A case-control study of cervical cancer screening in north east Scotland.

To estimate the relative risk of invasive cervical cancer in each succeeding year after a negative screening result the screening records of all women tested in the north east of Scotland were examined as the basis for a case-control study. The cases consisted of 115 women in whom invasive cervical cancer had been diagnosed in 1968-82 and who had appeared in the screening records at least once before diagnosis. For each patient five controls were selected from women of the same age who appeared in the screening records before the date of diagnosis in the patient. If the patient''s cancer had been detected by screening the controls were chosen from women of the same age screened the same year. A comparison was made between cases and controls of the number of negative smears taken before the diagnosis. The results showed a high relative protection (inverse of the relative risk) in the first two years after a negative test, falling steadily as time since the last negative test elapsed. Even after 10 years, however, a considerable residual effect was observed.     

Human papillomavirus and cervical intraepithelial neoplasia in women who subsequently had invasive cancer.

In a retrospective case-control study biopsy specimens of cervical intraepithelial neoplasia (CIN) lesions from 47 women in whom invasive cancer subsequently developed (cases) and from 94 control subjects in whom CIN was diagnosed within 6 months of the diagnosis for the matched case subject but invasive disease did not develop were tested for human papillomavirus (HPV) DNA with tissue in-situ hybridization. There were no significant differences in the frequency of detection of HPV DNA between the two groups. In a cross-sectional survey the prevalence of HPV DNA was found to be 11% in specimens without CIN, 27% in those with CIN I, 49% in those with CIN II and 56% in those with CIN III. The positivity rates for HPV 16/33 DNA increased with the severity of CIN, but this was not observed for HPV 6/11 and 18 DNA. A comparison of the results of the case-control and cross-sectional studies suggested that the younger cohort of women had higher prevalence rates of HPV DNA than the older cohort.     

Oral cancer in Scotland: changing incidence and mortality.

OBJECTIVES--To determine the incidence of oral cancer in Scotland between 1960 and 1989 and oral cancer mortality from 1911 to 1989. SETTING--Data were obtained on oral cancer incidence from the information and statistics division of the Common Services Agency of the Scottish Health Service and mortality data from the office of the registrar general for Scotland. RESULTS--Mortality from intraoral cancers in Scotland substantially declined throughout this century until the mid-1970s. This trend, however, was then reversed, and fourfold increases in incidence were observed in younger age groups after 1960. Death rates in these younger age groups increased to levels previously recorded in the 1940s. These increases seemed to be cohort based and may therefore continue into the future. CONCLUSIONS--Reasons for increasing rates among younger age groups are speculative and rely on combining knowledge about risk factors and available ecological data. Though increases in incidence at younger ages do not result in a large change in the number of cases diagnosed, possible similar increases continuing into older ages, when oral cancer is more common, will correspond to a much larger increase in the actual number of cases. Given that such a large attributable risk is associated with tobacco and alcohol, however, these increases may be preventable.     

Human papillomavirus in invasive cervical cancer and cervical intraepithelial neoplasia 2 and 3 in Venezuela: A cross-sectional study

BackgroundThis study investigated the distribution of human papillomavirus (HPV) types in invasive cervical cancer (ICC), cervical intraepithelial neoplasia 2 (CIN2) and cervical intraepithelial neoplasia 3 (CIN3) in Venezuela.MethodsParaffin-embedded samples from 329 women from 29 medical centers of the 24 states of Venezuela were analyzed to determine the distribution of HPV types for ICC, CIN2, and CIN3, the prevalence of single and multiple infection, and the association of HPV types with severity of lesion, comparing CIN2 versus CIN3+ (CIN3 and ICC). The samples were analyzed with the polymerase chain reaction (PCR) followed by reverse hybridization for the identification of HPV types.ResultsHPV was identified in 95/96 ICC specimens (98.9%), in 142/149 CIN3 (95.3%) and in 78/84 CIN2 samples (92.8%). The most common types for ICC and CIN3 were: HPV16, 18, 31, and 33, and for CIN2 were HPV16, 31, 51, 52, and 18. HPV single infection was found in 82.1% of ICC cases, in 79.4% of CIN2 cases, and in 77.4% of CIN3 cases. HPV16 was identified as a single infection more frequently in women with CIN3+ than in those with CIN2 (68.6% versus 46.7%, P = 0.002), and HPV16 or HPV18 types were more prevalent in CIN3+ than in CIN2 (73.4% versus 50%, P = 0.0006).Conclusionthis is the first study of the distribution of HPV types in ICC, CIN2, and CIN3 conducted throughout the territory of Venezuela. HPV16 and HPV18 were the most frequent HPV types identified in single and multiple infections in both ICC and CIN3 groups, and are associated with severity of lesion. The knowledge of the distribution of HPV types would allow organization of an HPV-DNA-based screening test, and consideration of the implementation of prophylactic vaccination in Venezuela.     

Changing cytologic detection rates for cervical intraepithelial neoplasia and invasive cancer in a population lacking a mass screening program

The secular trends in the detection rates for cervical intraepithelial neoplasia (CIN) and invasive carcinoma were evaluated for a population lacking a mass screening program. For the period from 1980 through 1987, 185,659 Papanicolaou smears from 176,511 women were examined. The average annual age-adjusted detection rate for invasive cervical cancer declined from 3.7 x 10(-3) in 1980 to 1.4 x 10(-3) in 1987. The rate of cytologic findings consistent with CIN 3 and verified by histology increased from 0.7 x 10(-3) to 2.6 x 10(-3), and the rate of findings consistent with CIN 1 and CIN 2 increased from 4.3 x 10(-3) to 7.2 x 10(-3). The yield of Papanicolaou smear diagnoses consistent with CIN 3 was substantial (more than one case per 1,000) for women up to 60 years old, but was insignificant for older women.     

Risk of cervical intraepithelial neoplasia in women with glomerulonephritis.

OBJECTIVE--To investigate the occurrence of cervical intraepithelial neoplasia in women with glomerulonephritis and its possible association with immunosuppressive treatment. DESIGN--Retrospective study of cytological or histological specimens from women presenting with glomerulonephritis and a group of case and age matched controls. SETTING--University department of pathology, Norway. PATIENTS--81 women presenting with glomerulonephritis from 1981 to 1988, from whom gynaecological cytological or histological specimens were available. A group of 162 case and age matched controls. MAIN OUTCOME MEASURES--Age when glomerulonephritis of cervical intraepithelial neoplasia was diagnosed, type and characteristics of kidney lesion, stage of cervical intraepithelial neoplasia and presence of human papillomavirus, use of immunosuppressive treatment. RESULTS--Cervical intraepithelial neoplasia was more common in women with glomerulonephritis than in their controls (16/81 (20%) v 7/162 (4%), p less than 0.001) and was more advanced in those with glomerulonephritis than in the controls (9/81 (11%) of the study group had grade III cervical intraepithelial neoplasia compared with 1/162 (1%) of the controls). The increased occurrence of cervical lesions was independent of the use of immunosuppressive treatment, but the individual lesions tended to be more advanced when it was used (four of the seven cervical lesions in women with glomerulonephritis who had received immunosuppressive treatment were carcinoma in situ). Of the nine cervical lesions tested, seven were virus associated. CONCLUSION--Women with glomerulonephritis should have regular cervical smears, irrespective of their use of immunosuppressive treatment.     

Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study

Objective To study the long term risk of invasive cancer of the cervix or vagina after treatment for cervical intraepithelial neoplasia grade 3.Design Prospective cohort study.Setting Swedish cancer registry.Participants All women in Sweden with severe dysplasia or cervical carcinoma in situ (equivalent to cervical intraepithelial neoplasia grade 3) treated during 1958-2002 (n=132 493) contributing 2 315 724 woman years.Main outcome measures Standardised incidence ratios with risk of cancer in the Swedish general female population as reference, and relative risks in multivariable log-linear regression model, with internal references.Results Women with previous cervical intraepithelial neoplasia grade 3 had an increased risk of invasive cervical cancer compared with the general female population (standardised incidence ratio 2.34, 95% confidence interval 2.18 to 2.50). The increased risk showed a decreasing trend with time since diagnosis for women treated later than 1970 but the risk was still increased after 25 years. An effect of age was found, with an accentuated increase in risk for women aged more than 50. The excess risk for cervical cancer associated with previous cervical intraepithelial neoplasia grade 3 has steadily increased since 1958. For vaginal cancer the standardised incidence ratio was 6.82 (5.61 to 8.21) but this decreased to 2.65 after 25 years. Adjustments in the multivariable log-linear regression model did not substantially alter these results.Conclusions Women previously treated for cervical intraepithelial neoplasia grade 3 are at an increased risk of developing invasive cervical cancer and vaginal cancer. This risk has increased since the 1960s and is accentuated in women aged more than 50. The risk is still increased 25 years after treatment.     

Cytophotometric analysis of cervical intraepithelial neoplasia grade III, with and without synchronous invasive squamous cell carcinoma

Cytophotometric analysis was performed in nuclei retrieved from paraffin-embedded cervical tissue from 57 cases of CIN III. CIN III lesions of patients without invasive squamous cell carcinoma (N = 37) were regarded to represent a mixture of progressive and nonprogressive lesions. The CIN III lesions of patients with a synchronous invasive squamous cell carcinoma (N = 20) were regarded as representing truly progressive precursor lesions (CIN.INV). Twenty-one photometric features describing geometrical, density, and texture characteristics were extracted from the digitized nuclear images. Statistical analysis of cytophotometric data indicated significant differences between the group of CIN III lesions and CIN.INV lesions. A cluster analysis, using one co-occurrency texture feature (S-HOMOG), one density feature (S-DI), and two geometrical features (S-AREA and M-CIRC), showed that two clusters (C1 and C2) were present in the total group of CIN III and CIN.INV lesions. The vast majority of CIN.INV lesions was member of one and the same cluster C1. The CIN III group appeared to consist of a mixture of two clusters, 54% C1 and 46% C2 lesions. Of patients 45 years or younger, the majority (62%) of CIN III lesions had feature values, corresponding with those of cluster C1, and as such possibly with a potentially progressive course. In patients older than 45 years the percentage of CIN III lesions with C1 feature values was 27%.     

Diagnosis and treatment of cervical intraepithelial neoplasia in general practice.

OBJECTIVE--To audit the first five years of a colposcopy and treatment service for cervical dysplasia established within a general practice. DESIGN--A cervical smear register was established to determine which women were "at risk" of dysplasia. The results of colposcopy and treatment of dysplasia were analysed. SETTING--A large rural general practice with community hospital facilities in mid-Wales. PATIENTS--4437 Women at risk in a total practice population of 14,100. INTERVENTIONS--Colposcopy of women with dyskaryotic smear results, persistent inflammatory smear results, or vulval warts. Treatment of women with proved dysplasia by electrodiathermy of the cervix or cone biopsy. RESULTS--138 Women with dysplasia were diagnosed over five years: 36 mild, 97 moderate or severe, and five with microinvasion. Despite a 78% smear rate of at risk women over five years, nine invasive cancers still occurred. CONCLUSIONS--The results of treatment are acceptable. Cervical dysplasia has become very common, the risk of a dysplasia in women aged 20-39 who had smear tests being one in 14 over five years.     

Plasma-free amino acid profiling of cervical cancer and cervical intraepithelial neoplasia patients and its application for early detection

In this study, plasma-free amino acid profiles were used to investigate pre-cancerous cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (CSCC) metabolic signatures in plasma. Additionally, the diagnostic potential of these profiles was assessed, as well as their ability to provide novel insight into CSCC metabolism and systemic effects. Plasma samples from CIN patients (n = 26), CSCC patients (n = 22), and a control healthy group (n = 35) were analyzed by high-performance liquid chromatography, and their spectral profiles were subjected to the t test for statistical significance. Potential metabolic biomarkers were identified using database comparisons that examine the significance of metabolites. Compared with healthy controls, patients with CIN and CSCC demonstrated lower levels of plasma amino acids; plasma levels of arginine and threonine were increased in CIN patients but were decreased in cervical cancer patients. Additionally, the levels of a larger group of amino acids (aspartate, glutamate, asparagine, serine, glycine, histidine, taurine, tyrosine, valine, methionine, lysine, isoleucine, leucine, and phenylalanine) were gradually reduced from CIN to invasive cancer. These findings suggest that plasma-free amino acid profiling has great potential for improving cancer screening and diagnosis and for understanding disease pathogenesis. Plasma-free amino acid profiles may have the potential be used to determine cancer diagnoses in the early stage from a single blood sample and may enhance our understanding of its mechanisms.     

Langerhans' cells and subtypes of human papillomavirus in cervical intraepithelial neoplasia.

There is strong circumstantial evidence that human papillomavirus is a cofactor in the development of cervical neoplasia. Systemic immunosuppression has also been implicated. A study was therefore carried out examining the relation between subtypes of human papillomavirus and local immunocompetent cells in the cervix. Colposcopically directed punch biopsy specimens were taken from normal cervix and from histologically proved cervical intraepithelial neoplasia for immunohistochemical studies. Human papillomavirus genome probing was performed on the abnormal specimens. A relation was apparent between decreased Langerhans'' cells and moderate to high copy numbers of human papillomavirus type 16. The reduction in Langerhans'' cells was significant for human papillomavirus type 18 even at low copy numbers. Conversely, the absence of human papillomavirus was associated with increased numbers of Langerhans'' cells in cervical intraepithelial neoplasia. These findings suggest that the proposed oncogenic potential of human papillomavirus type 16 and human papillomavirus type 18 in particular may be mediated by a specific effect on the afferent limb of the immune response.     

Observer variation in histopathological diagnosis and grading of cervical intraepithelial neoplasia.

To assess the variability among histopathologists in diagnosing and grading cervical intraepithelial neoplasia eight experienced histopathologists based at different hospitals examined the same set of 100 consecutive colposcopic cervical biopsy specimens and assigned them into one of six diagnostic categories. These were normal squamous epithelium, non-neoplastic squamous proliferations, cervical intraepithelial neoplasia grades I, II, and III, and other. The histopathologists were given currently accepted criteria for diagnosing and grading cervical intraepithelial neoplasia and asked to mark their degree of confidence about their decision on a visual linear analogue scale provided. The degree of agreement between the histopathologists was characterised by kappa statistics, which showed an overall poor agreement (unweighted kappa 0.358). Agreement between observers was excellent for invasive lesions, moderately good for cervical intraepithelial neoplasia grade III, and poor for cervical intraepithelial neoplasia grades I and II (unweighted kappa 0.832, 0.496, 0.172, and 0.175, respectively); the kappa value for all grades of cervical intraepithelial neoplasia taken together was 0.660. The most important source of disagreement lay in the distinction of reactive squamous proliferations from cervical intraepithelial neoplasia grade I. The histopathologists were confident in diagnosing cervical intraepithelial neoplasia grade III and invasive carcinoma (other) but not as confident in diagnosing cervical intraepithelial neoplasia grades I and II and glandular atypia (other). Experienced histopathologists show considerable interobserver variability in grading cervical intraepithelial neoplasia and more importantly in distinguishing between reactive squamous proliferations and cervical intraepithelial neoplasia grade I. It is suggested that the three grade division of cervical intraepithelial neoplasia should be abandoned and a borderline category introduced that entails follow up without treatment.     

Pretreatment plasma levels and diagnostic utility of hematopoietic cytokines in cervical cancer or cervical intraepithelial neoplasia patients

In this study, we compared plasma levels and the diagnostic utility of hematopoietic growth factors (HGFs) with SCC-Ag in cervical cancer patients in relation to control groups and cervical intraepithelial neoplasia (CIN) patients and healthy subjects. Pretreatment plasma levels of HGFs (SCF, GM-CSF, G-CSF and M-CSF) were determined by the use of immunoenzyme assay (ELISA), and SCC-Ag by chemiluminescent microparticle immunoassay (CMIA). Significantly different concentrations of GM-CSF, G-CSF and M-CSF were observed in the group of patients with cervical cancer and CIN compared to the healthy controls. Significant differences in plasma levels of GM-CSF and M-CSF between cervical cancer and benign lesions patients were also found. The HGFs and SCC-Ag diagnostic specificities received high values. The diagnostic sensitivity and the predictive value of a positive and negative test result were higher for M-CSF than for antigen SCC in the cancer group. The M-CSF area under the ROC curve (AUC) was the largest from hematopoietic cytokines and SCC-Ag. These results suggest the potential utility of M-CSF as a good candidate for a marker of cervical cancer as well as benign lesions of this organ (CIN).     

Clonality analysis of archival cervical smears. Correlation of monoclonality with grade and clinical behavior of cervical intraepithelial neoplasia

OBJECTIVE: To establish a polymerase chain reaction (PCR)-based clonality assay for archival cervical smears and examine its value in the detection of cervical intraepithelial neoplasia (CIN) and prediction of its clinical behavior. STUDY DESIGN: Dyskaryotic cells were microdissected from archival cervical smears of 33 cases and subjected to PCR-based clonality analysis of the androgen receptor gene. High-risk HPV subtypes were screened by PCR. RESULTS: Monoclonal patterns were found in 9/9 CIN 3 and 15/21 CIN 2, while polyclonal patterns were observed in the remaining 6 CIN 2 and 3/3 CIN 1. All patients with monoclonal CIN lesions, including 15 CIN 2, showed recurrence of the disease despite treatment. The original CIN 2 and recurrent CIN lesion in each of the 6 examined cases showed the same monoclonal pattern, suggesting a clonal link. In contrast, the patients with polyclonal CIN 1 or 2 became negative and remained disease free. High-risk HPV subtypes were found in all monoclonal CIN lesions, including 9 CIN 3 and 15 CIN 2, and in 4/6 polyclonal CIN 2 but not in CIN 1 lesions. CONCLUSION: Clonality analysis of cervical smears is potentially valuable in the identification of true neoplastic cells and prediction of clinical behavior of CIN 2 lesions.     

Combined Pap smear, cervicography and HPV DNA testing in the detection of cervical intraepithelial neoplasia and cancer

OBJECTIVE: The sensitivity of the Pap smear (PAP) continues to be the subject of debate. During the past several years, cervicography (CER) and HPV DNA testing have been suggested as optional tools in the screening of cervical cancer precursors. STUDY DESIGN: The performance characteristics of PAP, CER and HPV DNA testing (hybrid capture test [HCT]) in all potential combinations were evaluated in a series of 1,030 women (aged 16-70, median, 33), subjected to colposcopy (COLPO) as the reference tool. RESULTS: Of the 992 evaluable cases, 402/992 (41%) had positive COLPO (i.e., an abnormal transformation zone). Of them, 298 women underwent directed punch biopsy, while of the COLPO negative patients, 18/93 positive by at least one of the three tests had endocervical curettage. Of the 402 COLPO positive women, 146 (36%) remained negative on all tests, whereas 256 (64%) had at least one positive test. There were 84 cervical intraepithelial neoplasia (CIN) 2 and 3 lesions and 6 invasive carcinomas. Of the former, 10 were detected by PAP alone, 4 by CER alone and 3 by HCT alone. Three of the 6 carcinomas were HCT negative. The predictive value (PPV) of a positive test was 45% for PAP, 51% for CER and 48% for HCT. The combinations of PAP with CER (for PAP negative cases) and PAP with HCT were more sensitive for CIN 2 and 3 (95% and 94%, respectively) as compared with PAP alone but were associated with a significant decrease in specificity (44% and 46% vs. 57%, respectively). However, both combinations retained a PPV (43%) similar to that of PAP alone (45%). CONCLUSION: The potential combinations of PAP with CER and with HCT were more sensitive in detecting CIN 2 and 3 as compared with PAP alone and retained a PPV similar to that of PAP.     

The relation between resting heart rate and cancer incidence,cancer mortality and all-cause mortality in patients with manifest vascular disease

BackgroundPrevious studies suggest that elevated resting heart rate (RHR) is related to an increased risk of cancer mortality. The aim of this study was to evaluate the relation between RHR and cancer incidence and mortality in patients with vascular disease.MethodsPatients with manifest vascular disease (n = 6007) were prospectively followed-up for cancer incidence and mortality. At baseline, RHR was obtained from an electrocardiogram. The relation between RHR and cancer incidence, cancer mortality and total mortality was assessed using competing risks models.ResultsDuring a median follow-up of 6.0 years (interquartile range: 3.1–9.3) 491 patients (8%) were diagnosed with cancer and 907 (15%) patients died, 248 (27%) died from cancer. After adjustment for potential confounders, the hazard ratio (HR) for incident cancer per 10 beats/min increase in RHR was 1.00 (95% confidence interval [CI]: 0.93–1.07). There was a trend toward an increased risk of colorectal cancer in patients with higher RHR (HR 1.15, 95% CI 0.97–1.36). The risk of all-cause mortality was increased in patients in the highest quartile of RHR compared to the lowest quartile (HR 1.86, 95% CI 1.53–2.27), but no effect of RHR on cancer mortality was observed (HR 1.01, 95% CI 0.70–1.46).ConclusionsIn patients with manifest vascular disease, elevated RHR was related to a higher risk of premature all-cause mortality, but this was not due to increased cancer mortality. RHR was not related to risk of overall cancer incidence, although a relation between elevated RHR and incident colorectal cancer risk could not be ruled out.     

Perinatal characteristics in relation to incidence of and mortality from prostate cancer.

OBJECTIVE--To test the hypothesis that factors causing morbidity and mortality from prostate cancer may operate in utero. DESIGN--Matched case-control study of singleton men born between 1874 and 1946 at one hospital. SETTING--Uppsala University Hospital. SUBJECTS--250 patients with prostate cancer and 691 controls, including 80 patients who died from prostate cancer and their 196 matched controls. MAIN OUTCOME MEASURES--Mother''s age at menarche, parity, pre-eclampsia or eclampsia before delivery, age at delivery and socioeconomic status; case or control''s birth length and weight, placental weight, prematurity derived from gestational age, and presence of jaundice. RESULTS--Both pre-eclampsia (odds ratio 0, 95% confidence interval 0 to 0.71) and prematurity (0.31, 0.09 to 1.04) were inversely associated with incidence of prostate cancer. Among subjects born full term, placental weight, birth weight, and ponderal index (weight/height 3) showed non-significant positive associations with prostate cancer incidence, and stronger associations with mortality. CONCLUSION--Prenatal exposures that are likely correlates of pregnancy hormones and other growth factors are important in prostate carcinogenesis and influence the natural course as well as the occurrence of this cancer.