Various Grades Of Dysplasia Research Articles

Evaluation of Immunohistochemical Marker Bcl-2 in Epithelial Dysplasia and Squamous Cell Carcinoma of the Oral Cavity.

Squamous cell carcinoma of the oral cavity is the most common malignancy noted globally.Pathogenesis of premalignant and malignant oral lesions is mainly attributed to the alteration in the molecular mechanisms that regulate apoptosis and cell proliferation. B-cell lymphoma gene 2 (Bcl-2) is the anti-apoptotic gene that prolongs cell survival by inhibiting apoptosis and is associated with the aggressive behaviour of malignant tumours. The aim of the study was to evaluate Bcl-2 expression in oral squamous cell carcinoma and dysplastic lesions of the oral cavity and to compare its expression with various grades of dysplasia and carcinoma. A hospital-based cross-sectional study was done on 80 clinically suspected cases of dysplastic and malignant oral cavity lesions received in the histopathology section of the Department of Pathology of Shri BM Patil Medical College Hospital and Research Center, Vijaypura, Karnataka. Out of 80 cases, 40 were squamous cell carcinoma, and 40 were dysplastic lesions of the oral cavity. For each case, two sections measuring 4 μm thickness were prepared. Hematoxylin and eosin staining was performed on one section, and Bcl-2 IHC staining was performed on another. Bcl-2 expression evaluation was done for each case of oral epithelial dysplasia and squamous cell carcinoma. Out of 40 cases of squamous cell carcinoma, 15 were well-differentiated, 22 were moderately differentiated, and three were poorly differentiated. In well-differentiated oral squamous cell carcinoma, Bcl-2 positivity was grade 0 in 66.7% of cases and grade 1 in 33.3% of cases. In moderately differentiated oral squamous cell carcinoma, Bcl-2 positivity was grade 1 in 63.6% of cases and grade 2 in 36.4% of cases. In poorly differentiated oral squamous cell carcinoma, Bcl-2 positivity was grade 1 in 33.3% and grade 2 in 66.7% of cases. Out of 40 cases of dysplastic lesions, 11 cases showed severe dysplasia, 11 cases showed moderate dysplasia and 18 cases showed mild dysplasia. grade 2 positivity was seen in 72.7% of cases of severe dysplasia and 63.6 % of cases of moderate dysplasia. In mild dysplasia, all of the cases showed grade 0 Bcl-2 expression. In poorly differentiated oral squamous cell carcinoma Bcl-2 positivity was high and low in well-differentiated oral squamous cell carcinoma. Bcl-2 expression was higher in severe dysplasia compared to moderate dysplasia, which may indicate aggressive behaviour of tumour in poorly differentiated oral squamous cell carcinoma and severe dysplasia.

Use of Autoreactive Antibodies in Blood of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMN) for Grade Distinction and Detection of Malignancy.

Simple SummaryRisk stratification via biomarkers used with imaging could support predicting high-risk pancreatic intraductal papillary mucinous neoplasms (IPMN) with malignant potential. We explored the presence of autoreactive antibodies in the blood of patients with IPMN of different grades of dysplasia, including IPMN with associated invasive carcinoma and early-stage pancreatic ductal adenocarcinoma (PDAC), to identify signatures of early malignancy. Multivariate predictive models retained 14 proteins as potential biomarkers for discrimination between all disease classes. The integration of the autoreactive-antibody panel with clinical variables may aid in risk stratification of high-risk IPMN patients, which would subsequently improve clinical management.(1) Background: A reliable non-invasive distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMN) is needed to effectively detect IPMN with malignant potential. This would improve preventative care and reduce the risk of developing pancreatic cancer and overtreatment. The present study aimed at exploring the presence of autoreactive antibodies in the blood of patients with IPMN of various grades of dysplasia. (2) Methods: A single-center cohort was studied composed of 378 serum samples from patients with low-grade IPMN (n = 91), high-grade IPMN (n = 66), IPMN with associated invasive cancer (n = 30), pancreatic ductal adenocarcinoma (PDAC) stages T1 (n = 24) and T2 (n = 113), and healthy controls (n = 54). A 249 full-length recombinant human protein microarray was used for profiling the serum samples. (3) Results: 14 proteins were identified as potential biomarkers for grade distinction in IPMN, yielding high specificity but mediocre sensitivity. (4) Conclusions: The identified autoantibodies are potential biomarkers that may assist in the detection of malignancy in IPMN patients.

Prognostic Significance of p53 Expression in Various Grades of Epithelial Dysplasia

Background: Potentially malignant disorders in oral mucosa represent the morphological steps of epithelial transformation in the form of various grades of dysplasia. Only few cases of dysplasia evolve into carcinoma, and there is no specific markers invented which can predict the probability of progression. Oral carcinogenesis is a multistage course which constitutes a sequence of molecular events resulting in cell cycle dysregulation. p53 is the most commonly affected tumor suppressor gene. p53 mutation leads to uncontrolled proliferation of cancer cells as well as increased p53 protein. p53 overexpression has been suggested to be consistent indicator for the development of oral cancer. The objective of this study is to investigate p53 immunohistochemical expression in various grades of oral epithelial dysplasia (ED) and to estimate the correlations between their expression levels in various grades of dysplasia. Materials and Methods: This study is done at the Department of Oral Pathology and Microbiology, SPDC, Wardha. Total four groups were taken. Ten patients each of mild, moderate, and severe ED, i.e., total-30 patients and 10 control patients. The sample size required for the group was calculated by using the required formula. p53-positive cells were counted in 5 high power field (HPF) in all grades of ED and labeling index was measured. Results: Analysis of variance test was applied to see the differences in the p53 expression. Conclusion: The increase in the p53 expression in epithelium correlates to various grades of EDs.

Correlation of Mast Cell and Angiogenesis in Oral Lichen Planus, Dysplasia (Leukoplakia), and Oral Squamous Cell Carcinoma.

ObjectiveThe aim of this study was to compare and correlate mast cell density (MCD) and microvessel density (MVD) between normal oral mucosa, oral lichen planus, various grades of dysplasia, and oral squamous cell carcinoma (OSCC).Materials and MethodsThe study comprised a total of 75 samples, of which 65 were archival tissue blocks of histopathologically confirmed cases, which included 10 cases of oral lichen planus, 25 cases of dysplasia (mild [n=10], moderate [n=10], and severe [n=5]), and 30 cases of OSCC (well differentiated [n=10], moderately differentiated [n=10], and poorly differentiated [n=10]), and 10 samples of normal oral mucosa. All the sections were immunohistochemically stained with anti-CD34 and counterstained with toluidine blue stain. Mean MCD and MVD were determined and analyzed using ANOVA test and compared between the lesions using Tukey HSD test. Pearson’s correlation coefficient test was used to correlate these two factors between various lesions.ResultsMean MCD and mean MVD were found to be increased in all the lesions compared to normal oral mucosa, and the values were statically significant. Overall, MCD and MVD showed a significant positive correlation (r=0.640).ConclusionIncrease of MCD and MVD and their positive correlation in all the lesions have emphasized their role in the pathogenesis and disease progression.

GLUT-1 Expression: An Aid in Complementing the WHO Oral Epithelial Dysplasia Grading System

The clinicopathologic parameters alone are not sufficient to precisely predict if oral potentially malignant disorders (OPMDs) remain unchanged, i.e., without any malignant changes, regress, or advance to oral squamous cell carcinomas (OSCC). Few of the OPMDs, with or without epithelial dysplasia, may transform to frank OSCC. Discovering various molecular markers that can predict OSCC transformation is essential to develop effective therapeutic strategies. GLUT-1 is one of the hypoxia as well as metabolic indicator markers that have been used to study the metabolic activity of the cells. Hence, given by the World Health Organization (WHO), GLUT-1 expression was studied in various grades of dysplasia to see whether it complements the WHO grading system (mild, moderate, and severe). The study was carried out on paraffin-embedded tissues of 10 normal oral mucosa and 30 OPMD cases. OPMD cases were classified into hyperkeratosis, mild dysplasia, moderate dysplasia, and severe dysplasia groups. Immunohistochemistry was carried out to evaluate the expression of GLUT-1 antigen. According to the WHO grading system of dysplasia, 11 (36.66%) cases were classified as hyperkeratosis, 9 (30%) cases were classified as mild dysplasia, 6 (20%) cases as moderate dysplasia, and 4 (13.33%) cases as severe dysplasia. There was a significant increase in GLUT-1 expression from normal to mild, moderate, and severe dysplasia (p value = 0.00). The expression of GLUT-1 marker complements the WHO grading system of oral epithelial dysplasia. GLUT-1 expression can be used to complement the WHO grading system to grade epithelial dysplasia.

Morphological Analysis of Elastic Fibers in Various Grades of Oral Squamous Cell Carcinoma and Epithelial Dysplasia Using Verhoeff-Van Gieson Stain.

BackgroundOral squamous cell carcinoma (OSCC) is the sixth most common malignancy in India. The aggressiveness of OSCC is analyzed not only based on the dysplastic features and tumor infiltration pattern, but also by means of the stromal changes that pave the way for an invasion into the connective tissue. The role of elastic fibers in the progression of OSCC is still unknown because of sparse literature and the masking effect of overlying inflammatory cells and the lower number of elastic fibers in the lamina propria. The present study provides further insight into the qualitative assessment of elastic fibers in various grades of dysplasia and OSCC.ObjectivesTo analyze the morphological changes exhibited by the elastic fibers in epithelial dysplasia and OSCC.Materials and methodsTwo sections were cut from each of 60 samples of varying grades of OSCC and 60 samples of varying grades of epithelial dysplasia followed by staining with hematoxylin and eosin and Verhoeff–Van Gieson stain.ResultsStatistically significant results were obtained for qualitative analysis of elastic fibers. A change in density and orientation to overlying epithelium and tumor islands was seen on progressing from well-differentiated to poorly differentiated OSCC and in progressing grades of dysplasia.ConclusionThe uniqueness of this study lies in the exploration of elastic fibers in dysplasia and well-differentiated OSCC, a less explored field. The study of the connective tissue stromal changes can be used as an adjunct to histological grading.

Stratification of the dysplasia and neoplasia risk using autofluorescence endoscopic surveillance of Barrett's esophagus.

This study assessed the efficacy of autofluorescence endoscopy (AFE) using the Onco-LIFE system and numerical color value (NCV) estimation in comparison to white light endoscopy (WLE) in endoscopic surveillance for identification of early dysplasia in Barrett's esophagus (BE) to aid in real-time image elucidation and minimize the overreliance on biopsy and histology. AFE, performed simultaneously during WLE, with biopsy was performed among 24 patients with BE. None of these patients had any obvious mucosal abnormalities in WLE. A total of 376 biopsies were taken, include 325 randomly collected according to Seattle Protocol and 51 additional biopsies, taken from the sites with pathological AF and NCV. All biopsy sites were assessed in vivo using WLE, AFE and NCV and compared to histological examinations, to estimate the efficacy of these methods in dysplasia assessment in BE. In the case of 248 biopsies taken from sites with NCV below 1.0, two cases of unspecified dysplasia were recognized; in 14 biopsies with NCV above 2.0 in all cases the various grades of dysplasia were documented. Dysplasia was found in 42% of AFE + NCV- guided biopsy specimens, and in 7.1% of WLE-guided biopsy specimens. AFE + NCV detected high-grade dysplasia in 7 patients, 6 more than according to Seattle Protocol in WLE. The expected odds of dysplasia detection in a sample increases almost 1.9 times, if it was selected by the AFE method (p < 0.001), when compared to WLE and with accordance with Seattle Protocol guided biopsy. The above results indicate that AFE + NCV using the Onco-LIFE system leads to improved BE lesion visualization for targeted biopsy with accurate histologic correlation compared to WLE and Seattle Protocol guided biopsy alone, and can serve to minimize additional biopsies.

Symptomatic HPV-related neovaginal lesions in transgender women: case series and review of literature

ObjectiveWorldwide, transgender women are an at-risk population for contracting sexually transmitted infections. Little information exists on symptoms and characteristics of neovaginal human papillomavirus (HPV) infections and associated diseases. We describe...

Confocal Laser Endomicroscopy in Precancerous Lesions of the Head and Neck

Objectives: Distinguishing precancerous lesions from invasive carcinoma is a challenge due to field cancerization. Extensive biopsies are required to determine histology and sampling errors result in inaccurate diagnosis. The probe based confocal laser endomicroscopy (pCLE) is an emerging technology of real time microscopic imaging of mucosal surfaces at the cellular level. It has been studied extensively in the lung and gastrointestinal tract but not the head and neck. Methods: We performed a study on awake patients with 15 precancerous and cancerous lesions of the oral cavity. After intravenous injection of fluorescein, a 1.8-mm gastroflex probe helped visualize normal mucosa, carcinoma, and precancer to assess image quality on various grades of dysplasia. The histology from biopsies of visualized areas was compared to optical images. Results: The dorsal surface of the tongue was not well visualized due to the keratinized filiform papillae. The remaining non-keratinized subsites, buccal mucosa, floor of mouth, and ventral tongue were well visualized. Although leukoplakia was widespread, only some areas demonstrated suspicious microarchitecture, including abnormal vasculature and disruption of membranes. This correlated with final histology. Flat, well-organized scale-like cells were noted in normal mucosa. In patients with carcinoma in situ there were increased ectatic blood vessels. In high grade dysplasia there was complete disorganization of the epithelium and fluorescein leakage with an abrupt change to the so called “black cells.” Conclusions: The pCLME has significant potential in determining areas more likely to progress to carcinoma, resection margins in head and neck squamous cell carcinoma patients plagued with field cancerization, and response to chemopreventive agents.

Type-dependent E6/E7 mRNA expression of single and multiple high-risk human papillomavirus infections in cervical neoplasia

BackgroundCoinfection with multiple HPV types is common in cervical lesions, but the biological significance of the individual infections is difficult to establish. Expression of oncogenic E6/E7 HPV mRNA is correlated to risk of malignant progression, commercial assays for genotyping E6/E7 mRNA of all HR-HPV are lacking. ObjectivesTo characterize the tendency of 12 HR-HPV to express mRNA, correlated to the severity of the cervical lesion. Furthermore, we wanted to analyse mRNA expression in multiple infections, in order to establish which genotype may be responsible for cellular transformation. Study design245 samples from women with normal histology, various grades of dysplasia (cervical intraepithelial neoplasia grade 1–3), and cancer, were analysed for presence and genotyping of HPV DNA and mRNA using an in house real-time PCR test. ResultsPresence of mRNA was detected for 64% of the in total 422 HPV infections present in the samples, and more commonly in high-grade lesions. In 88% of DNA-positive samples from CIN2+ lesions, mRNA could be detected, compared to 33% of DNA-positive samples from women in screening with normal cytology. The genotype most prone to express mRNA in high-grade lesions was HPV45, followed by HPV16 and HPV31, less prone was HPV59. Expression of mRNA was significantly enhanced in CIN2+ lesions, an association also found for HPV16. In 52% of multiple infections (in which mRNA expression was generally more common), more than one genotype expressed mRNA, a phenomenon increasing with severity of lesion. Presence of mRNA could more often be detected in samples with multiple infections than in samples with single infections. ConclusionsThe frequent expression of E6/E7 by HPV45 may promote oncogenicity and could be of clinical importance. Since presence of E6/E7 mRNA was common in multiple infections regardless of histology, multiple infection could be a clinically important finding. In multiple HPV infections, mRNA testing may identify the genotype that causes transformation. However, since mRNA expression of several genotypes in one sample is common, further and larger studies using complementary techniques are required.

Reproducibility of grading systems in oral epithelial dysplasia

Objective: To assess inter and intra observer variability in grading oral epithelial dysplasia (OED) using Smith and Pindborg grading system, WHO classification system and Brothwell DJ et al. classification system. Study design: In the study 45 histological tissues of dysplasia, 15 each of mild, moderate and severe dysplasia were coded and blindly graded by three observers in three grading systems. Further on the same observers graded 15 slides again of the previous 45 for analyzing the reproducibility in the three grading systems. The individual significance of various indicators of dysplasia among various grades of dysplasia was also assessed. Result: Inter observer agreement was significantly higher in Brothwell system as compared to WHO and Smith and Pindborg system. Intra observer agreement was significantly higher in Smith and Pindborg system, but the predictability and the probability index was distributed over a larger range in this system. Each indicator of dysplasia was also found to be statistically significant (P<0.05) for grading dysplasia. Conclusion: The present study puts forth the inherent intricacies in the grading of oral premalignant lesions. Key words:Carcinoma, dysplasia, grading systems, reproducibility.

Abstract CN07-03: Natural history of bronchial preneoplasia

Abstract Preinvasive bronchial lesions defined as dysplasia and carcinoma in-situ (CIS) have been considered as precursors of squamous cell carcinoma of the lung. The risk and rate of progression of preinvasive lesions to invasive squamous cell carcinoma as well as the mechanism of progression or regression are incompletely understood. The evidence for the multistage, stepwise progression model is weak with relatively few documented lesions that progress through normal to hyperplasia, metaplasia and various grades of dysplasia to CIS and then to invasive carcinoma. Collective data from longitudinal studies using autofluorescence bronchoscopy directed sequential bronchial biopsies from the Netherlands, Canada, France, and Japan as well as published data suggest that the time to development of CIS or invasive squamous cell carcinoma from precursor lesions does not follow an anticipated trend from a stepwise progression model. Aside from severe dysplasia that has the shortest progression time, there is no pattern between the baseline pathology and the time of development of CIS or invasive cancer. The presence of dyspalsia or CIS is a field cancerization risk marker for lung cancer both in the central airways and peripheral lung. Specific genetic alterations and host factors such as the inflammatory load and levels of anti-inflammatory proteins in the lung likely influence the progression or regression of pre-invasive lesions. Recently, using integrative genomic approach, combining high-resolution comparative genomic hybridization and gene expression microarray profiles, the focal amplification of an oncogene -BRF2 in chromosome region 8p12 was found to be specific for development of lung squamous cell carcinoma through the increase of Pol III mediated transcription. BRF2 was frequently activated in carcinoma in situ and dysplasia (PLoS Med 7(7): e1000315. doi:10.1371/journal.pmed.1000315). Molecular analysis of rare lesions that progress from normal, hyperplasia, metaplasia or dysplasia to CIS or invasive cancer will shed further light on the key molecular determinants driving development to an invasive phenotype versus those associated with tobacco smoke damage. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN07-03.

Natural history of bronchial preinvasive lesions

Preinvasive bronchial lesions defined as dysplasia and carcinoma in situ (CIS) have been considered as precursors of squamous cell carcinoma of the lung. The risk and rate of progression of preinvasive lesions to invasive squamous cell carcinoma as well as the mechanism of progression or regression are incompletely understood. While the evidence for the multistage, stepwise progression model is weak with relatively few documented lesions that progress through various grades of dysplasia to CIS and then to invasive carcinoma, the concept of field carcinogenesis is strongly supported. The presence of high-grade dysplasia or CIS is a risk marker for lung cancer both in the central airways and peripheral lung. Genetic alterations such as loss of heterozygosity in chromosome 3p or chromosomal aneusomy as well as host factors such as the inflammatory load and levels of anti-inflammatory proteins in the lung influence the progression or regression of preinvasive lesions. CIS is different than severe dysplasia at the molecular level and has different clinical outcome. Molecular analysis of dysplastic lesions that progress to CIS or invasive cancer and rare lesions that progress rapidly from hyperplasia or metaplasia to CIS or invasive cancer will shed light on the key molecular determinants driving development to an invasive phenotype versus those associated with tobacco smoke damage.

Role of small proline rich protein in dysplasia and squamous cell carcinoma

Background and Objectives: The small proline rich protein (SPRR) genes constitute a family of conserved genes which are part of the human epidermal differentiation complex (EDC) on chromosome 1q21 and code for precursor proteins of the cornified cell envelope. The expression of these genes is strictly linked to keratinocyte terminal differentiation The objective of this study was to compare the expression of SPRR2 in normal buccal mucosa, and various grades of dysplasia and oral squamous cell carcinoma.

Mucin core polypeptide expression in the progression of neoplasia in Barrett's esophagus

We have previously demonstrated a specific pattern of mucin (MUC) core polypeptide expression in Barrett's esophagus (BE) characterized by MUC1 and MUC6 positivity in goblet cells in a proportion of cases. The aim of this study was to determine the pattern of MUC expression associated with the development and progression of dysplasia in BE. Endoscopic mucosal biopsies from 35 patients with BE (10 with no dysplasia, 6 with indefinite for dysplasia, 12 with low-grade dysplasia [LGD], and 7 biopsies with high-grade dysplasia [HGD]) were immunostained (ABC method) with antibodies against MUC1, MUC2, MUC3, MUC5AC, and MUC6. The extent and pattern of staining for each marker was evaluated in intestinalized Barrett's epithelium and in the various grades of dysplasia. For cases with dysplasia, staining was evaluated separately in nondysplastic epithelium adjacent to (<1 cm) and distant from (>2 cm) areas of dysplasia. In nondysplastic BE, MUC1, MUC2, MUC3, MUC5AC, and MUC6 stained 40%, 100%, 100%, 100%, and 90% of cases, respectively, in goblet or nongoblet columnar epithelium. With the progression of dysplasia (from metaplasia to indefinite, LGD and HGD), there was a significant decrease in expression of MUC1, MUC2, and MUC3, and alterations in the staining patterns of MUC5 and MUC6. In fact, MUC1 and MUC3 were entirely absent from all cases of HGD. Interestingly, BE-associated adenocarcinomas showed an MUC phenotype distinct from that of HGD, with expression of MUC1 and MUC3 in 47% and 67% of cases, and expression of MUC1 in a membranous pattern. There was no significant difference in MUC staining in nondysplastic BE between patients with and without dysplasia. Alterations in MUC expression occur in the progression of dysplasia in BE. However, none of these markers helps identify a subgroup of patients at increased risk for neoplasia.

Intraductal papillary mucinous tumor of the pancreas and multiple adenomas of the colon

Intraductal papillary mucinous tumor (IPMT) of the pancreas is an extremely rare entity. This type of neoplasm was first described by Ohashi et al. 1 Ohashi K Murakami Y Takekoshi T Ohta H Ohhashi I Four cases of mucus producing cancer of the pancreas on specific findings of the papilla of Vater. Prog Dig Endosc. 1982; 20: 348-351 Google Scholar in 1982 as a diffuse dilatation of the main pancreatic duct with filling defects on pancreatography and extrusion of mucin from the duodenal papilla. IPMTs exhibit various grades of dysplasia and can progress to frank carcinoma. However, the prognosis for patients is favorable if the tumor is resected. 2 Loftus EV Olivares-Pazkzad BA Batts KP Adkins MC Stephens DH Sarr MG et al. Intraductal papillary-mucinous tumors of the pancreas: clinicopathologic features, outcome, and nomenclature. Gastroenterology. 1996; 110: 1909-1918 Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar There are few cases reported of IPMT associated with other premalignant conditions. In cited cases, the association has been with colorectal adenoma and adenocarcinoma. The K-ras mutation may be a genetic link between IPMT and colorectal adenomas that progress to frank adenocarcinoma. 3 Sugiyama M Atomi Y Hachiya J Intraductal papillary tumors of the pancreas: evaluation with magnetic resonance cholangiopancreatography. Am J Gastroenterol. 1998; 93: 156-159 Crossref PubMed Scopus (100) Google Scholar This report describes a patient with IPMT and multiple adenomas of the colon.

K-ras gene mutations and loss of heterozygosity at the p53 gene locus relative to histological characteristics of mucin-producing tumors of the pancreas

Mucin-producing tumors (MPTs) of the pancreas accompanied by carcinomas usually include various grades of dysplasia in the ductal epithelium, and invasive areas are histologically similar to those of common invasive ductal carcinomas, suggesting that MPTs provide a good tool to investigate early stages of pancreatic carcinogenesis. Thus, to clarify genetic alterations in the early stage of pancreatic carcinogenesis, we analyzed K-ras gene mutations and loss of heterozygosity (LOH) at the p53 gene locus using 37 cases of MPTs harboring dysplastic epithelium. Further, we conducted an extended, multifocal microdissection analysis focusing on the histological features of ductal epithelium and the distribution of genetic alterations for 3 cases of MPT positive for LOH of the p53 gene to determine the relation to tumor progression. K-ras gene mutations were detected with high frequency in 50% or more cases of the adenomas (14 of 19), borderline tumors (4 of 7), and carcinomas (8 of 11), whereas LOH of the p53 gene was limited to carcinomas (3 of 5 informative cases, 60%) and always accompanied by K-ras gene mutation. Investigation of a total of 126 microdissection sites from 3 cases showed the presence of K-ras gene mutations in mild dysplasia and all (100%) regions of moderate or more marked dysplasia, whereas LOH of the p53 gene showed more gradual tendency to increase with grade from moderate dysplasia. In addition, the multifocal genetic analysis showed K-ras gene mutations to be widely distributed throughout tumors, whereas LOH of the p53 gene was localized to 1 or a few areas. Further, topographically delimited areas with the same histology in the same tumor did not always show the same genetic alteration. In conclusion, we could confirm that both the K-ras and p53 gene alterations occur in the intraductal stage of MPT, and the latter is superimposed on the former during the course of tumor progression. However, the pattern of association of histological features with genetic alteration differs from tumor to tumor. HUM PATHOL 31:795-803.

Human papillomavirus findings in relation to cervical intraepithelial neoplasia grade: A study on 476 stockholm women, using pcr for detection and typing of HPV

Among human papillomavirus (HPV) types found in humans, there is a strong association between HPV 16, 18, 31, and 33, and cervical cancer. The relationship between various grades of dysplasia and HPV type is less clear. To elucidate this point, the authors tested 476 cytological and histological samples from cervix with polymerase chain reaction (PCR) for HPV using consensus primer My 09–11 and type-specific primers. All cases were divided into groups on the basis of cytology: “normal cases” (ie, women with other disease than cervical intraepithelial neoplasia [Cin]), and CIN I, II, and III. Out of the “normal cases,” in which women with a previous history of condyloma and dysplasia were included, 69% had HPV with type 6 as the most common one. Of all CIN I cases, 71% were HPV positive, and HPV type 6 and 16 were equally common. In CIN II cases, HPV 16 was the most common type, whereas HPV 6 accounted for only 7.5% of cases in this group as single virus type. HPV 16 was also the most common type in the CIN III group, followed by type 33. Double and even multiple infections occurred in all groups.

The value of p53 and Ki67 as markers for tumour progression in the Barrett's dysplasia-carcinoma sequence

In the Barrett's oesophagus (BE) progression from metaplasia, via dysplasia, into invasive cancer, an aberrant cell proliferation governed by genetic change plays a central role. Alterations of the p53 tumour-suppressor gene appear especially critical and, like the proliferation marker Ki67, can be detected by immunohistochemistry. The purpose of this study therefore was to investigate the clinical value of p53 and Ki67 as markers for tumour progression in BE, and at the same time test the validity of the concept of a metaplasia-dysplasia-carcinoma sequence in BE by correlating the expression of these markers with various grades of dysplasia. Thirty-two lesions (seven negative for dysplasia, five indefinite for dysplasia, 11 low-grade dysplasia and nine high-grade dysplasia) from 25 archival resection specimens were selected for study. Increasing grades of dysplasia showed increasingly p53 accumulation; p53 accumulation was never observed in mucosa without dysplasia. The increasing p53 expression was accompanied by an increased Ki67-labelling index and an upward shift of the proliferative compartment. The results lend support to the multistep progression model of a metaplasia-dysplasia-carcinoma sequence in BE. Expression of p53 and Ki67, markers which can be easily applied on archival material, can be valuable adjuncts for the histopathological diagnosis of dysplasia and may have predictive value for cancer risk.

Expression of the proliferating cell nuclear antigen in cervical neoplasia.

The expression of the proliferating cell nuclear antigen (PCNA) was examined to determine the proliferative activity of the cells in nonneoplastic and neoplastic lesions of the uterine ectocervix. Formalin-fixed, paraffin-embedded tissue sections of uterine cervix including normal, metaplasia, condyloma, intraepithelial neoplasia and invasive squamous cell carcinoma were stained immunohistochemically using monoclonal antibody to PCNA. The percentage of PCNA-positive cells was significantly higher in premalignant and malignant lesions of the uterine cervix than in nonneoplastic lesions. Furthermore, the growth fraction of tumor cells as detected by PCNA was increased in accordance with the progression of neoplasia. The results of this study suggest that the cell proliferation index as detected immunohistochemically using PCNA may be a useful adjunct to histological diagnosis of various grades of dysplasia.