Pathology correlates of a Papanicolaou diagnosis of low‐grade squamous intraepithelial lesion,cannot exclude high‐grade squamous intraepithelial lesion

BACKGROUND.

The objective of this study was to compare findings after a cytologic report of low‐grade squamous intraepithelial lesion, cannot exclude high‐grade squamous intraepithelial lesion (LSIL‐H) with findings after a report of low‐grade squamous intraepithelial lesion (LSIL).

METHODS.

A review of patient records revealed that 312 women had cytologic findings of LSIL‐H, and 324 consecutive women in a comparison group had cytologic findings of LSIL during 2005. Findings over 6 months after diagnosis were retrieved and analyzed using chi‐square tests, Fisher exact tests, and independent group t tests.

RESULTS.

Histology was available for 194 of 312 women (64%) with LSIL‐H and for 184 of 324 women (57%) with LSIL. Of these, 47 of 194 women (24%) with LSIL‐H had grade 2 cervical intraepithelial neoplasia or greater (CIN2+) versus 13 of 184 women (7%) with LSIL (P < .0001). No cancers were identified. High‐grade SIL cytology was reported in 2 of 105 women who had LSIL (2%) and in 4 of 93 women who had LSIL‐H (4%). Women with LSIL‐H who were positive for CIN2+ were younger than those without CIN2+ (25 years vs 30 years; P = .0067)

CONCLUSIONS.

Clinicians whose laboratories report LSIL‐H should manage women who have LSIL‐H with colposcopy, whereas only serial cytologic surveillance is required after a report of LSIL. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

Should LSIL‐H be a distinct cytology category?

BACKGROUND:

The 2001 Bethesda System for gynecologic cervical cytology reporting classifies squamous intraepithelial lesions into low‐grade (LSIL) and high‐grade (HSIL) lesions. An intermediate term, “low‐grade squamous intraepithelial lesion, cannot exclude high‐grade squamous intraepithelial lesion (LSIL‐H),” has been used in a small percentage of LSIL cases. To the authors' knowledge, little is known regarding the human papillomavirus (HPV) status in patients with LSIL‐H.

METHODS:

A total of 808 SurePath specimens obtained between December 2009 and April 2011 were tested for 40 HPV genotypes using DNA microarray, followed by a confirmatory DNA sequencing assay.

RESULTS:

The infection rate for high‐risk HPV in women with LSIL‐H (92%) was strikingly close to that for women with HSIL (91%), which was higher than that for those with LSIL (74%); atypical squamous cells, cannot rule out high‐grade lesion (ASC‐H) (78%); or LSIL and ASC‐H combined (74%). HPV type 16, the most common carcinogenic HPV genotype, was detected in 36% of women with LSIL‐H, which was significantly higher than that in women with LSIL and ASC‐H combined (13.8%), but less than that in women with HSIL (44.6%). Patients with LSIL‐H and HSIL had similar infection rates for low‐risk/intermediate‐risk HPV genotypes, which were lower than those in LSIL or LSIL and ASC‐H combined.

CONCLUSIONS:

Women found to have LSIL‐H on a Papanicolaou test appear to have a unique HPV distribution pattern that clearly differs from LSIL and is comparable to that for HSIL, suggesting an increased risk of high‐grade lesions over that of women with LSIL. Recognizing LSIL‐H as an independent diagnostic category may help in the early identification of the high‐risk subgroup that may require a management algorithm comparable to that for patients with HSIL. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.     

Atypical squamous cells,cannot exclude a high‐grade intraepithelial lesion and its clinical significance in postmenopausal,pregnant, postpartum,and contraceptive‐use patients

BACKGROUND.

Previous studies have confirmed the low predictive value of a diagnosis of atypical squamous cells, cannot exclude a high‐grade squamous intraepithelial lesion (ASC‐H) in a Papanicolaou (Pap) smear for subsequent high‐grade dysplasia in the postmenopausal age group. It appears plausible that the decrease in estrogen inherent in the postmenopausal state likely produces reactive cytologic atypia, which is misinterpreted as ASC‐H. The change in hormone levels observed in pregnant patients, postpartum patients, and contraceptive users, as a corollary, potentially could create a similar diagnostic dilemma. In the current study, the impact of age and altered hormone status on the frequency of ASC‐H was assessed to answer the following questions: Is the low predictive value of ASC‐H in postmenopausal women an age‐related phenomenon, and do other states that result in decreased levels of estrogen relative to progesterone have a similar association?

METHODS.

Pap smears that were diagnosed as ASC‐H were divided into postmenopausal, pregnant, postpartum, and contraceptive‐use categories. Each Pap smear slide was reviewed to assess the degree of atrophy and the character of atypical cells. The frequency of high‐grade follow‐up (histology and/or Digene Hybrid Capture II) in the postmenopausal group was compared with the frequency of high‐grade follow‐up in the pregnant, postpartum, and contraceptive‐use categories using the chi‐square test. The pregnant, postpartum, and contraceptive‐use categories also were compared statistically among each other with the chi‐square test.

RESULTS.

In total, 195 cases met the criteria for study inclusion. The percentage of patients who had subsequent high‐grade follow‐up was 22.5% in the postmenopausal group, 79.6% in the pregnant group, 66.7% in the postpartum group, and 60% in the contraceptive‐use group. When these data were subjected to the chi‐square test, there was a statistically significant difference (P<.0001) between the predictive value of subsequent high‐grade follow‐up in the postmenopausal group compared with the other patient groups. When the chi‐square test was applied to the intercomparison of the pregnant, postpartum, and contraceptive‐use categories, there were no significant differences (P > .05) in high‐grade follow‐up between any of these groups.

CONCLUSIONS.

The diagnosis of ASC‐H in postmenopausal Pap smears has a low predictive value in the subsequent diagnosis of high‐grade squamous lesions in stark contrast to the pregnant, postpartum, and contraceptive‐use categories. This suggests that age rather than hormone alterations affects the capacity of ASC‐H to predict subsequent high‐grade squamous intraepithelial lesions. In addition, there are no definite cytomorphologic criteria that can be used to distinguish reliably between benign cellular changes and possible high‐grade squamous lesions in these Pap smears. Digene Hybrid Capture II testing, although helpful, does not have 100% correlation with subsequent tissue/Pap smear follow‐up and cannot be used alone to triage this group of women for colposcopy. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

Papanicolaou test interpretations of “atypical squamous cells,cannot exclude high‐grade squamous intraepithelial lesion”

BACKGROUND.

Management guidelines for women with Papanicolaou (Pap) test interpretations of ASC‐H (atypical squamous cells, cannot exclude high‐grade squamous intraepithelial lesion) reflect substantial risk, which ranges from 10% to 68%, of a cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in their follow‐up histologic samples. The present study was initiated to determine the number of colposcopic procedures and the time frame that are typically required for a definitive diagnosis of a CIN2+ lesion after a Papanicolaou (Pap) test interpretation of ASC‐H in routine practice.

METHODS.

Clinicopathologic data on consecutive ASC‐H interpretations, 97% of which were on liquid‐based preparations, were reviewed. The number of biopsies (which was used in this context as a surrogate indicator for the number of colposcopic procedures) as well as the average duration required for a follow‐up histologic diagnosis of CIN2+ were determined.

RESULTS.

Of 500 ASC‐H interpretations, 75 were excluded for a variety of reasons and 165 lacked follow‐up in our records. The average age and follow‐up duration for the remaining 260 patients was 35.6 years and 18.5 months, respectively. CIN2+ was diagnosed in 49 (40%) of the 122 patients with at least 1 histologic follow‐up. Of these 49 patients, 72% (35 of 49) were diagnosed on the first follow‐up cervical biopsy, 14% (7 of 49) and 8% (4 of 49) were diagnosed on the second and third follow‐up biopsies, respectively; in only 6% (3 of 49) was a fourth follow‐up biopsy required. Overall, an average of 1.53 biopsies (range, 1–4) was required to attain a definitive diagnosis of CIN2+, and 28% of patients required more than 1 follow‐up biopsy. The average period between the index ASC‐H interpretations and CIN2+ diagnoses was 5.5 months. The average time to CIN2+ diagnoses by the first follow‐up biopsy was 3 months; for diagnoses made on subsequent biopsies, the average additional follow‐up duration was 8 months. Of the eventual CIN2+ diagnoses, 84% were rendered within 12 months of their associated index ASC‐H interpretations.

CONCLUSIONS.

1) A substantial subset—28%—of patients with biopsy‐proven CIN2+ after ASC‐H interpretations required more than 1 colposcopy for a definitive diagnosis of a high‐grade dysplastic lesion. 2) If a CIN2+ lesion is present, the vast majority can be diagnosed in a biopsy performed within 1 year of the ASC‐H interpretation. Cancer (Cancer Cytopathol) 2007. © Published 2007 by the American Cancer Society.     

宫颈细胞学诊断低度鳞状上皮内病变不除外高度鳞状上皮内病变的临床意义

目的:对宫颈细胞学诊断为低度鳞状上皮内病变不除外高度鳞状上皮内病变(low-grade squamous intraepithelial lesion,cannot exclude high-grade squamous intraepithelial lesion,LSIL-H)与TBS-2001系统中的LSIL、非典型鳞状细胞不除外高度病变(atypical squamous cells,cannot rule out a high grade lesion,ASC-H)和高度鳞状上皮内病变(high-grade squamous intraepithelial lesion,HSIL)的组织病理学结果进行比较,评估LSIL-H的临床风险。方法:对细胞学诊断异常标本即未明确意义的非典型鳞状上皮细胞(atypical squamous cells of undetermined significance,ASC-US)、LSIL、ASC-H和HSIL,采用盲法重新进行回顾性诊断,分级为ASC-US、LSIL、LSIL-H、ASC-H和HSIL。同时追踪组织病理学诊断结果,并分析高危型人乳头瘤病毒(highrisk-HPV)阳性率。结果:总共49000例被纳入分析。重新诊断后,LSIL-H有88例(88/49000,0.17%)。重新分级诊断前,LSIL-H在各异常分级中所占的比例分别为:ASC-US为19.32%(17/88)、LSIL为43.18%(38/88)、ASC-H为34.09%(30/88)、HSIL为3.41%(3/88)。LSIL-H罹患高度病变CIN2/3的概率要高于LSIL,两者相比差异有统计学意义(P<0.01),但均低于HSIL(P<0.01)。LSIL-H与ASC-H的CIN2/3患病率相当(分别为39.47%和38.46%),差异无统计学意义。结论:LSIL-H组织病理学结果证实,其与高度病变之间的关系与ASC-H相近,建议采用与ASC-H同样的方法对这类患者进行临床管理。     

The role of human papillomavirus type 16/18 genotyping in predicting high‐grade cervical/vaginal intraepithelial neoplasm in women with mildly abnormal Papanicolaou results

BACKGROUND:

The authors compared the predictive value of type 16 and/or 18 human papillomavirus (HPV) versus non‐16/18 HPV types for high‐grade (grade ≥2) cervical neoplasm/vaginal intraepithelial neoplasm and carcinoma (CIN/VAIN2+) in women with mildly abnormal Papanicolaou (Pap) results (ie, atypical squamous cells of undetermined significance [ASCUS] or low‐grade squamous epithelial lesion [LSIL]).

METHODS:

The authors retrospectively selected Pap specimens with HPV testing results obtained from 243 women (155 with ASCUS and 88 with LSIL Pap results) in their Department of Pathology. HPV genotyping was performed using the EasyChip HPV blot assay. The Pap specimens with HPV16/18 and non‐16/18 HPV types were compared with follow‐up biopsy results. Follow‐up duration ranged from 1 month to 58 months (mean, 26 months).

RESULTS:

In total, 58 of 155 specimens (37%) that had ASCUS and 29 of 88 specimens (33%) that had LSIL were positive for HPV16/18. CIN/VAIN2+ biopsies were identified in 43 of 155 women (28%) with ASCUS and in 28 of 88 women (32%) with LSIL. Women with ASCUS and HPV16/18 had a significantly higher rate (43%) of CIN/VAIN2+ than women with ASCUS and non‐16/18 HPV types (19%; P = .003; odds ratio, 3.10; 95% confidence interval, 1.48‐6.53). There was no statistically significant difference in the rate of CIN/VAIN2+ between women who had LSIL and HPV16/18 (45%) and those who had LSIL and non‐16/18 HPV types (29%; P = .16; odds ratio, 1.96; 95% confidence interval, 0.77‐4.97).

CONCLUSIONS:

HPV genotyping for HPV16/18 improved risk assessment for women with ASCUS Pap results and may be used to predict the risk of CIN/VAIN2+ to better guide follow‐up management. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.     

Use of high-risk human papillomavirus testing in patients with low-grade squamous intraepithelial lesions

BACKGROUND

The role of testing for high‐risk human papillomavirus (HR HPV) when triaging women with a cytologic diagnosis of low‐grade squamous intraepithelial lesion (LSIL) has not been well established. The objective of the current study was to correlate the status of HR HPV with the incidence of cervical intraepithelial neoplasia 2 and more severe lesions (CIN 2+) on tissue follow‐up in women with LSIL.

METHODS

A total of 1046 women with LSIL and HR HPV testing were identified in the database of a large teaching hospital within a 12‐month period. HR HPV testing was performed using the Hybrid Capture 2 assay with 1 relative light unit/cutoff as the cutoff.

RESULTS

Of the 1046 women with LSIL and concurrent HR HPV testing, 82.3% tested positive for HR HPV, 91.1% of whom were women aged < 30 years and 73% of whom were women aged ≥ 30 years (P < .001). Cytologic and/or histologic follow‐up was available in 979 (93.6%) women; 25.5% had negative follow‐up, 62.5% were found to have CIN 1 lesions, and 12.0% had CIN 2+ lesions. The sensitivity and negative predictive value of HR HPV status as a marker of CIN 2+ lesions were 98.3% and 98.9%, respectively. The colposcopy rate was 73.3% and 96.9% for women aged ≥ 30 years and women aged < 30 years, respectively (P = .01).

CONCLUSIONS

Using 1 RLU/CO as the cutoff value, HR HPV testing was found to be highly sensitive for detecting CIN 2+ lesions in women with LSIL. The colposcopy rate was significantly lower in women aged ≥ 30 years compared with women aged < 30 years. Triaging with HR HPV testing may be indicated in women aged ≥ 30 years with LSIL cytology, but not in women aged < 30 years. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

Evaluation of p16INK4a/Ki‐67 dual stain in comparison with an mRNA human papillomavirus test on liquid‐based cytology samples with low‐grade squamous intraepithelial lesion

BACKGROUND:

The objective of the current study was to investigate the clinical performance of detecting high‐grade lesions with the CINtec PLUS p16^INK4a/Ki‐67 dual stain and the APTIMA human papillomavirus (HPV) Assay in a cohort of women with low‐grade squamous intraepithelial lesion (LSIL) cytology. The authors also assessed the reproducibility of the evaluation of immunocytochemical staining.

METHODS:

The 2 tests were performed on liquid‐based residual material from 469 women with LSILs. The samples had at least 5 years of follow‐up and the gold standard used was high‐grade cervical intraepithelial neoplasia (CIN2+/CIN3+) proven on histology.

RESULTS:

Approximately 69% of all the women included in the study had a positive test for HPV mRNA and 56% was positive for the dual stain. The 2 tests demonstrated high sensitivities. When examining the specificities, the APTIMA HPV Assay performed with significantly lower values than the CINtec PLUS test. For patients with CIN2+, the APTIMA HPV Assay had a specificity of 36.1% versus 51.3% for the CINtec PLUS test, and for women with CIN3+, the specificity was 33.8% versus 48.2%, respectively. The difference was even more pronounced when analyzing women aged < 30 years separately. The kappa values between the 3 observers in scoring the dual stain ranged from 0.43 to 0.49 and improved in a second evaluation round to values ranging from 0.50 to 0.66.

CONCLUSIONS:

The CINtec PLUS p16^INK4a/Ki‐67 dual‐staining test in LSIL cytology samples demonstrated high sensitivity that was similar to that of the APTIMA HPV Assay in the detection of underlying high‐grade disease but with enhanced specificity, especially among women aged < 30 years. The kappa value for the evaluation of the CINtec PLUS dual‐staining test was moderate but could be improved through training. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.     

The role of deeper levels and ancillary studies (p16Ink4a and ProExC) in reducing the discordance rate of Papanicolaou findings of high‐grade squamous intraepithelial lesion and follow‐up cervical biopsies

BACKGROUND:

Discordant results of cervical biopsy histology after a cytologic diagnosis of high‐grade squamous intraepithelial lesion (HSIL) are often attributed to sampling variation. The purpose of the current study was to determine whether deeper levels and ancillary staining (p16^Ink4a and ProExC) reduce the discordant rate.

METHODS:

A total of 246 cases of HSIL were retrieved from the computerized database from 2005 and 2006. Of these cases, 151 were followed by cervical biopsy. There was cytologic‐histologic correlation in 87 cases, as defined by the presence of high‐grade (2 or 3) cervical intraepithelial neoplasia (HGCIN). For each discordant biopsy (n = 64), 2 deeper levels for hematoxylin and eosin (H&E) were taken at 30‐μ and 90‐μ depths, and 4 sections for p16^Ink4a and ProExC staining were taken at a 60‐μ depth. All cytologic and histologic material from these 64 cases was reviewed by 3 cytopathologists. In 2 cases, the original HSIL diagnoses were downgraded and the cases censored from the study.

RESULTS:

Fifty‐seven of the 62 discordant cases had sufficient tissue for deeper levels and ancillary staining. Two of 57 cases were reclassified to HGCIN. In both of these cases, reclassification was suggested by results of immunostains; however, the H&E sections were necessary for definitive interpretation of the immunostain results.

CONCLUSIONS:

In the current study, deeper levels and ancillary staining with p16^Ink4a and ProExC did not significantly reduce the discordance rate. Although there are many known causes of sampling variation, including factors related to colposcopic technique, regression of infection, and insufficient histologic sectioning, sampling variation remains a valid justification of noncorrelation in women with HSIL followed up by cervical biopsy alone. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Visual inspection with acetic acid for detection of high grade lesion in atypical squamous cells and low grade squamous intraepithelial lesions from cervical Pap smear

Objective

To evaluate the value of visual inspection with acetic acid (VIA) test to detect high grade lesion in women with atypical squamous cells or low grade squamous intraepithelial lesions cervical cytology.

Methods

Women with atypical squamous cells or low grade squamous intraepithelial lesions who were scheduled to undergo colposcopy at Vajira Hospital and met inclusion criteria were included. All participants underwent VIA test prior to usual steps of colposcopy. The VIA results were interpreted as positive or negative using the criteria by the International Agency for Cancer Research. The standard colposcopic examination and appropriate investigations for cervical pathology were then continued. The diagnostic values of VIA test including sensitivity, specificity, positive predictive value, and negative predictive value were determined using high grade lesion including cervical intraepithelial neoplasia 2-3 and squamous cell carcinoma as a threshold.

Results

Total of 106 women was included. The VIA test was positive in 33 women (31.1%) and negative in 73 women (68.9%). Among the women with VIA test positive, 14 had high grade lesion (42.4%) while 19 had no significant lesions. Only 2/73 (2.7%) cases with negative VIA test had high grade lesion (both had cervical intraepithelial neoplasia 2). The sensitivity, specificity, positive predictive value and negative predictive value with 95% confidence interval were 87.5% (81.2 to 93.8%), 78.8% (71.1 to 86.7%), 42.4% (33.0 to 51.8%), and 97.2% (94.2 to 1.0%) respectively.

Conclusion

VIA as the intermediate test in atypical squamous cells and low grade squamous intraepithelial lesions cytology may reduce the necessity to refer some women for colposcopy.     

Comparison of ProEx C with p16INK4a and Ki‐67 immunohistochemical staining of cell blocks prepared from residual liquid‐based cervicovaginal material

BACKGROUND.

Although liquid‐based cervicovaginal cytology has high sensitivity for detecting dysplastic/malignant lesions, many pitfalls exist. Cell blocks can be prepared from residual liquid‐based cervicovaginal material and used for immunohistochemistry. The aim of this study was to evaluate a new marker, ProEx C, on cell blocks and its ability to distinguish dysplastic/malignant lesions from morphologically abnormal but benign cells. The results of this study were compared with previously reported results for p16 and Ki‐67 on the same material.

METHODS.

ProEx C is a cocktail of monoclonal antibodies against proteins associated with aberrant S phase cell cycle induction (topoisomerase IIA, minichromosome maintenance protein 2). ThinPrep (CytycCorp., Boxborough, Mass) cervicovaginal specimens from 79 patients were selected. Four cases had no residual abnormal cells in the cell block. On the basis of the cell block diagnosis, 29 cases were negative for intraepithelial lesion or malignancy (NILM), 27 had low‐grade squamous intraepithelial lesions (LSIL), 16 had high‐grade squamous intraepithelial lesions (HSIL), and 3 had squamous cell carcinomas (SCC). Cell block sections were immunostained with ProEx C.

RESULTS.

Thirteen of 16 (81%) cases of HSIL stained positively with ProEx C. Two of 27 (7%) LSIL stained positively, and 2 (7%) cases of NILM stained positively. All 3 cases of SCC were strongly positive (100%). Staining for ProEx C showed a higher positive predictive value compared with p16.

CONCLUSIONS.

ProEx C can be used on cell blocks prepared from residual liquid‐based cervicovaginal cytologic specimens. Being a nuclear only stain, it is cleaner and easier to interpret even in scant specimens. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

Reflex Human Papillomavirus Test Results as an Option for the Management of Korean Women With Atypical Squamous Cells Cannot Exclude High‐Grade Squamous Intraepithelial Lesion

Background.

Current guidelines recommend initial colposcopy with biopsy regardless of human papillomavirus (HPV) test results in women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). The purpose of this study was to evaluate the value of HPV testing in women with ASC-H based on colposcopic pathology results.

Materials and Methods.

A multicenter cross-sectional study was carried out at three academic hospitals and involved 40,847 Korean women who underwent cervical cancer screening with cytology and HPV tests with or without subsequent colposcopic biopsies between January 2007 and December 2013.

Results.

ASC-H was diagnosed in 276 women (0.7%). Only 6 of 68 (8.8%) women with ASC-H who were HPV negative had cervical intraepithelial neoplasia grade ≥2 (CIN ≥2) lesions, whereas 47.4% of the women with ASC-H who were HPV positive had CIN ≥2 lesions. No cases of invasive cervical cancer were diagnosed among women with ASC-H who were HPV negative. Logistic regression analysis was performed using the group with normal Papanicolaou test results and HPV-negative status as the reference group. Women with ASC-H who were HPV positive had a significantly increased risk of CIN ≥2 lesions, whereas no significant increase was observed in patients with ASC-H and HPV-negative status.

Conclusion.

If the result of the HPV test was negative, the risk of CIN ≥2 lesions in Korean women with ASC-H cytology was low. Reflex HPV testing should be an option for the management of women with cytology showing ASC-H to decrease unnecessary colposcopic biopsies, which are expensive and invasive.

Implications for Practice:

Current American Society for Colposcopy and Cervical Pathology guidelines recommend universal colposcopy for the management of women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) on cytology, regardless of human papillomavirus (HPV) test results. The present study suggested that HPV cotesting in patients with ASC-H cytology can provide more detailed and useful information regarding the risk of high-grade cervical intraepithelial neoplasia (CIN) lesions and the need for further treatment. When the result of the HPV test was negative, the risk of CIN lesions of grade ≥2 in women with ASC-H cytology was low. Consequently, reflex HPV testing, rather than immediately performance of invasive and expensive colposcopy with biopsy, should be an option for the management of women with ASC-H.     

The significance of high‐risk human papillomavirus detection in women aged ≥ 50 years with atypical squamous cells of undetermined significance cytologic preparations

BACKGROUND.

The use of high‐risk human papillomavirus (HRHPV) testing in the triage of women with a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC‐US) has gained widespread acceptance. To date, very little has been reported on the significance of the detection of HRHPV in elderly women.

METHODS.

Results of HRHPV testing performed on women aged ≥50 years were examined for a 20‐month period. Reflex testing for HRHPV was performed on residual liquid‐based cytology specimens from women who were diagnosed with ASC‐US by using the Digene Hybrid Capture method. Follow‐up information on women who had HRHPV detected was obtained from subsequent pathology reports (cytology and surgical).

RESULTS.

HRHPV testing was performed on 762 specimens from women aged ≥50 years; virus was detected in 105 specimens (13.8%), and follow‐up was available in 63 of those women (60%). Follow‐up results included negative tests in 32 women (50.8% of those with follow‐up available), low‐grade squamous intraepithelial lesion in 26 women (41.3%), and high‐grade squamous intraepithelial lesion (HSIL) in 5 women (7.9%). No glandular neoplasia or invasive carcinoma was identified. Relative light units/cutoff (RLU/CO) values ranged from 1 RLU/CO to 1705 RLU/CO; no significant associations were identified between RLU/CO values and follow‐up results.

CONCLUSIONS.

Although HRHPV was detected in a minority of samples, HSIL was present in 7.9% of those with HRHPV. This confirms that the presence of HRHPV in women aged ≥50 years with ASC‐US specimens needs clinical follow‐up. There were no significant differences in RLU/CO values between women with positive versus negative follow‐up to allow for further discrimination for follow‐up. Cancer (Cancer Cytopathol) 2007. Published 2007 by the American Cancer Society.     

Implementation of the Thinprep imaging system in a tertiary military medical center

BACKGROUND:

The ThinPrep Imaging System (TIS) was implemented at Brooke Army Medical Center (BAMC) in February 2006 and has been a crucial part of the ability of the Department of Pathology and Laboratory Services ability to improve efficiency and turnaround times for Papanicolaou (Pap) test reporting. The increased detection rate of squamous abnormalities, specifically high‐grade squamous intraepithelial lesions (HSIL), has been well documented by many studies. In addition, the TIS has increased productivity for many laboratories. The objective of this study was to evaluate the effects of implementing the TIS at BAMC, a tertiary military medical center. Specifically, the following were assessed: 1) whether the detection of squamous abnormalities was increased with the TIS, 2) how the rate of high‐risk human papillomavirus (HR‐HPV) detection in atypical squamous cells (ASC) of undetermined significance (ASC‐US) cases changed (or did not change) before and after implementation of the TIS, and 3) how the TIS influenced productivity.

METHODS:

All gynecologic cytology at BAMC has been collected and processed using the ThinPrep system since 2002. Before February 2006 and before implementation of the TIS, Pap tests were screened manually by the cytotechnologists. Detection rates of squamous abnormalities were compared between the period from February 2005 to December 2005 (manual screening) and the period from February 2006 to December 2006 (image‐assisted screening). Squamous abnormalities included ASC‐US; ASC, cannot rule out HSIL (ASC‐H); low‐grade squamous intraepithelial lesion (LSIL); HSIL; glandular abnormalities; and malignancies (squamous or glandular). In addition, the rates of HR‐HPV‐positive, HR‐HPV‐negative, and HR‐HPV‐quantity not sufficient were compared for the same periods. During both periods, testing for HR‐HPV was performed only on ASC‐US Pap tests. HR‐HPV was tested with Digene Hybrid Capture 2 methodology. Productivity was calculated as the change in average slides screened per hour before and after imager implementation.

RESULTS:

In total, 107,647 Pap tests were analyzed in the 2005 (54,438 Pap tests) and 2006 (53,209 Pap tests) timeframes. Increases in the detection of ASC‐H, atypical glandular cells (AGC), LSIL, and HSIL were statistically significant. The proportion of negative for intraepithelial lesion or malignancy (NILM) and unsatisfactory cases decreased significantly with implementation of the TIS. The ASC to squamous intraepithelial lesion (ASC:SIL) ratio decreased from 1.5 to 1.0 after TIS implementation. Decreases in the ASC‐US HR‐HPV‐positive proportion and increases in the ASC‐US HR‐HPV‐negative proportion after implementation of the TIS were statistically significant. In our laboratory, a 60% increase in productivity was noted with use of the TIS.

CONCLUSIONS:

Implementation of the TIS at BAMC significantly increased the detection of ASC‐H, AGC, LSIL, and HSIL but had no significant impact on the ASC‐US detection rate. Although the ASC‐US rate did not change, both the HR‐HPV‐positive rate and the ASC:SIL ratio decreased. The data from the current study suggested that, at least initially, the use of imager‐directed screening may increase the number of clinically insignificant ASC‐US Pap tests. Cancer (Cancer Cytopathol) 2009. Published 2009 by the American Cancer Society.     

Histopathologic follow-up and human papillomavirus DNA test results in 290 patients with high-grade squamous intraepithelial lesion Papanicolaou test results

BACKGROUND:

The study documents histopathologic outcomes and high‐risk (hr) human papillomavirus (HPV) test results in a large cohort of patients with high‐grade squamous intraepithelial lesion (HSIL) liquid‐based cytology (LBC) Pap test results.

METHODS:

A total of 352 patients with HSIL results (338 cervical and 14 vaginal) who had hrHPV testing and 290 patients with biopsy follow‐up were studied. hrHPV detection rates were compared at different ages, with or without an endocervical/transformation zone sample (EC/TZS), and for cervical and vaginal HSIL Pap smears. Histopathologic follow‐up findings were also compared. hrHPV‐negative HSIL slides were re‐evaluated in a blinded manner.

RESULTS:

A total of 325 of 338 (96.2%) cervical HSIL and 12 of 14 (87.5%) vaginal HSIL tested hrHPV‐positive. A total of 271 of 281 (96.4%) EC/TZS‐positive cervical HSIL and 54 of 57 (94.7%) EC/TZS‐negative cervical HSIL tested hrHPV‐positive. The percentage of hrHPV‐positive HSIL declined slightly with increasing age. 197 of 273 (72.3%) hrHPV‐positive cervical HSIL had histopathologic cervical intraepithelial neoplasia (CIN) 2/3+ follow‐up, including 8 squamous carcinomas, compared with 4 of 12 (33.3%) hrHPV‐negative HSIL with CIN2/3 (no carcinomas). 167 of 241 (69.2%) EC/TZS‐positive HSIL had CIN2/3+ follow‐up, compared with 34 of 44 (77.3%) EC/TZS‐negative HSIL. Equivocal HSIL morphology characterized some HPV‐negative HSIL without CIN2/3+ follow‐up.

CONCLUSIONS:

hrHPV was detected in LBC vials from 96.2% of 338 cervical HSIL and 85.7% of 14 vaginal HSIL. CIN2/3+ was significantly more likely with hrHPV‐positive cervical HSIL than with hrHPV‐negative cervical HSIL. Presence or absence of an EC/TZS did not significantly impact HSIL hrHPV or CIN2/3+ rates. Some hrHPV‐negative HSIL cases may represent HSIL cytologic mimics. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

Accuracy of liquid‐based cytology

BACKGROUND:

In the New Technologies for Cervical Cancer Screening (NTCC) randomized controlled trial, no significant increase in the sensitivity of liquid‐based cytology (LBC) was observed compared with conventional cytology. Both were interpreted by cytologists who had limited previous LBC experience. The objective of the current study was to assess whether different results could be expected with experienced LBC interpreters.

METHODS:

A stratified, random sample of 818 LBC slides from the NTCC study was obtained. These slides were reviewed blindly and independently by 3 international experts who did not participate in the NTCC. The sensitivity and specificity of external experts were estimated for cervical intraepithelial neoplasia grade 2 or greater (CIN2+) and for CIN3+ histology, and the differences were compared with the sensitivity and specificity of the original cytologic interpretation using cutoffs of atypical squamous cells of undetermined significance (ASCUS) and low‐grade squamous intraepithelial lesion (LSIL).

RESULTS:

With the endpoint of CIN2+ histology, the difference in sensitivity between external experts and the original interpretation was ?5.3 (95% confidence interval [CI], ?16.0 to 5.4) with ASCUS as the cutoff and 3.8 (95% CI, ?8.2 to 15.8) with LSIL as the cutoff. External experts had slightly lower specificity using ASCUS as the cutoff (?3.4; 95% CI, ?3.9 to ?2.9) and LSIL as the cutoff (?0.7; 95% CI, ?1.0 to ?0.4).

CONCLUSIONS:

The accuracy of the external experts' interpretation was similar to that of the original interpretation. Therefore, the current results indicated that LBC is not expected to increase sensitivity even if it is used by interpreters who have extensive experience with this technique. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

Comparative sensitivities of ThinPrep and Papanicolaou smear for adenocarcinoma in situ (AIS) and combined AIS/high‐grade squamous intraepithelial lesion (HSIL): Comparison with HSIL

BACKGROUND.

Despite the historic belief that cytologic screening offers little protection against cervical adenocarcinoma (CAC), there is emerging evidence that, by detecting the precursor lesion, adenocarcinoma in situ (AIS), cervical screening may reduce the incidence of CAC as it has for cervical squamous carcinoma. Because liquid‐based cytology is fast replacing the conventional Papanicolaou smear (PS), it is important to establish that it is at least as effective in detecting AIS.

METHODS.

The authors calculated the sensitivities of PS and ThinPrep (TP) for 100 women with histologic AIS (from 160 PS slides and 60 TP slides), for 94 women with AIS+high‐grade squamous intraepithelial lesion (HSIL) (from 151 PS slides and 50 TP slides), and for 558 women with HSIL (from 788 PS slides and 383 TP slides). All smears were taken up to 36 months before the histologic diagnosis.

RESULTS.

In no category was there a significant difference between PS sensitivity and TP sensitivity. The HSIL category had a significantly higher overall sensitivity than the other categories. However, when sensitivity was defined as cytologic detection of high‐grade disease, there was no difference between any of the categories. For the detection of a high‐grade glandular lesion, the presence of a concurrent histologic HSIL was associated with reduced sensitivity for the detection of AIS.

CONCLUSIONS.

The current results indicated that it may prove possible for cervical screening, with either PS or TP, to reduce the incidence of CAC. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.     

Diagnostic value of p16INK4A,Ki‐67, and human papillomavirus L1 capsid protein immunochemical staining on cell blocks from residual liquid‐based gynecologic cytology specimens

BACKGROUND:

This study was conducted to evaluate the reliability and role of cell block preparations in the diagnosis of neoplastic and preneoplastic lesions of the cervix and to improve the value of cell block preparations in diagnosing and predicting the prognosis of cervical lesions through immunostaining of p16INK4A (p16), Ki‐67, and human papillomavirus (HPV) L1 capsid protein (HPV L1).

METHODS:

In total, 138 specimens were diagnosed on liquid‐based cytology (LBC) and cell block preparations, and 63 specimens were subjected subsequently to tissue follow‐up and immunostaining for p16, Ki‐67, and HPV L1 on cell block sections.

RESULTS:

In 42 specimens that were diagnosed as low‐grade squamous intraepithelial lesion, high‐grade squamous intraepithelial lesion (HSIL), and squamous cell carcinoma (SCC) on cell blocks, 38 specimens (90.5%) were confirmed by histopathologic reports, and there was slightly better than 81.6% agreement between LBC and tissue follow‐up. Immunointensity and cells that were positive for p16 were enhanced according to increased pathologic grade and differed statistically between cervical intraepithelial neoplasia 1 (CIN‐1) and CIN‐2/CIN‐3 as well as SCC. The positive rates of HPV L1 decreased gradually according to the severity of cervical neoplasia, and HPV L1/p16 expression patterns were related to the severity of cervical lesions.

CONCLUSIONS:

The cell block preparation technique was complementary to LBC, and the authors concluded that the application of LBC combined with cell block preparations may improve the diagnostic accuracy of cytology. Immunostaining for p16 and Ki‐67 on cell block preparations can help to improve the diagnostic accuracy of HSIL and SCC. A combined expression pattern of p16 and HPV L1 may serve as a valuable index for predicting prognosis and follow‐up of cervical dysplastic lesions. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

A validation study of the FocalPoint GS imaging system for gynecologic cytology screening

BACKGROUND:

Studies of the performance of the automated FocalPoint Guided Screening (FPGS) imaging system in gynecologic cytology screening relative to manual screening have yielded conflicting results. In view of this uncertainty, a validation study of the FPGS was conducted before its potential adoption in 2 large laboratories in Ontario.

METHODS:

After an intense period of laboratory training, a cohort of 10,233 current and seeded abnormal slides were classified initially by FPGS. Manual screening and reclassification blinded to the FPGS results were then performed. Any adequacy and/or cytodiagnostic discrepancy between the 2 screening methods subsequently was resolved through a consensus process (truth). The performance of each method's adequacy and cytodiagnosis vis‐a‐vis the truth was established. The sensitivity and specificity of each method at 4 cytodiagnostic thresholds (atypical squamous cells of undetermined significance or worse [ASC‐US+], low‐grade squamous intraepithelial lesion or worse [LSIL+], high‐grade squamous intraepithelial lesion or worse [HSIL+], and carcinoma) were compared. The false‐negative rate for each cytodiagnosis was determined.

RESULTS:

The performance of FPGS in detecting carcinoma, HSIL+, and LSIL+ was no different from the performance of manual screening, but the false‐negative rates for LSIL and ASC‐US were higher with FPGS than with manual screening.

CONCLUSIONS:

The results from this validation study in the authors' laboratory environment provided no evidence that FPGS has diagnostic performance that differs from manual screening in detecting LSIL+, HSIL+, or carcinoma. Cancer (Cancer Cytopathol) 2013;121:189–196. © 2013 American Cancer Society.     

The APTIMA HPV assay versus the hybrid capture 2 test in triage of women with ASC‐US or LSIL cervical cytology: A meta‐analysis of the diagnostic accuracy

Testing for DNA of 13 high‐risk HPV types with the Hybrid Capture 2 (HC2) test has consistently been shown to perform better in triage of women with cervical cytology results showing atypical squamous cells of undetermined significance (ASC‐US) but often not in triage of low‐grade squamous intraepithelial lesions (LSIL) detected in cervical cancer screening. In a meta‐analysis, we compared the accuracy of the APTIMA HPV test, which identifies RNA of 14 high‐risk HPV types, to HC2 for the triage of women with ASC‐US or LSIL. Literature search‐targeted studies where the accuracy of APTIMA HPV and HC2 for detection of underlying CIN2/3+ was assessed concomitantly including verification of all cases of ASC‐US and LSIL. HSROC (Hierarchical Summary ROC) curve regression was used to compute the pooled absolute and relative sensitivity and specificity. Eight studies, comprising 1,839 ASC‐US and 1,887 LSIL cases, were retrieved. The pooled sensitivity and specificity of APTIMA to triage ASC‐US to detect underlying CIN3 or worse was 96.2% (95% CI = 91.7–98.3%) and 54.9% (95% CI = 43.5–65.9%), respectively. APTIMA and HC2 showed similar pooled sensitivity; however, the specificity of the former was significantly higher (ratio: 1.19; 95% CI = 1.08–1.31 for CIN2+). The pooled sensitivity and specificity of APTIMA to triage LSIL were 96.7% (95% CI = 91.4–98.9%) and 38.7% (95% CI = 30.5–47.6%) for CIN3+. APTIMA was as sensitive as HC2 but more specific (ratio: 1.35; 95% CI = 1.11–1.66). Results were similar for detection of CIN2 or worse. In both triage of ASC‐US and LSIL, APTIMA is as sensitive but more specific than HC2 for detecting cervical precancer.