Walter Ryd

Efficacy of HPV DNA Testing With Cytology Triage and/or Repeat HPV DNA Testing in Primary Cervical Cancer Screening

BACKGROUND Primary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective. METHODS We used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided. RESULTS Compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests). CONCLUSIONS Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

Screening-Preventable Cervical Cancer Risks : Evidence From a Nationwide Audit in Sweden

BACKGROUND The effectiveness of cervical cancer screening programs differs widely in different populations. The reasons for these differences are unclear. Routine and comprehensive audits have been proposed as an ethically required component of screening. We performed a nationwide audit of the effectiveness of the Swedish cervical cancer screening program. METHODS We identified all invasive cervical cancer cases that were diagnosed in Sweden from January 1, 1999, through December 31, 2001, and had been reported to the Swedish Cancer Registry (n = 1230 cases). We verified the diagnoses by histopathologic rereview and matched each case subject to five (population-based) age-matched control subjects who were identified from the National Population Register. The Pap smear screening histories for case and control subjects were reviewed for a 6-year period using the National Cervical Cancer Screening Register, which contains data on essentially all relevant cytological and histological diagnoses in Sweden. Odds ratios (ORs), and their 95% confidence intervals (CIs), of cervical cancer according to screening history were calculated in conditional logistic regression models. All statistical tests were two-sided. RESULTS Women who had not had a Pap smear within the recommended screening interval had higher risk of cervical cancer than women who had been screened (OR = 2.52, 95% CI = 2.19 to 2.91). This risk was similarly increased for all age groups (P(homogeneity) = .96). The risk for non-squamous cell cervical cancers (OR = 1.59, 95% CI = 1.20 to 2.11) was also increased. Women who had not had a Pap smear within the recommended screening interval had a particularly high risk of advanced cancers (OR = 4.82, 95% CI = 3.61 to 6.44). Among women who had been screened within the recommended interval, those with abnormal Pap smears had a higher risk of cervical cancer than those with normal smears (OR = 7.55, 95% CI = 5.88 to 9.69) and constituted 11.5% of all women with cervical cancer. CONCLUSIONS Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against non-squamous cancers.

Chlamydia trachomatis infection and persistence of human papillomavirus

Human papillomavirus (HPV) persistence is the major cause of cervical cancer, but most HPV infections will not persist and risk factors for HPV persistence are not well known. Chlamydia (C.) trachomatis infection seems to also be associated with cervical cancer. We investigated whether C. trachomatis infection is a risk factor for HPV persistence. In a cohort of 12,527 women participating in a population‐based HPV screening trial in Sweden, 6,418 women completed testing for HPV DNA by general primer PCR and typing by reverse dot blot hybridization. On average 19 months later, 303 women that had been HPV‐positive and had normal cytology at enrollment completed a new HPV test. Environmental exposures were assessed by an 87‐item questionnaire. Previous sexually transmitted infections were also investigated by serology. At follow‐up, 44% of the women were positive for the same type of HPV DNA as at enrollment. Persistence correlated with length of follow‐up (p < 0.01) and condom use seemed to protect against HPV persistence (p < 0.05). The most significant risk factor for persistent presence of HPV DNA was self‐reported history of previous C. trachomatis infection (relative risk in multivariate model = 2.09; 95% confidence interval = 1.05–4.18). We conclude that persistence of oncogenic HPV infections is more likely among women with a previous C. trachomatis infection.

Screening and cervical cancer cure : population based cohort study

Objective To determine whether detection of invasive cervical cancer by screening results in better prognosis or merely increases the lead time until death. Design Nationwide population based cohort study. Setting Sweden. Participants All 1230 women with cervical cancer diagnosed during 1999-2001 in Sweden prospectively followed up for an average of 8.5 years. Main outcome measures Cure proportions and five year relative survival ratios, stratified by screening history, mode of detection, age, histopathological type, and FIGO (International Federation of Gynecology and Obstetrics) stage. Results In the screening ages, the cure proportion for women with screen detected invasive cancer was 92% (95% confidence interval 75% to 98%) and for symptomatic women was 66% (62% to 70%), a statistically significant difference in cure of 26% (16% to 36%). Among symptomatic women, the cure proportion was significantly higher for those who had been screened according to recommendations (interval cancers) than among those overdue for screening: difference in cure 14% (95% confidence interval 6% to 23%). Cure proportions were similar for all histopathological types except small cell carcinomas and were closely related to FIGO stage. A significantly higher cure proportion for screen detected cancers remained after adjustment for stage at diagnosis (difference 15%, 7% to 22%). Conclusions Screening is associated with improved cure of cervical cancer. Confounding cannot be ruled out, but the effect was not attributable to lead time bias and was larger than what is reflected by down-staging. Evaluations of screening programmes should consider the assessment of cure proportions.

HPV type-specific risks of high-grade CIN during 4 years of follow-up: A population-based prospective study

We followed a population-based cohort of 5696 women, 32–38 years of age, by registry linkage with cytology and pathology registries during a mean follow-up time of 4.1 years to assess the importance for CIN2+ development of type-specific HPV DNA positivity at baseline. HPV 16, 31 and 33 conveyed the highest risks and were responsible for 33.1, 18.3 and 7.7% of CIN2+ cases, respectively. Women infected with HPV 18, 35, 39, 45, 51, 52, 56, 58, 59 and 66 had significantly lower risks of CIN2+ than women infected with HPV 16. After adjustment for infection with other HPV types, HPV types 35, 45, 59 and 66 had no detectable association with CIN2+. In summary, the different HPV types found in cervical cancer show distinctly different CIN2+ risks, with high risks being restricted to HPV 16 and its close relatives HPV 31 and HPV 33.

Liquid-based cytology versus conventional Papanicolaou smear in an organized screening program : a prospective randomized study.

The objective of this study was to evaluate whether liquid‐based cytology (LBC) can improve high‐standard cervical cancer screening cytology further. The primary endpoint was histopathologic high‐grade lesions in current and subsequent screening rounds. The secondary endpoints were cytologic diagnosis and inadequate samples.

Effects of fine-needle aspiration and other biopsy procedures on tumor dissemination in mice

Using five syngeneic tumor‐host systems in mice, we studied the influence of fine‐needle aspiration biopsy, incisional biopsy, and excisional biopsy on tumor death rates. Guided by results from pilot studies a very strict test protocol was developed which made possible a comparison between the tumor systems in spite of their differences in tumor growth rates and dissemination patterns. The compiled results from the experiments did not reveal any differences in tumor death rates, neither between the test groups and their controls, nor between the three biopsy methods: fine‐needle aspiration biopsy, incisional biopsy, and excisional biopsy. Additional experiments confirmed, however, earlier observations that tumor cell seeding and tumor outgrowth by way of the aspiration needle track may occur under extreme test conditions.

Fine‐needle aspiration characteristics of hibernoma

Hibernoma is a rare, benign lipomatous tumor with features of brown fat. The preoperative diagnosis of hibernoma is difficult at times because its clinical, radiographic, and fine‐needle aspiration (FNA) characteristics overlap with those of liposarcoma.

Risk of invasive cervical cancer in relation to management of abnormal Pap smear results

OBJECTIVE We sought to evaluate the management of women with abnormal cytology in terms of subsequent risk of invasive cervical cancer. STUDY DESIGN The screening histories of all invasive cervical cancer cases diagnosed in Sweden 1999-2001 and of 5 population-based controls per case were reviewed. In all, 159 patients and 258 control subjects aged < 67 years had an abnormal smear result 0.5-6.5 years prior to cancer diagnosis. The cervical cancer risk was estimated in relation to management by calculating odds ratios. RESULTS Histologic assessment of low-grade squamous abnormalities strongly reduced the risk compared to repeated cytology (odds ratio, 0.46; 95% confidence interval, 0.24-0.89). Delaying histologic assessment was also associated with a higher risk (odds ratio, 5.65; 95% confidence interval, 1.39-23.05). After high-grade squamous atypia, absence of any cytologic or histologic specimen was a major determinant of cancer risk (odds ratio, 12.52; 95% confidence interval, 1.42-infinitive). CONCLUSION For adequate protection against invasive cervical cancer, further assessment with histology must be recommended also for women with low-grade squamous abnormalities.

125IUDR labelling efficiency and cytotoxicity for murine tumours in vivo and in vitro

We have reviewed the literature on 125IUDR (5-iodo-2-deoxyuridine), the DNA label of choice for cell distribution studies. In previous studies, the cytotoxicity in relation to labelling efficiency has often been inadequately investigated or reported. We have studied four syngeneic mouse tumours and compared in vitro with in vivo labelling procedures. Ascites tumours could be effectively labelled in vivo by IP injections of 60–80 μCi per mouse during 24 h, without apparent cytotoxicity. Comparable in vitro labelling was also effective, but caused a dose-related cytotoxicity, as measured by growth rate and transplantability. Comparison with ‘cold” IUDR disclosed that the toxicity was not chemical, but radiological. Our attempt to label a solid lymphoma in vivo was unsuccessful, obviously because the tumour grows too slowly. We conclude that 125IUDR-labelling is suitable for cell distribution studies, but in view of labelling efficiency versus cytotoxicity the procedure has to be adjusted to each new tumour individually.