确的不典型鳞状细胞（ASCUS）中检测HR-HPV,预测宫颈上皮内瘤样病变及浸润癌的诊断价值。方法对宫颈薄层液基细胞学诊断为ASCUS的248例患者分别进行HR-HPV检测、阴道镜下活组织检查。结果在ASCUS患者中,CIN发生率为41.1%（102/248）,高级别CIN（CIN2、CIN3）和浸润癌发生率为9.3%（23/248）;在HR-HPV阳性组CIN检出率为68.1%（92/135）,在HR-HPV阴性组CIN检出率为8.8%（10/113）,两组间差异有统计学意义（χ2=89.330,P〈0.001）。阳性组发生CIN和浸润癌的风险是阴性组的22.037倍[OR（95%CI）=22.037（10.479～46.342）]。HR-HPV检测CIN和浸润癌的敏感度和特异度分别为68.1%和91.2%;阳性预测值和阴性预测分别为90.1%和70.5%。阴道镜拟诊CIN和浸润癌126例,检出率为80.4%（82/102）,其中高级别CIN和浸润癌20例,检出率为87.0%（20/23）;阴道镜检测CIN和浸润癌的敏感度和特异度分别为65.1%和83.6%;阳性预测值和阴性预测分别为80.4%和69.9%,与HR-HPV检测功效相似,关联系数为r=0.833;而阴道镜检测高级别CIN和浸润癌的敏感度和特异度分别为80.0%和98.7%;阳性预测值和阴性预测值分别为87.0%和97.8%。结论 HR-HPV阳性的ASCUS患者CIN发生率高,即行阴道镜检查;HR-HPV阴性患者可不行阴道镜检查而不会增加高级别CIN和浸润癌发生风险。     

阴道镜联合HPV-DNA检测宫颈不典型鳞状细胞患者100例

[目的]探讨宫颈细胞学诊断为性质未定的不典型鳞状细胞（ASCUS）的进一步临床处理的方法。[方法]对100例宫颈细胞学诊断为ASCUS的患者进行高危型HPV检测及阴道镜下多点活检。[结果]100例ASCUS患者中,病理诊断为慢性炎症59例（59%）,CINⅠ25例（25%）,CINⅡ8例（8%）,CINⅢ5例（5%）,鳞癌3例（3%）。HPV阳性34例（34%）,其中CINⅠ以上的28例（82.35%）,HPV阴性66例（66%）其中CINⅠ以上的13例（19.70%）,两者比较有统计学意义（P〈0.05）。[结论]应重视ASCUS患者,高危型HPV-DNAS检测和阴道镜下活检是对ASCUS进一步处理的有效方法。     

Comparison of three management strategies for patients with atypical squamous cells of undetermined significance, after six months delay: A three-year experience in an Iranian university hospital

Background: A Pap test result of atypical squamous cells of undetermined significance (ASCUS) presents a clinical challenge. Only 5–10% of women with ASCUS harbour serious cervical disease.
Methods: We screened 3619 women, who attended to Mirza Koochak Khan Hospital at Tehran University of Medical Sciences with Pap smears, of whom 100 returned with ASCUS. After six months, each subject underwent a standard cytology (conventional Pap smear), human papillomavirus (HPV) DNA testing (identifying high-risk HPV types with polymerase chain reaction) and colposcopy with multiple cervical biopsies.
Results: Mean age was 44.09 ± 8.6 years. The estimated prevalence of cervical intraepithelial neoplasia (CIN) II or higher was 4%. When histologically verified high-grade lesions (≥ CIN II) were observed, the relative sensitivity of HPV DNA testing was 100% compared with conventional Pap smear, which performed 75% versus 100% relative sensitivity, respectively, using cytological diagnosis high-grade squamous intraepithelial lesion, or low-grade squamous intraepithelial lesion (LSIL) as the cut-off. Negative and positive predictive values (NPV and PPV) of Pap test were 98.9% and 100%. The NPV and PPV of HPV DNA testing were 100%.
Conclusions: Although less complicated than colposcopy, the repeat Pap smear triage algorithm for ASCUS may underdiagnose some women with high-grade CIN, when compared with colposcopy. Considering the high sensitivity of HPV testing, it may be useful as an alternative to the current policy of six-month repeat cytology for women with ASCUS results.     

Distribution of human papillomavirus genotypes in women with cervical alterations from north Argentina

Background: Cervical cancer remains a major public health problem in northern Argentina, showing the highest mortality rate in the country (approximately 22 cases/100000 women). Objective: The aim of this study was to provide epidemiological data on the prevalence and type distribution of human papillomavirus (HPV) in women with pre-neoplastic lesions before the massive introduction of HPV vaccination in the country. Materials and Methods: Exfoliated cervical cells were collected to screen for HPV using the widely known MY09/11 PCR, followed by the restriction fragment-length polymorphism (RFLP) technique from a total of 714 women with previously diagnosed atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LG-SIL) and high-grade squamous intraepithelial lesion (HG-SIL). Results: Overall HPV prevalence was 48.2% in ASCUS (24 different HPV types detected), 66.5% in LG-SIL (37 HPV types detected) and 82.6% in HG-SIL (16 HPV types detected). HPV-16 was the most prevalent type among all cases. With respect to multiple HPV infections, 9.6% were observed in ASCUS, 14.3% in LG-SIL and 11.4% in HG-SIL. Conclusion: The major strength of our study is the assessment of a large series of women with cytological alterations in this region. The information attained will be useful as a regional baseline for future epidemiological vigilance, in the context of the national HPV vaccination program.     

意义不明的非典型鳞状细胞的临床诊断价值

目的:评价意义不明的非典型鳞状细胞(ASCUS)的临床诊断价值。方法:利用新柏氏细胞学检查(TCT)技术筛查2005年8月~2007年8月在该院妇科门诊就诊的9 751例病人。结果:共筛查出ASCUS 267例(2.74%)。其中一年后二次复查66例,结果为子宫颈上皮内高度病变(HSIL)1例(1.52%),子宫颈上皮内低度病变(LSIL)20例(30.30%),LSIL伴HPV感染2例(3.03%),仍为ASCUS 12例(18.18%),炎症反应性细胞改变31例(46.97%)。结论:ASCUS存在子宫颈上皮内瘤变的危险,应注意随访。     

Long‐term HPV type‐specific risks for ASCUS and LSIL: A 14‐year follow‐up of a randomized primary HPV screening trial

Human papillomavirus (HPV) infections result in a significant burden of low‐grade cervical lesions. Between 1997 and 2000, our randomized trial of primary HPV screening enrolled 12,527 women participating in population‐based screening. Women between 32 and 38 years of age (median: 34, interquartile range: 33–37) were randomized to HPV and cytology double testing (intervention arm, n = 6,257 enrolled, n = 5,888 followed‐up) or to cytology, with samples frozen for future HPV testing (control arm, n = 6,270 enrolled, n = 5,795 followed‐up). We estimated the HPV type‐specific, long‐term absolute risks (AR), and population attributable proportions (PAR) for cytological diagnoses of atypical squamous cells of undetermined significance (ASCUS) or low‐grade squamous intraepithelial lesion (LSIL) and for histopathologically diagnosed cervical intraepithelial neoplasia grade 1 (CIN1). The women were followed using comprehensive, nationwide register‐based follow‐up. During a mean follow‐up time of 11.07 years, 886 ASCUS and LSIL lesions were detected, 448 in the intervention arm and 438 in the control arm. Poisson regression estimated the incidence rate ratios (IRRs) of low‐grade lesions by HPV type. The IRRs were strongly dependent on follow‐up time. The IRRs for ASCUS/LSIL associated with high‐risk HPV positivity were 18.6 (95% CI: 14.9–23.4) during the first screening round, 4.1 (95% CI: 2.8–6.2) during the second, 2.6 (95% CI: 1.7–4.1) during the third, and 1.1 (95% CI: 0.7–1.8) for >9 years of follow‐up, with similar declines seen for the individual types. Type 16 contributed consistently to the greatest proportion of ASCUS, LSIL, and CIN1 risk in the population (first screening round PAR: ASCUS: 15.5% (95% CI: 9.7–21.9), LSIL: 14.7% (95% CI: 8.0–20.9), and CIN1: 13.4% (95% CI: 3.2–22.5)), followed by type 31 [8.4% (95% CI: 4.2–12.5) for ASCUS to 17.3% (95% CI: 6.8–26.6) for CIN1]. In summary, most ASCUS/LSIL lesions associated with HPV infection are caused by new HPV infections and most lesions are found during the first screening round.