Neoplasia Grade Research Articles

Association between carotenoids and outcome of cervical intraepithelial neoplasia: a prospective cohort study

It has been suggested that micronutrients such as alpha-tocopherol, retinol, lutein, cryptoxanthin, lycopene, and alpha- and beta-carotene may help in the prevention of cervical cancer. Our aim was to investigate whether serum concentrations and/or dietary intake of micronutrients influence the regression or progression of low-grade cervical abnormalities. In a prospective cohort study of 391 patients with cervical intraepithelial neoplasia (CIN) grade 1-2 lesions, we measured serum micronutrient concentrations in addition to a self-administered questionnaire about dietary intake. We evaluated the hazard ratio (HR) adjusted for CIN grade, human papillomavirus genotype, total energy intake and smoking status. In non-smoking regression subjects, regression was significantly associated with serum levels of zeaxanthin/lutein (HR 1.25, 0.78-2.01, p=0.024). This benefit was abolished in current smokers. Regression was inhibited by high serum levels of alpha-tocopherol in smokers (p=0.042). In progression subjects, a significant protective effect against progression to CIN3 was observed in individuals with a medium level of serum beta-carotene [HR 0.28, 95% confidence interval (CI) 0.11-0.71, p=0.007), although any protective effect from a higher level of serum beta-carotene was weaker or abolished (HR 0.52, 95% CI 0.24-1.13, p=0.098). Increasing beta-carotene intake did not show a protective effect (HR 2.30, 95% CI 0.97-5.42, p=0.058). Measurements of serum levels of carotenoids suggest that regression is modulated by smoking status. Maintaining a medium serum level of beta-carotene has a protective effect for progression; however, carotene intake is not correlated with serum levels of carotenoids.

Effect Of Drd2/Ankk1 Taqia Allelic Polymorphism On The Risk And Prognosis Of Cervical Precancer And Cancer

Objectives: The aim of this study was to elucidate the role of dopamine receptor D2 / ankyrin repeat and protein kinase domain containing 1 (DRD2/ANKK1) TaqIA allelic polymorphism in the HPV-induced cervical carcinogenesis.Methods: 1. Effect on the risk of cervical precancer: After an 8-year follow-up, out of 214 women with persisting high-risk HPV infection, 102 developed high-grade cervical dysplasia or cervical intraepithelial neoplasia (CIN) grade III, while 112 did not. The subjects were genotyped for the DRD2/ANKK1 TaqIA polymorphism by PCR-RFLP, and the allelic distributions were compared between groups with and without high-grade dysplasia. 2. Prognostic value: Two hundred and thirty nine women with cervical precancer/cancer were followed for 5 years. Complete remission was achieved at 182 women. To assess the prognostic value of the TaqIA polymorphism, genotype frequencies were compared between patients reaching and not reaching complete remission.Results: The frequency of A1/A1+A1/A2 genotypes was higher among women who developed high-grade cervical dysplasia (OR: 1.87, 95% CI: 1.05-3.33; p=0.034) than in the other group. Occurrence of the A1 allele was more frequent among women who did not reach complete remission (OR: 2.00, 95% CI: 1.07-3.74; p=0.030) than in women with complete remission.Conclusions: This is the first report on the possible involvement of DRD2/ANKK1 TaqIA polymorphism in cervical carcinogenesis. The A1 allele seems to increase the risk of cervical precancer, and it may also be associated with a worse prognosis in women with HPV-induced cervical cancer. The results need further validation in large-scale molecular epidemiological studies.

Abstract LB-268: Loss of HPV16 E2 protein expression and transcriptional modulation of cellular and viral genes correlate with progression to cervical carcinoma

Abstract Integration of the viral DNA in the cellular genome has been suggested to be critical in carcinogenic progression of HPV-associated cervical neoplasia. This event can be accompanied by disruption of the open reading frame (ORF) encoding the E2 repressor, thus leading to transcriptional up-regulation of the E6 and E7 viral oncogenes. At this stage, it is unclear whether disruption of the E2 ORF is mandatory for carcinogenic progression. We measured E2 RNA and protein expression in clinical samples of various grades of HPV16-associated cervical neoplasia and compared it with the status of the viral genome. RNA extracted from paraffin embedded tissues was hybridized to specific probes and quantified by the NanoString technology. Protein expression was appreciated by immunohistochemistry and the status of viral DNA was determined by in situ hybridization, all performed on serial sections of the same samples. E2 protein was found highly expressed in CIN2 lesions where the HPV DNA was highly replicating, while it was decreased in more advanced grade lesions where replication is decreased or lost (CIN3 and SCC). Our data demonstrate that integration of the viral DNA in the cellular genome is always accompanied by drastic reduction of expression of the E2 protein, even when the E2 ORF is not disrupted by integration. The viral genes appear differentially expressed during progression as transcription of the HPV16 E6/E7 oncogenes, only when compared to E2-E4, is significantly higher in high grade lesions than in CIN2. In addition, transcription of 400 cellular genes of the cell cycle and immune-response were also studied in 20 clinical samples that show modulation during progression. We will discuss the establishment of a transcriptional signature for progression in cervical cancer and the role of local immune response in the fate of cervical lesions associated with HPV16. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-268. doi:1538-7445.AM2012-LB-268

PROFILE OF CERVICAL SMEAR CYTOLOGY IN WOMEN ATTENDING HEALTH CENTER IN RURAL AREA OF WESTERN MAHARASHTRA

Background: Cervical cancer caused by infection with a sexually transmitted agent human papillomavirus (HPV), can be readily prevented by identifying and treating women with HPV-induced precancerous lesions of the cervix. Objective: To study the profile of cervical smear cytology in rural women in western Maharashtra. Methods: The study was designed to look at the previous reports of the Pap smear present at the health center Pravaranagar in rural area of Western Maharashtra. The reports of 186 smears were analyzed. Results: Maximum numbers of the women (70.43%) were less than 40 years of age. Â Majority of the women were from lower socio-economic status. There were 29.03 % Pap smears, negative for intraepithelial lesion. Intraepithelial neoplasia of various grade and invasive cervical carcinoma were diagnosed in some cases. Other infections were also detected on Pap smear like bacterial vaginosis, candidial infection and trichomonas vaginalis infestation. Conclusion: An Awareness and education program needs to be implemented to target women about cervical cancer and Pap smear screening. The goal of any screening programme should be to pick up majority of the precursor lesions and not frank cancers; it is desirable to initiate Pap smear screening in women from lower socio-economic status before the 40 years of age.

Evaluating the Epidemiology and Morbidity Burden Associated with Human Papillomavirus in Israel

Human papillomavirus (HPV) infection is mostly associated with cervical cancer (CC). However, it can cause other illnesses as well, all of which impact on people's wellbeing and consume healthcare resources. Measures for prevention or early detection of these conditions differ in their effectiveness and cost. An informative evaluation of the projected benefit of these measures depends on understanding the current unmet need, not only limited to CC. To evaluate the burden of HPV-related conditions in Israel, including CC, cervical precancerous lesions and genital warts. A retrospective database analysis was conducted for the second largest health management organization (HMO) in Israel, covering approximately 1.8 million people. Records were drawn following a search for key words indicative of related diagnoses, lab results, medications, or procedures for the time period of 2006-2008. Prevalence, incidence and resource utilization were analysed. Findings were extrapolated to the whole Israeli population using age and gender incidence rates. Incidence of CC was found to be 5 per 100,000 females. Incidences of cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3 were 74, 27 and 36 per 100,000 females, respectively. Incidence of genital warts was 239 and 185 per 100,000 for men and women, respectively. The overall annual economic burden was calculated to be $US48,838,058 (year 2010 values). HPV poses a significant burden in terms of health (clinical and quality of life) and in monetary terms, even for conditions that are sometimes regarded as benign, such as CIN1 or genital warts. Current findings should be used for proper evaluation of measures to reduce HPV-related morbidity and mortality, such as regular screening and vaccination.

Abstract A14: Finding biomarkers in the differential expression patterns between epithelial layers in cervical dysplasia

Abstract Normal human cervical epithelium consists of a differentiating continuum of cell layers. It has been hypothesized that the most basal layer consists of stem cells and that cells migrate towards the surface as they mature and differentiate. Hence, cells in different layers of the epithelium are expected to be at different stages of maturity and express different genes. Carcinogenesis is a multi-step process frequently occurring over many years. Understanding the early genetic changes, most of which manifest as changes in this maturation process, will hopefully lead to better biomarkers for detecting precancers at highest risk to progress. Objective: By studying differences in expression between cervical epithelial layers and across various grades of cervical intraepithelial neoplasia (CIN), we hope to gain a better understanding of the molecular basis of the carcinogenic process, which will hopefully lead to novel biomarkers for the early detection of cervical cancer. Materials and Methods: CIN biopsies representing various histopathological grades of dysplasia were used for this study. These included some from a previous study that had been stored at −80°C in RNAlater, which we embedded in O.C.T., as well as newer biopsies that were fixed immediately in Tissue-Tek Xpress Molecular Fixative and embedded in paraffin (MFPE). Specimens were sectioned on to slides following standard protocols for their embedding medium. Microdissection to separate various layers of epithelium was performed manually with a needle. The epithelium was collected as 2 layers. RNA was extracted using the TRIzol reagent method for frozen specimens and the Qiagen RNeasy FFPE kit for MFPE specimens. mRNA was labeled using the Agilent Low Input Quick Amp Labeling kit and tested on the Agilent Whole Human Genome 4×44K Microarray. Data was normalized against the array median intensity and data from replicate probes was averaged. Genes that are differentially expressed in different layers of the epithelium and/or in different grades will be identified for further study and validation through immunohistochemistry. Results and Conclusions: An earlier attempt to use laser capture microdissection was hampered by slow cutting speed and processing time, leading to low-quality RNA and weak expression array signal. Using manual microdissection, one CIN II case was done from the frozen samples. Duplicate samples of the stroma left over from microdissection were analyzed concurrently with the two epithelial layers. The scatter observed in comparing the duplicate samples was used to define what constituted differential expression between the epithelial layers, resulting in the identification of 114 genes overexpressed in the superficial layer and 2 genes overexpressed in the basal layer. Subsequent attempts to repeat this procedure showed that many of our frozen samples had poor quality RNA. Hence, we sought out newer MFPE specimens. Results from some of these samples will also be presented. A comparison of the results between the multiple dysplastic grades should be revealing as we hope to identify genes whose altered expression may play a role in cancer progression. Our success with manual microdissection suggests that this analysis is feasible. Work is ongoing to expand our sample size and to better comprehend the biochemical implications of our results. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A14.

Discrimination of grade 2 and 3 cervical intraepithelial neoplasia by means of analysis of water soluble proteins recovered from cervical biopsies

BackgroundCervical intraepithelial neoplasia (CIN) grades 2 and 3 are usually grouped and treated in the same way as "high grade", in spite of their different risk to cancer progression and spontaneous regression rates. CIN2-3 is usually diagnosed in formaldehyde-fixed paraffin embedded (FFPE) punch biopsies. This procedure virtually eliminates the availability of water-soluble proteins which could have diagnostic and prognostic value.AimTo investigate whether a water-soluble protein-saving biopsy processing method followed by a proteomic analysis of supernatant samples using LC-MS/MS (LTQ Orbitrap) can be used to distinguish between CIN2 and CIN3.MethodsFresh cervical punch biopsies from 20 women were incubated in RPMI1640 medium for 24 hours at 4°C for protein extraction and subsequently subjected to standard FFPE processing. P16 and Ki67-supported histologic consensus review CIN grade (CIN2, n = 10, CIN3, n = 10) was assessed by independent gynecological pathologists. The biopsy supernatants were depleted of 7 high abundance proteins prior to uni-dimensional LC-MS/MS analysis for protein identifications.ResultsThe age of the patients ranged from 25-40 years (median 29.7), and mean protein concentration was 0.81 mg/ml (range 0.55 - 1.14). After application of multistep identification criteria, 114 proteins were identified, including proteins like vimentin, actin, transthyretin, apolipoprotein A-1, Heat Shock protein beta 1, vitamin D binding protein and different cytokeratins. The identified proteins are annotated to metabolic processes (36%), signal transduction (27%), cell cycle processes (15%) and trafficking/transport (9%). Using binary logistic regression, Cytokeratin 2 was found to have the strongest independent discriminatory power resulting in 90% overall correct classification.Conclusions114 proteins were identified in supernatants from fresh cervical biopsies and many differed between CIN2 and 3. Cytokeratin 2 is the strongest discriminator with 90% overall correct classifications.

No clinical predictors of intraepithelial neoplasia in HIV-positive patients with external condilomata acuminata

To identify clinical parameters in association with human papilloma virus (HPV) genotypes and histopathology diagnosis in HIV-positive patients with external condylomata acuminata (ECA), 400 Chilean HIV-positive patients were included in the study. Forty-seven patients presented ECA. Clinical parameters and socio demographic data were recorded. Histopathology study and HPV linear array genotyping assay were performed. Intraepithelial neoplasia (IEN) grade 2 or 3 was found in 8.5% of patients, associated to HPV-16. Patients were mainly single, MSM, with history of sexually transmitted disease (STD), multiple sexual partners, receiving antiretroviral therapy and with recurrent lesions. All ECA were mainly perianal, grey or pink colored, exophytic with less than two years evolution. No clinical parameter could predict the development of high grade IEN in HIV patients with ECA. It seems necessary to perform biopsy and genotype all HIV positive patients with ECA.

Abstract 1612: Validation of CSE1L/hCAS as a potential therapeutic target in pancreatic cancer

Abstract Background: The nuclear export protein CSE1L/hCAS has recently gained attention as a putative oncogene, which is amplified in several human malignancies. The role of hCAS in pancreatic cancer is unknown. In this work, we sought to evaluate the expression of hCAS in pancreatic cancer cell lines and tumor tissue and to further explore the potential of hCAS as a therapeutic target. Methods: The nuclear and cytosolic hCAS protein expression was determined in human pancreatic cancer cell lines and tumor tissues and compared with those of immortalized normal pancreatic ductal cells and normal pancreatic tissues. The cellular effects of hCAS knockdown using small interfering RNA oligonucleotides were investigated in MiaPaCa-2 human pancreatic cancer cells with regard to proliferation (MTT assay), cell death (Trypan blue and Flow cytometry), and malignant transformation (colony formation assay). Results: hCAS protein expression increased in pancreatic cancer cell lines relative to the immortalized pancreatic ductal epithelial cell line. Immunohistochemical staining of a human pancreatic tumor tissue microarray showed that hCAS expression was higher in pancreatic tumors compared with their normal counterparts. There was increasing nuclear to cytoplasmic staining with progression from normal pancreatic duct to increasing grade of pancreatic intraductal neoplasia to invasive pancreatic cancer. Treatment with hCAS targeting small interfering RNAs effectively reduced pancreatic cell growth in tissue culture, induced apoptosis, and inhibited growth in soft agar. Conclusion: This is the first report of hCAS expression and cellular distribution in human pancreatic cancer. Our data suggest that hCAS might be an attractive target for human pancreatic cancer prevention and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1612.

Clinical effect of loop electrosurgical excision procedure (LEEP) in diagnosis and treatment of cervical diseases

Objective To study the clinical effect of cervical loop electrosurgical excision procedure (LEEP) in diagnosis and treatment of cervical diseases (including cervical intraepithelial neoplasia of different grade, cervical erosion of moderate and severe degree, cervical with human papillomavims (HPV) infection and cervi-cal polyp) . Method The data of 136 cases with cervical disease treated by LEEP were analyzed retrospectively. Re-sult The postoperative diagnosis were upgraded in 18 cases (13.2%) ,and downgraded in 38cases (27.9 %) . The preoperative diagnosis of 80 cases (58.8 %) were in accordance with the postoperative ones. The difference was sig-nificant(P<0.05). The mean operative time was 11minutes, the mean bleeding volume was 15 ml. Postoperative bleeding of LEEP occurred in 2.2 % (3/136) patients. Postoperative cervical conglutination of LEEP occurred in 1. 5 % (2/136) patients. The cure rate of CIN was 96 % after LEEP. The residual CIN occurred in 4 patient (4 %). Recurrence CIN occurred in 2 patient (2 %). At 12th months after LEEP,the negative rate of HPV detection was 86. 7% and the persistent positive rate was 13.3%. The HPV clearance rate was increased gradually after LEEP. Conclu-sion LEEP was safe and effective for the treatment of the cervical disease and was a kind of good method to clear HPV infection in cervical. Key words: Cervical intraepithelial neoplasia; Microwaves; Gynecologic surgical procedures

P1111 Human telomerase gene amplification does not correlate with the grade of cervical intraepithelial neoplasia

P1111 Human telomerase gene amplification does not correlate with the grade of cervical intraepithelial neoplasia

The influence of margin width and volume of disease near margin on benefit of radiation therapy after breast-conserving surgery for DCIS: Results of long-term follow-up

531 Background: There remains variation in the use of radiation (RT) in women with DCIS, despite prospective randomized trials documenting its benefit in reducing the risk of ipsilateral breast tumor recurrence (IBTR). Methods: Patients with DCIS treated with excision alone or excision plus radiation at our institution from 1991–1995 were identified. A dedicated breast pathologist assessed margin width, number of involved ducts at closest margin, nuclear grade, and presence of necrosis and lobular neoplasia. Pathological variables, age, and presence of palpable mass were tested in uni- and multivariate analysis for association with risk of IBTR and added value of RT. Results: 294 patients with a median follow-up of 11 years had actuarial 10- and 15-year overall IBTR rates of 22 and 29%. For lesions excised with margins of &lt;1mm, 1–9mm, and ≥10mm, the actuarial 10-year IBTR rates were 28, 21, and 19%, respectively. RT reduced adjusted IBTR rates by 62% (12 vs. 28%; p=0.002) for all patients; 83% for lesions with &lt;1mm margins (p=0.002), 70% for 1–9mm (p=0.05), and 27% (p=0.55) for ≥10mm. Following adjustment for other variables, higher volume of disease near the margin was associated with risk of IBTR in the no RT group (HR=3.37, p=0.002) and greater benefit of RT (HR 0.14; p=0.004). Conclusions: Effect of RT on local recurrence risk is influenced by both margin width and number of involved ducts at nearest margin. Patients with higher volume of disease near the margin derive a greater benefit from the addition of RT. Despite margins of ≥10mm, the risk of local recurrence remains substantial in patients with DCIS. [Table: see text] No significant financial relationships to disclose.

Expression of blood group-related antigens in neoplastic uterine cervix

Expression of blood group antigens in normal, displastic and tumoral uterine cervix from 35 hysterectomised women with carcinoma of the cervix was investigated; the results were correlated with patients' ABH phenotype and secretor status. We used an indirect immunoperoxidase technique and a panel of monoclonal antibodies and lectins directed against different antigenic specificities. Anomalous expression of blood group antigens in premalignant lesions from cervix was found. Partial loos of expression of blood group antigens and some lectins in different grades of cervical intraepithelial neoplasia, and a total loss of expression in CIN III and in infiltrating carcinoma of the cervix from secretor patients was revealed. The findings herein described confirm the importance of these antigens as tumour markers and they might be useful for the study of cervical carcinogenesis.

Human Papillomavirus DNA versus Papanicolaou Screening Tests for Cervical Cancer

To the Editor: The outcome measures appear to have been chosen post hoc by Mayrand et al. (Oct. 18 issue)1 in their screening trial comparing human papillomavirus (HPV) testing with Papanicolaou (Pap) testing.1,2 The “conservative” outcome definition excludes biopsy-confirmed lesions identified at colposcopy but not verified on final excision or on biopsy immediately before ablation. Such lesions are included in the “liberal” definition, along with lesions identified by random biopsy and endocervical curettage. With the conservative definition, HPV testing is clearly superior, whereas with the liberal definition, neither strategy is clearly superior. Lesions included in the liberal definition may have no potential to progess, but it is unusual to extend this rationale to lesions seen at colposcopy. The authors suggest that these visible lesions may have been squamous metaplasia histologically misinterpreted as high-grade cervical intraepithelial neoplasia (grade 2 or higher), but this hypothesis was never confirmed by pathological re-review of the targeted biopsy specimens. We propose an alternative outcome measure: the presence of histologically verified, high-grade cervical intraepithelial neoplasia in either the colposcopically targeted biopsy specimen or the final excision specimen.

In VivoMolecular Imaging of Cervical Neoplasia Using Acetic Acid as Biomarker

In this paper, a molecular imaging method employing acetic acid dilute solution as a biomarker is described. An interpretation of the biophysical processes that are involved in the biomarker-tissue interaction and are determining the in vivo measured dynamic scattering characteristics is presented. On the basis of this interpretation, a compartmental model of the epithelium is developed for predicting the epithelial transport phenomena that are expected to be correlated with the dynamic characteristics of the backscattered light. The model predictions have been compared with the experimental data obtained from patients with cervical neoplasia of different grade, with the aid of a specially developed imaging system. Comparisons confirmed the validity of the interpretation of the phenomenon, and particularly, the fact that dynamic scattering characteristics are largely determined by the intracellular proton concentration kinetics. In addition, the correlation of the latter with both structural and functional alterations, associated with cervical neoplasia development, has been predicted theoretically and confirmed experimentally. The established correlation enables the derivation of quantitative indices expressing disease-specific microstructural and functional alterations, from the in vivo measured dynamic optical characteristics. This highlights the potential of the developed imaging method and technology for the noninvasive diagnosis, guided therapeutics, and screening of cervical neoplasia.

Human Papillomavirus Infections in Cuban Women With Cervical Intraepithelial Neoplasia

The aims of the current study were to detect different HPV types in Cuban patients with different grades of cervical intraepithelial neoplasia (CIN) and to assess the association between HPV infection and other risk factors involved in the development of cervical cancer in Cuban women. We analyzed 60 samples from women with a previous diagnosis of abnormal cytology (15 CIN-1 36 CIN-2 and 9 CIN-3) who were referred to the Gynecology and Obstetrics Department at Eusebio Hernandez Maternity Hospital in Havana Cuba by their primary clinics. Epidemiologic data were obtained from standardized questionnaires. The questionnaire was designed to provide information on sexual and reproductive behavior (reproductive and gynecological history sexual history and the age of the first intercourse) socioeconomic conditions cigarette smoking and oral contraceptive use. During the first visit to the hospital an informed consent was obtained from each patient. For HPV detection ectocervical and endocervical scrapings were used; Pap smears were also analyzed. Every patient underwent colposcopic examination which included two schematic drawings of the reactions of the acetic acid and Lugol solution. This method allowed the detection of leucoplastic lesions atypical transformation zones cervicitis colpitis and condylomatous lesions. (excerpt)

Is urinary tract cytology still useful for diagnosis of bladder carcinomas? A large series of 592 bladder washings using a five‐category classification of different cytological diagnoses

The aim of this study was to estimate the efficiency of a recent five-category urinary cytological classification. A total of 592 bladder washings were fixed immediately with Saccomanno's fixative. All samples were centrifuged in a Hettich cyto-centrifuge. For each sample, the reference standard was the histology when a lesion was present at the time of cystoscopy. A five-category cytological classification was used: negative, suspicious of low (S-Lg) or high (S-Hg) grade neoplasia and consistent with low (Lg) or high (Hg) grade neoplasia. For cytological diagnoses of S-Lg and Lg, sensitivity was 37% and specificity was 95% for the histological diagnosis of low-grade non-invasive urothelial papillary tumour (Lg-UPT), which included papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma. For cytological diagnosis of S-Hg and Hg, sensitivity was 44% for high-grade non-invasive urothelial papillary carcinoma (Hg-UPC), 70% for carcinoma in situ (CIS) and 81% for invasive carcinoma (T1 and higher). Specificity was 99% in each case. Cytological diagnosis of S-Hg or Hg was not found for Lg-UPT (0/59) and no cytological diagnosis of S-Lg or Lg was found for invasive carcinoma, but was seen for Hg-UPC in 10% (3/28) and for CIS in 6% (3/50) of cases. Despite the absence of international consensus, the recent five-category cytological classification for urine is accurate for current urological practice.

The histopathologic patterns of cervical lesions and visual inspection with acetic acid on excised uterine cervices

The histologic patterns of cervical lesions as detected by visual inspection of the cervix with acetic acid (VIA) method were studied in 162 excised uterine cervices. There were 103 cervices of previous histologically confirmed cervical neoplasia treated by loop electrosurgical excision procedure (LEEP) or hysterectomy (group 1) and 59 cervices of hysterectomy specimens without known cervical pathology (group 2). Each freshly received cervix was examined with naked eye, photographed, 4% acetic acid applied, and then reexamined with naked eye for any color changes. Then it was rephotographed, divided spatially into 12 segments like on a face of a clock, processed to produce hematoxylin and eosin-stained glass slides, and histologically examined. The raised dull white changes, positive VIA, were highly correlated with the higher grade of cervical intraepithelial neoplasia (CIN) (CIN 2 + CIN 3). In group 1, the sensitivity of the acetic acid in detecting high-grade CIN was 98.6%, the specificity was 82.4%, the positive predictive value was 91.9%, and the negative predictive value was 96.6%. The flat white changes, negative VIA, were mostly correlated with CIN 1-koilocytosis. This study found that the validity of the VIA technique in detecting high-grade CIN was acceptable.

Distinction of high-grade intraepithelial neoplasia and invasive Barrett's adenocarcinoma

Grading of intraepithelial neoplasia and diagnosis of mucosal carcinoma in Barrett's esophagus provokes controversy when discussed because there is wide interobserver and intraobserver variation of such diagnoses. With new endoscopic techniques, it might become easier to target biopsies to the most relevant structural changes to achieve more-precise diagnoses. Nevertheless, the distinction between high-grade intraepithelial neoplasia and mucosal carcinoma is almost without clinical relevance because both lesions need to be removed endoscopically if it is proven that they are definitively limited to the mucosal level. Studies on the “natural course” of high-grade intraepithelial neoplasia show that overdiagnoses and underdiagnoses occur at receipt of the surgical specimen. Our knowledge of diagnostic criteria should be increased.

Epigenetic alterations in intraductal papillary mucinous neoplasms of the pancreas

Intraductal papillary mucinous neoplasm (IPMN), an increasingly recognized cystic neoplasm of the pancreas with a broad spectrum of malignant potential, has been considered a precursor to infiltrating ductal adenocarcinoma. Because of its unique clinical, radiological, pathological, and molecular features, IPMN has attracted considerable interest among clinicians and researchers. Although some genetic alterations have been described in IPMNs, the molecular features that characterize the evolution and progression of these neoplasms are largely unknown. Recent studies have shown that aberrant methylation of the promoter cytosine-phospho-guanine (CpG) island is a common mechanism associated with the silencing of tumor-suppressor and cancer-related genes in IPMNs. Importantly, the prevalence of such methylation increases along with the grade of neoplasia, suggesting that these epigenetic events may contribute to the progression of IPMNs. Further studies of epigenetic alterations in IPMN will shed light on the molecular pathogenesis of this unique neoplasm and lead to the identification of epigenetic markers that can be applied in the clinical setting.