An economic evaluation of two cervical screening algorithms in Belgium: HR-HPV primary compared to HR-HPV and liquid-based cytology co-testing.

OBJECTIVE: To assess the costs and benefits of two algorithms for cervical cancer screening in Belgium (1) high-risk human papillomavirus (HR-HPV) primary screening and (2) HR-HPV and liquid-based cytology (LBC) co-testing. METHODS: A decision tree was adapted from published work and parameterised using HORIZON study data and Belgian cost and population data. The theoretical model represents two different screening algorithms for a cohort of 577 846 women aged 25-64 attending routine cervical screening. Scenario analyses were used to explore the impact of including vaccinated women and alternative pricing approaches. Uncertainty analyses were conducted. RESULTS: The cost per woman screened was €113.50 for HR-HPV primary screening and €101.70 for co-testing, representing a total cost of €65 588 573 and €58 775 083, respectively, for the cohort; a 10% difference. For one screening cycle, compared to HR-HPV primary, co-testing resulted in 13 173 more colposcopies, 67 731 more HR-HPV tests and 477 020 more LBC tests. Co-testing identified 2351 more CIN2+ cases per year (27% more than HR-HPV primary) and 1602 more CIN3+ cases (24% more than HR-HPV primary) than HR-HPV primary. CONCLUSION: In Belgium, a co-testing algorithm could increase cervical pre-cancer detection rates compared to HR-HPV primary. Co-testing would cost less than HR-HPV primary if the cost of the HPV test and LBC were cost-neutral compared to the current cost of LBC screening but would cost more if the cost per HPV test and LBC were the same in both co-testing and HR-HPV primary strategies.

Long-term clinical significance of benign endometrial cells identified on routine cervical cytology in women aged more or equal to 45 years.

INTRODUCTION: Within the Bethesda System, the recommendation of describing benign-appearing endometrial cells (BECs) has changed over recent years. Since the 2014 revision, their presence in cervical cytology reports has been deemed essential, beginning with age 45. Recent studies have suggested rising the reporting age to 50 years. Does the presence of these cells necessitate further assessment? MATERIALS AND METHODS: This retrospective cohort study included patients aged between 45 and 65 years in whom BECs were present on cervical cytology between January 2001 and December 2010, with a follow-up at 5 and 10 years. Women who had abnormal cervical cells or atypical endometrial cells on cervical cytology were excluded, as well as women with a history of cervical or endometrial cancer, or a history of hysterectomy and incomplete follow-up data. RESULTS: One hundred seventy-six women were included. Of these, 31% were postmenopausal of which 65% used hormonal substitution therapy. Twenty-eight percent presented with abnormal uterine bleeding at inclusion. During the follow-up period of 10 years, 87.5% had a normal gynecological follow-up and 11.4% underwent a hysterectomy for benign pathology. One percent (2 patients) had been diagnosed with endometrial malignancy, both presenting with postmenopausal bleeding and aged over 60 years. CONCLUSIONS: Our study confirmed that the presence of BECs is not a reason for concern when no additional clinical indicator is recognized, especially with normal ultrasonographic examination. Further invasive exploration may be controversial. If reporting BECs in cervical cytology continues, we strongly agree on rising the reporting age to 50 years or postmenopausal state.

Gigantic parasitic leiomyoma of 19 kg in a postmenopausal woman: A case report and review of the literature.

Parasitic leiomyomas are a rare subtype of subserosal uterine leiomyomas and are mostly found incidentally. Diagnosis is challenging and treatment consists out of complete surgical resection. Cases are few in women without history of uterine surgery. In this extraordinary case, a 56-year-old menopausal female suffering from backache and abdominal swelling, was suspected to have a huge malignant ovarian tumor. She underwent a resection of the mass along with hysterectomy and bilateral salpingo-oöphorectomy. Histopathology revealed a gigantic leiomyoma of 19.1 kg in the broad ligament. This unique case suggests taking this diagnosis into account in future clinical cases presenting with large abdominal masses even without previous uterine surgery.

Role of protein biomarkers in the detection of high-grade disease in cervical cancer screening programs.

Since the Pap test was introduced in the 1940s, there has been an approximately 70% reduction in the incidence of squamous cell cervical cancers in many developed countries by the application of organized and opportunistic screening programs. The efficacy of the Pap test, however, is hampered by high interobserver variability and high false-negative and false-positive rates. The use of biomarkers has demonstrated the ability to overcome these issues, leading to improved positive predictive value of cervical screening results. In addition, the introduction of HPV primary screening programs will necessitate the use of a follow-up test with high specificity to triage the high number of HPV-positive tests. This paper will focus on protein biomarkers currently available for use in cervical cancer screening, which appear to improve the detection of women at greatest risk for developing cervical cancer, including Ki-67, p16(INK4a), BD ProEx C, and Cytoactiv HPV L1.

Prior knowledge of HPV status improves detection of CIN2+ by cytology screening.

OBJECTIVE: The objective of the study was to investigate whether knowledge of human papillomavirus (HPV) deoxyribonucleic acid test results increases sensitivity of guided cytology screening for the detection of cervical intraepithelial neoplasia (CIN)-2 or higher-grade cervical lesions. STUDY DESIGN: This was a prospective colposcopy-controlled study of 2905 BD SurePath samples to identify cases with CIN2+ within a 24 month follow-up period. Sensitivity and specificity to detect CIN2+ was evaluated, comparing guided cytology screening with and without prior knowledge of HPV status. RESULTS: Prior knowledge of HPV status resulted in significantly higher detection rate of CIN2+ compared with screening blinded to HPV status (P = .005) with limited loss of specificity (P = .026). Gain in sensitivity is higher in older women (43.8%, P = .008) vs in younger women (10.2%, P = .317), whereas loss of specificity is more pronounced in younger women (P < .001) vs older women (P = .729). CONCLUSION: Guided cytological screening performed with prior knowledge of HPV status results in an improved detection of CIN2 or higher-grade lesions.

Stromal issues in cervical cancer: a review of the role and function of basement membrane, stroma, immune response and angiogenesis in cervical cancer development.

The carcinogenesis of cervical carcinoma implies an intricate interplay of neoplastic, human papillomavirus infected epithelial cells and stromal tissue, in which different factors have distinct but interacting influence. Persistent infection with an oncogenic human papillomavirus type may lead to epithelial dysplasia with progressive severity. To access the adjacent stromal tissue, tumour cells have to breach the basement membrane. The stroma partly controls tumour growth, invasion and angiogenesis. Last but not least there is considerable influence of the immune response. In this review we describe the importance of various stromal factors in carcinogenesis of cervical cancer.

Human papillomavirus: E6 and E7 oncogenes.

The recognition of a causal relationship between human papillomaviruses and cancer almost 30 years ago led to a rapid expansion of knowledge in the field, resulting in the description of the main mediators of HPV-induced carcinogenesis, the viral proteins E6 and E7. These oncoproteins show a remarkable pleiotropism in binding host-cell proteins, with the tumour suppressor genes p53 and pRb as their major targets. These interactions induce proliferation, immortalization and malignant transformation of infected cells. The link between HPV and cervical cancer led to the development of molecular methods, often based on the detection of E6 and E7, for screening and diagnosis. Therapeutic vaccines and gene therapy are primarily directed at E6 and E7. Although prophylactic vaccines are available, further understanding of the viral life cycle and the mechanisms underlying HPV-induced oncogenesis is necessary to face the many challenges in the field of HPV and cancer.

Immunocytochemistry in liquid-based cervical cytology: analysis of clinical use following a cross-sectional study.

Cytological screening for cervical cancer is hampered by imperfect sensitivity and low inter-observer reproducibility. Human papillomavirus (HPV) testing lacks specificity as a primary screening method. Studies indicate that immunocytochemical detection of alterations caused by HPV in the host cells can optimise screening. Here, the potential of p16(INK4a) (cyclin-dependent kinase inhibitor p16) and MIB-1 (Ki-67 proliferation marker) as adjunct molecular markers for cervical lesions was investigated in a prospective, cross-sectional study of 500 samples in the framework of opportunistic screening in Flanders, Belgium. A consecutive series of 200 samples and 100 samples from the cytological categories ASC, LSIL and HSIL were investigated. Surepath samples were interpreted according to the Bethesda 2001 reporting system. HPV testing was done with MY09/MY11 consensus PCR. Immunocytochemistry for p16(INK4a) and MIB-1 was performed with an automated staining protocol. The number of immunoreactive cells/1,000 cervical cells was assessed. There was a higher mean number of p16(INK4A) and MIB-1 immunoreactive cells/1,000 cells in HSIL (4.06 +/- 1.93 and 11.13 +/- 2.83, respectively) compared to other cytological categories. Both markers showed a large spread in counts, for all categories. In cases of HSIL without immunoreactive cells for either marker, low cellularity and long-term storage in water were often the cause of false negativity. This study confirms that positive staining for p16(INK4a) and MIB-1 is highly correlated with presence of high-grade lesions. These markers could be used as adjuncts to increase the sensitivity of cytological screening as well as the specificity of the HPV test. However, clear methodological standards are needed for optimal performance of immunocytochemistry in a clinical setting.

P16INK4a as an adjunct marker in liquid-based cervical cytology.

Cytological screening for cervical cancer is hampered by high false negative rates. Inter-observer reproducibility needs optimizing. The potential of p16(INK4a) as a biomarker for cervical lesions was examined in a study of liquid-based cytology (LBC), HPV DNA testing by MY09/MY11 consensus PCR and type-specific PCRs and p16(INK4a) immunocytochemistry on a series of 291 patients selected from routine screening. Comparison of the number of p16(INK4a) immunoreactive cells/1,000 cells exhibited a significantly higher mean count in HSIL (8.80 +/- 1.13) than other cytological groups. The mean count of LSIL (1.09 +/- 0.18) was significantly higher than that of the negative group (0.82 +/- 0.40). ASC-H and HSIL combined showed a significantly higher mean count (6.46 +/- 1.17) than negative, ASC, ASC-US and LSIL. The mean count of immunoreactive cells/1,000 cells was significantly higher in HPV16 positive samples (3.22 +/- 0.72) than in samples containing infections with types of unknown malignant potential (0.83 +/- 0.26) or HPV negative samples (1.17 +/- 0.41). The mean count in infections with other high-risk HPV types (2.55 +/- 0.52) was significantly higher than that in HPV negative samples. Receiver-operating characteristic curves yielded a test accuracy (area under curve) of 0.76, 0.79, 0.88 and 0.95 for ASCUS, LSIL, ASC-H/HSIL and HSIL, respectively. Thresholds for 95% sensitivity were at 0.005, 0.007, 0.098 and 0.445 immunopositive cells/1,000 cells for ASCUS, LSIL, ASC-H/HSIL and HSIL, respectively. The 95% specificity threshold for the detection of HSIL was at 1.87 immunopositive cells/1,000 cells. P16(INK4a) immunocytochemistry can be used as an adjunct to LBC in cervical screening, because it has a good diagnostic accuracy to discriminate HSIL and ASC-H from other lesions. It could be used as a surrogate marker of high-risk HPV infections.