Liquid-based endometrial cytology using SurePath™ is not inferior to suction endometrial tissue biopsy for detecting endometrial malignancies: Midterm report of a multicentre study advocated by Japan Association of Obstetricians and Gynecologists.

OBJECTIVE: We conducted a prospective, multicentre study to compare the clinical performance of liquid-based endometrial cytology (LBEC) using SurePath™ with that of suction endometrial tissue biopsy (SETB). This study is officially advocated and reported by the Japan Association of Obstetricians and Gynecologists. By publishing our midterm data, we intend to disseminate the benefits of LBEC system, using the descriptive reporting format and algorithmic interpretational approach. METHODS: From April 2014 to December 2015, we consecutively assessed 1116 LBEC specimens and 1044 SETB specimens in our five outpatient clinics. RESULTS: The sensitivity of suction tissue biopsies was 85.2%, whereas the sensitivity of LBEC was 92.2%. The specificity of suction tissue biopsies was 98.9% and that of LBEC was 98.5%. The negative predictive value of LBEC (99.1%) was higher than that of SETB (98.1%), although the difference between these values was not significant. CONCLUSIONS: The clinical performance of LBEC for detecting endometrial malignancies was almost identical to the performance of SETB. This indicates that LBEC was not inferior to SETB for the detection of endometrial cancer. The LBEC is appropriate for various clinical situations as the first-step detecting tool. In addition, it could be used for cancer surveillance for women with signs highly suggestive of endometrial malignancies and in Lynch syndrome patients, on a larger scale.

Cervical Cancer Screening With Human Papillomavirus DNA and Cytology in Japan.

OBJECTIVE: The aim of this study was to determine the value of human papillomavirus (HPV) testing for primary cervical cancer screening in Japan. METHODS: In total, 5065 women who underwent primary screening with cytology and HPV between January 2005 and December 2006 were enrolled. In the baseline phase, these women were stratified by age, and the rates of HPV-positive and abnormal cytology were compared between women younger than and older than 30 years. In the follow-up phase, women aged 20 to 69 years and cytology negative for intraepithelial lesions or malignancy at baseline were followed up until December 2011 (n = 2383). Progression to grade 2/3 cervical intraepithelial neoplasia or worse (CIN2+/CIN3+) was compared between the HPV-positive and HPV-negative groups. RESULTS: In the baseline phase, HPV-positive rates were significantly higher in women younger than 30 years at 20.7% (95% confidence interval [CI], 18.4-22.9; 255/1234) compared with women 30 years or older at 7.2% (95% CI, 6.4%-8.0%; 275/3831; P < 0.001). However, there was no statistical difference for high-grade squamous intraepithelial lesion or worse rates between them, at 2.7% (95% CI, 1.8%-3.6%; 33/1234) and 2.4% (95% CI, 1.9%-2.9%; 91/3831), respectively, P = 0.55. In the follow-up phase, the rate of progression to CIN2+/CIN3+ was significantly higher in the HPV-positive group than in the HPV-negative group (P < 0.001). Moreover, relative risk of progression to CIN2+ was 15.9 times higher in the HPV-positive group, and that of progression to CIN3+ was 16.1 times higher in the HPV-positive group. CONCLUSIONS: Human papillomavirus testing is a useful test for predicting progression to CIN and is recommended as a primary screening tool. However, screening with cytology alone is still appropriate for younger women, younger than 30 years, because HPV testing yields more false-positive results in younger women.

Is cytology/HPV co-testing for cervical cancer screening useful in Japan?

OBJECTIVE: In Japan, no region has introduced primary HPV testing for cervical cancer screening. We assessed the diagnostic value and possible harm of HPV testing in Japan. METHODS: This cross-sectional study with historical controls used cytology-based screening and co-testing data in Japan. As surrogate indicators of possible harm, colposcopy referral rate and cervical intraepithelial neoplasm (CIN) 1 detection rates were calculated. As surrogate indicators with diagnostic values, the detection rates of CIN2 or greater (CIN2+) and CIN3+ were calculated. RESULTS: The data of 297 970 women (182 697 for cytology-based, 115 273 for co-testing) were examined. The detection rates of CIN1, CIN2+, and CIN3+ were significantly higher in the co-testing group than in the cytology-based group (P < 0.001, P < 0.0001, P < 0.01, respectively). Between ages 25-49, CIN2+ detection rates were significantly higher in the co-testing group than in the cytology-based group (P < 0.05 for each 5-year age group). Between ages 30-49, CIN3+ detection rates were significantly higher in the co-testing group than in the cytology-based group (P < 0.05 for each 5-year age group). CONCLUSION: Limiting the target age group may minimize the possible harm of screening. Cytology/HPV co-testing may be useful in Japanese populations if balance is maintained between benefit and harm.

Effectiveness of human papillomavirus vaccination in young Japanese women: a retrospective multi-municipality study.

In Japan, government support for human papillomavirus (HPV) vaccination began in November 2010. However, the mass media repeatedly reported on severe adverse events. The Japanese Ministry of Health, Labor and Welfare suspended proactive recommendations for HPV vaccines in June 2013. Japan's HPV vaccination rate dropped from 70% to less than 1% in 2017.We examined cervical cancer screening results in terms of abnormal cytology, histology, and HPV vaccination status among 11,903 women aged 20 to 25 y in the fiscal year 2015. The overall rate of HPV vaccination was 26.1% (3,112/11,903). Regarding cytology, the rate of atypical squamous cells of undetermined significance (ASC-US) or worse was 3.3% (103/3,112) in women who received HPV vaccination (vaccine (+) women) and 5.6% (496/8,791) in women who did not (vaccine (-) women). The rate of high-grade squamous intraepithelial lesion (HSIL) or worse was 0.26% (8/3,112) in vaccine (+) women and 0.81% (72/8,791) in vaccine (-) women. Regarding histology, the rate of cervical intraepithelial neoplasia 1 or worse (CIN1+) was 1.4% (42/3,112) in vaccine (+) women and 2.1% (178/8,791) in vaccine (-) women. The rates of CIN2+ and CIN3+ were similar regardless of vaccination. We found a significantly lower incidence of CIN in vaccine (+) women. These results suggest that the resumption of recommending HPV vaccination as primary prevention for cervical cancer is needed in Japan.

Implementation of primary HPV testing in Japan.

Cervical cancer screening has been shifting from primary cytology to primary HPV testing worldwide as primary HPV testing is more sensitive than primary cytology. To the best of our knowledge, the current study is the first in Japan to examine the feasibility of primary HPV testing. One of the disadvantages of this shift is that hrHPV-/≥LSIL/CIN2+ (high-risk HPV negative cancers or pre-cancerous lesions with abnormal cytology results) can be missed. The objectives of the present study are to clarify in detail CIN2+ missed by this shift and to evaluate the feasibility of primary HPV testing in Japan. Data from 115,273 women who underwent co-testing with cytology and HPV testing in cancer screening were used in the current study. The cases with hrHPV-/≥LSIL ('hrHPV-/≥L-SIL' include CIN2-, in contrast, 'hrHPV-/≥L-SIL/CIN2+' doesn't include CIN2-) were analysed in detail. Women with hrHPV-/≥LSIL comprised 0.3% of the total. The prevalence of CIN2, CIN3, SCC or cervical adenocarcinomas in the lesions with HPV-/≥LSIL was 0.03% in the cancer screening group. Only one case of 14 cervical adenocarcinomas in ≥LSIL was hrHPV-. The prevalence of cancer missed by the shift in patients >50 years of age was significantly higher compared with patients younger than 49 years. In conclusion, the prevalence of CIN2+, which might be missed by the shift from primary cytology to primary HPV testing, was remarkably low in this Japanese cancer screening. The data indicated that primary HPV testing, which was more sensitive for CIN2+ than primary cytology, was a feasible method that can be used in Japan. In particular, primary HPV testing should be introduced for women <50 years old.

Direct intrauterine sampling with Uterobrush: cell preparation by the "flicked" method.

The aim of this study was to evaluate the efficacy of endometrial cytology using the Uterobrush in the collection of samples for the diagnosis of endometrial lesions. The preparation technique for endometrial brushing specimens was also demonstrated. In their earlier study, the authors described the cyto-architectural criteria that appear to be more useful for the cytological assessment of endometrial lesions. Therefore, for the application of the diagnostic criteria, endometrial cytological sampling will become more important. With regard to the cell sample collection, the authors used the Uterobrush because the insertion into the uterine cavity is easy and painless. The authors compared the Uterobrush with the Endocyte, since they thought that cell clumps using the former device tended to be smaller. The purpose of the current study was to improve and evaluate cell preparation methods using the Uterobrush. The authors investigated three methods [i.e., conventional and improved techniques ("flicked" method) with the Uterobrush and the Endocyte] of endometrial cell collection and preparation. Using conventional methods, a brush was rolled along a glass slide and the collected material spread and smeared. However, using the "flicked" method, a brush is strongly flicked with forceps, so that the cells are transferred to the slide and its position is moved along the slide little by little and smeared. The frequency by size of cell clumps with tube or sheet-shaped pattern was examined in the preparations. Cell block specimens with the Uterobrush were also investigated. Endometrial cytology from a total of 90 women was evaluated. Most were outpatients and all were older than 20 yr (ranging from 20 to 54, average 42.7 yr). Of these, 30 cases from each group were examined by three methods. Uterobrush samples prepared by the "flicked" method have a greater quantity of cell clumps than those using the Endocyte sampler, while the frequency-by-size of cell clumps was by degree the same as the Endocyte. The cell clumps obtained in the Uterobrush "flicked" method preparation was considered equivalent or superior as an aid to making a diagnosis of endometrial lesions and it became obvious that the same criteria were applicable to both of instruments. Our cytological examination may be a potent aid to making a diagnosis of endometrial lesions and these findings will be helpful in the standardization of criteria in direct intrauterine cell samples.

Thymidine kinase in epithelial ovarian cancer: relationship with the other pyrimidine pathway enzymes.

TK is a pyrimidine metabolic pathway enzyme involved in salvage DNA synthesis. What roles TK may play in epithelial ovarian cancer and the relationships between TK and the other pyrimidine pathway enzymes remain unclear. We examined TK1 gene expression by RT-PCR and related it to gene expression of TS, TP and DPD in 69 samples from epithelial ovarian cancer, 8 low-malignant-potential tumors, 16 benign ovarian tumors and 34 normal ovaries. Additionally, cytosolic and serum TK activities were determined by radioenzymatic assay. TK1 gene expression, the ratio of TK1 to TS gene expression, that of TK1 to TP and that of TK1 to DPD were significantly higher in epithelial ovarian cancer than in normal ovaries. In epithelial ovarian cancer, TK1 gene expression correlated with cytosolic and serum TK activities, TS and TP gene expression and the ratio of TP to DPD gene expression. Patients with high-TK1 gene expression had a significantly poorer survival than those with low TK1 gene expression. Combined analysis demonstrated that the relative risk of cancer death for tumors with high TK1, high TS and high TP gene expression was greater than that for tumors with high TK1 gene expression alone. TK1 gene expression together with TS, TP and DPD gene expression may play important roles in influencing the malignant behavior of epithelial ovarian cancer. Combination therapy including TK inhibitor is a possible therapeutic intervention in patients with epithelial ovarian cancer.