Johanna M.M. Grefte

Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial.

CONTEXT Liquid-based cytology has been developed as an alternative for conventional cervical cytology. Despite numerous studies and systematic reviews, controversy remains about its diagnostic accuracy. OBJECTIVE To assess the performance of liquid-based cytology compared with conventional cytology in terms of detection of histologically confirmed cervical intraepithelial neoplasia (CIN). DESIGN, SETTING, AND PARTICIPANTS Cluster randomized controlled trial involving 89,784 women aged 30 to 60 years participating in the Dutch cervical screening program at 246 family practices. One hundred twenty-two practices were assigned to use liquid-based cytology and screened 49,222 patients and 124 practices were assigned to use the conventional Papanicolaou (Pap) test and screened 40,562 patients between April 2004 and July 1, 2006. Patients were followed up for 18 months through January 31, 2008. INTERVENTION Screening for CIN using liquid-based cytology or conventional papanicolaou (Pap) test and the blinded review of all follow-up of screen-positive women (blinded to the type of cytology and the initial result). MAIN OUTCOME MEASURES Intention-to-treat and per-protocol analysis of the detection rates of and positive predictive values for histologically verified CIN in both cytology systems. Outcomes are presented as crude and adjusted rate ratios (adjustment for age, urbanization, study site, and period). RESULTS The adjusted detection rate ratios for CIN grade 1+ was 1.01 (95% confidence interval [CI], 0.85-1.19); for CIN grade 2+, 1.00 (95% CI, 0.84-1.20); for CIN grade 3+, 1.05 (95% CI, 0.86-1.29); and for carcinoma, 1.69 (95% CI, 0.96-2.99). The adjusted positive predictive value (PPV) ratios, considered at several cytological cutoffs and for various outcomes of CIN did not differ significantly from unity. CONCLUSION This study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors. TRIAL REGISTRATION trialregister.nl Identifier: NTR1032.

Trends in incidence and mortality of thyroid carcinoma in The Netherlands between 1989 and 2003: Correlation with thyroid fine-needle aspiration cytology and thyroid surgery

A persistent increase in incidence of thyroid carcinoma (TC) has been reported worldwide. The aim of our study was to assess trends in incidence and mortality of TC in The Netherlands between 1989 and 2003 and to examine whether these trends correlate with changes in diagnostic practices such as changes in the number of fine needle aspiration biopsies (FNAB) and/or thyroid surgeries. Population‐based incidence and mortality data were retrieved from the Netherlands Cancer Registry. Data concerning FNAB and thyroid surgeries were obtained through the nationwide network and registry of histo‐ and cytopathology in The Netherlands (PALGA). Overall, the incidence of TC remained unchanged. However, there was a slight increase in incidence of papillary TC of 2.1% per year (p < 0.001) particularly in stage I tumors, possibly, in part, because of a marked increase in use of FNAB. Appropriate iodine intake, reduced radiation exposure and a more conservative diagnostic approach toward asymptomatic thyroid nodules may explain why this increase is less pronounced compared to other countries. Incidence of other subtypes of TC decreased (follicular TC, 1.3% per year, p = 0.02 and anaplastic TC, 7.1% per year, p = 0.006) or remained unchanged (medullary TC). The number of FNABs per year progressively increased from 1,093 in 1989 to 4,123 in 2003, whereas the number of thyroid surgeries decreased from 3,419 in 1989 to 2,825 in 2003. The mortality rates decreased by 2.3% per year (p = 0.01). The decrease in incidence of both follicular and anaplastic TC is assumed to be largely responsible for the decrease in TC mortality rates.

EUS-FNA for the detection of left adrenal metastasis in patients with lung cancer

In patients with lung cancer, enlarged or (18)Fluoro-deoxyglucose positron emission tomography ((18)FDG-PET) positive left adrenal glands are suspected for distant metastases and require tissue confirmation for a definitive assessment. The aim of this study was to assess the sensitivity of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for left adrenal metastases in lung cancer patients with a suspect adrenal gland based on imaging. EUS-FNA findings of patients with (suspected) lung cancer and CT enlarged or (18)FDG-PET positive left adrenal glands were retrospectively evaluated. In the absence of metastases at EUS, clinical and radiological follow-up was obtained. In 85 patients, EUS-FNA demonstrated left adrenal metastases of lung cancer in 53 (62%), benign adrenal tissue in 25 (29%), a metastasis from colon carcinoma in 1 (1%) and a primary adrenocortical carcinoma in 1 (1%) patient. In five patients (5.9%), the aspirates contained non-representative material. EUS outcomes were false negative in two patients. Sensitivity and negative predictive value (NPV) for EUS-FNA of the left adrenal gland were at least 86% (95% CI 74-93%) and 70% (95% CI 50-85%). No complications occurred. EUS-FNA is a sensitive, safe and minimally invasive technique to provide tissue proof of left adrenal metastases in patients with (suspected) lung cancer and enlarged or (18)FDG-PET positive adrenal glands. Therefore, EUS-FNA qualifies as the staging test of choice for patients with lung cancer with suspected left adrenal metastases.

MIB1 expression in basal cell layer : a diagnostic tool to identify premalignancies of the vulva

Lichen sclerosus, high-grade usual vulvar intraepithelial neoplasia (VIN) and differentiated VIN have a different malignant potential. The objective of this study was to quantify the proliferative activity in the basal region of the epithelium of vulvar premalignancies. Furthermore, we investigated whether MIB1 expression in the basal region of vulvar epithelium can be helpful in diagnosing differentiated VIN, which may be hard to discern from normal epithelium. MIB1 was used to immunohistochemically visualise proliferating cells within formalin-fixed, paraffin-embedded, archival tissue sections of different vulvar premalignancies (N=48) and normal vulvar epithelium (N=16). Automatic digital image analysis software was developed to quantify the proliferating fraction in different parts of the epithelium (MIB1 positivity index). MIB1 expression differed among the various vulvar premalignancies; a MIB1-negative basal cell layer was a distinct feature of normal vulvar epithelium. No MIB1-negative basal cell layer was noted in differentiated VIN or other vulvar premalignancies. Owing to this negative cell layer, the MIB1 proliferation index in normal vulvar epithelium was significantly lower than in vulvar premalignancies. In conclusion, MIB1 expression can be a helpful tool in diagnosing a premalignancy and has additional value especially to distinguish differentiated VIN neoplasia from normal vulvar epithelium, but cannot explain the differences in malignant potential.

Quantitation of Ki-67 expression in the differential diagnosis of reserve cell hyperplasia vs. small cell lung carcinoma

OBJECTIVE To investigate whether the detection of proliferation-associated Ki-67 antigen may be of value in differentiating between reserve cell hyperplasia (RCH) and small cell lung cancer (SCLC). STUDY DESIGN Retrospectively, 20 Papanicolaou-stained bronchial brushes or washings from 20 patients were selected. Ten were diagnosed as RCH (and had no SCLC in follow-up) and the other 10 as SCLC (histologically confirmed). All 20 Papanicolaou-stained slides were restained with the monoclonal antibody MIB1, directed against Ki-67 antigen; that simple and reliable procedure was described recently. In each specimen 5 coherent cell groups were identified, corresponding to RCH or SCLC, respectively; photographed; and studied for Ki-67 antigen expression after MIB1 staining of the slides. At least 3 cell groups remained in each specimen. The Ki-67 labeling index (LI) of the specimens was determined as the number of MIB1-positive cells divided by the total number of cells in the remaining cell groups. RESULTS All cases of SCLC showed a mean Ki-67 LI of at least .415 (mean .684, SD .151), whereas in the cases with RCH the mean Ki-67 LI never was more than .158 (mean .048, SD .049). The difference was highly significant (P<.001, Students t test). Linear discriminant analysis resulted in a classifier with which we were able to discriminate correctly between SCLC and RCH in 100% of the 20 bronchial brushings and washings. CONCLUSION The results clearly demonstrate that measuring proliferative activity in Papanicolaou-stained bronchial brushings and washings by MIB1 restaining of the slides may be of great practical value in accurately discriminating RCH from SCLC. The method is simple and can be performed in any laboratory that is able to carry out immunocytochemical staining. However, an additional (prospective) study with a series of difficult cases is necessary to confirm these findings.

Objective Assessment of Cancer Biomarkers Using Semi-Rare Event Detection

Objective and reproducible assessment of cancer biomarkers may be performed using rare event detection systems. Because many biomarkers are not true ‘rare events’, in this study a semi-rare event detection system was developed. The system is capable of assigning a discriminant score to detected positive cells, expressing the extent and intensity of the immunocytochemical staining. A gallery image is constructed showing the diagnostically most interesting cells as well as quantitative data expressing the biomarker staining pattern. To increase scanning speed, an adaptive scanning strategy is studied in which scanning is aborted when a sufficient number of positive cells has been identified. System performance was evaluated using liquid based cervical smears, stained with an antibody directed against p16 tumor suppressor protein. Overexpression of p16 in cervix is related to high-risk HPV infection, which is associated with carcinogenesis. Reproducibility of the system was tested on specimens containing limited positivity. Quantitative analysis was evaluated using 10 cases within normal limits and 10 high grade lesions. The system was highly reproducible in detecting positive cells and in calculating discriminant scores (average CV 0.7%). Quantitative features were significantly increased in high grade lesions (p < 0.001). Adaptive scanning decreased scanning time with only minor impact on scanning results. The system is capable of automated, objective and reproducible assessment of biomarker expression and may be useful for a variety of applications.

Comparison of Liquid-based Cytology With Conventional Cytology for Detection of Cervical Cancer Precursors: A Randomized Controlled Trial

ABSTRACTThe Papanicolaou (Pap) test—the conventional screening method for cervical intraepithelial neoplasia (CIN)—is suboptimal due to high false-negative and false-positive test results due to the poor quality of sampling, preparation problems and errors in detection and interpretation. In a large