Search

In the past decade, research efforts were made to identify molecular biomarkers useful as therapeutic targets in Non-Small Cell Lung Cancer (NSCLC), the most frequent type of lung carcinoma. NSCLC presents different histological subtypes being the most prevalent LUSC (Lung Squamous Cell Cancer) and LUAD (Lung Adenocarcinoma), and only a subset of LUAD patients' present tumors expressing known targetable genetic alterations. Telomeres and its components, including telomerase, the enzyme that replenishes telomeres, have been considered potential cancer biomarkers due to their crucial role in cell proliferation and genome stability. Our study aims to quantify expression changes affecting telomere-associated genes and ncRNAs associated with telomere regulation and maintenance in NSCLC. We first assessed the transcriptome (RNA-Seq) data of NSCLC patients from The Cancer Genome Atlas (TCGA) and then we tested the expression of telomere-associated genes and telomeric ncRNAs (TERC, telomerase RNA component, and TERRA, telomere repeat-containing RNA) in Brazilian NCSLC patient samples by quantitative RT-PCR, using matched normal adjacent tissue samples as the control. We also estimated the mean size of terminal restriction fragments (TRF) of some Brazilian NSCLC patients using telomeric Southern blot. The TCGA analysis identified alterations in the expression profile of TERT and telomere damage repair genes, mainly in the LUSC subtype. The study of Brazilian NSCLC samples by RT-qPCR showed that LUSC and LUAD express high amounts of TERT and that although the mean TRF size of tumor samples was shorter compared to normal cells, telomeres in NSCLC are probably maintained by telomerase. Also, the expression analysis of Brazilian NSCLC samples identified statistically significant alterations in the expression of genes involved with telomere damage repair, as well as in TERC and TERRA, mainly in the LUSC subtype. We, therefore, concluded that telomere maintenance genes are significantly deregulated in NSCLC, representing potential biomarkers in the LUSC subtype., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Morphologic evaluation of anal dysplasia remains problematic, especially in cases with limited biopsy samples or obscuring inflammation. Studies in cervical neoplasia have shown that human papillomavirus (HPV) L1 capsid production is highest in low-grade squamous intraepithelial lesions (LSILs) and progressively decreases in high-grade squamous intraepithelial lesions (HSILs). The combined utility of HPV L1 and p16 expression in assessing anal squamous intraepithelial lesions (SILs) has never been analyzed and forms the basis of this study., Methods: In total, 145 anal lesions were reviewed and immunohistochemically stained for HPV L1 and p16. p16 expression was recorded as negative, patchy/focal, or diffuse. For analytical purposes, condylomas were evaluated separately from rest of the LSILs., Results: There were 34 (23%) condylomas, 64 (44%) LSILs, and 47 (32%) HSILs. HPV L1 was significantly associated with condylomas (68%) and LSILs (52%) compared with HSILs (9%; P < .0001). Diffuse p16 staining was present only in HSILs (P < .0001), whereas a patchy/focal p16 staining pattern was observed in both LSILs and condylomas., Conclusions: HPV L1 and diffuse p16 expression is mutually exclusive in most anal SILs and helps separate LSIL and HSIL cases. Application of both HPV L1 and p16 can not only facilitate accurate grading but also contribute to risk assessment in anal neoplasia., (Copyright© by the American Society for Clinical Pathology.)

Introduction: The current edition of the tumor, node and metastasis (TNM) classification of lung cancer (LC) divides the presence of metastasis (M1) into two categories: M1a and M1b, depending on its anatomical location. To assess this new classification, the survival and the M descriptors of LC patients with metastatic disease registered by the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery II (GCCB-S-II), were analyzed., Methods: Non-small cell lung cancer (NSCLC) patients, with M1a or M1b disease, included in the GCCB-S-II, from April 2009 to December 2010, staged in accordance with the prospective staging project protocol of the International Association for the Study of Lung Cancer (IASLC), and with complete TNM staging and follow-up data, were studied. The overall survival associated with each M1 category and each M descriptor, besides other prognostic factors (sex, age, performance status [PS] and others) were analyzed by univariate and multivariate models., Results: 640 NSCLC patients (195 M1a and 445 M1b) were included. M1b tumors had significantly worse survival than M1a tumors (p < 0.001). The prognostic value of M1 category was independent from other prognostic variables such as PS, weight loss, and others. The number of metastatic sites (isolated versus multiple) and the number of lesions (single versus multiple) in patients with isolated metastasis showed prognostic value, especially in those with brain metastasis., Conclusion: The current division of the M1 category into two subsets (M1a and M1b) is warranted by their prognostic significance. The number of metastatic sites and the number of lesions in patients with isolated metastasis should be taken into account, because they also have prognostic relevance., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The current state in the field of classifying oral and laryngeal precursor lesions, as proposed in the WHO 2005 Blue Book is not ideal. The results of various inter-observer studies have shown that the currently used grading systems, with different basic concepts and different terminology, cannot continue to be reliably used in the future. The different etiology of cervical and head and neck precursor lesions requires a classification designed to cater to the specificities of the head and neck region. Trying to harmonize different classifications of the oral and laryngeal precursor lesions, we have proposed four crucial steps to set up a unified classification of squamous intraepithelial lesions (SILs): (a) the classification should contain two grades, low-grade and high-grade lesions and, specifically for the larynx, an additional grade-carcinoma in situ (CIS) which must be separated from high-grade laryngeal SILs; (b) the terminology should be unified; our preference is for the term SIL over squamous intraepithelial neoplasia; (c) all leading morphological criteria for low- and high-grade lesions, as well as for CIS, should be clearly defined; (d) agreement between clinicians and pathologists should be achieved on the most appropriate choice of treatment of different grades of SILs in separate head and neck areas.

Objectives: To examine data correlating high-risk human papillomavirus (hrHPV) results in patients with both low-grade squamous intraepithelial lesion (LSIL) and atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H) cytology findings (LSIL-H) with follow-up histopathology., Methods: A total of 494 LSIL-H ThinPrep (Hologic, Marlborough, MA) cases with hrHPV testing were identified. Histopathologic follow-up was available in 347 patients., Results: Among 347 patients with follow-up histopathology after LSIL-H cytology and hrHPV testing, 90.5% tested hrHPV positive. Cervical intraepithelial neoplasia (CIN) 2/3 was diagnosed in 29.4% and CIN 1 in 53.6%. CIN 2/3 was diagnosed in significantly more patients with hrHPV-positive LSIL-H than following hrHPV-negative LSIL-H results. Compared with published institutional data, LSIL-H had significantly lower hrHPV and histopathologic CIN 2/3+ rates (90.5% and 29.4%, with no cervical cancers) than high-grade squamous intraepithelial lesion (HSIL) (95.7% and 70.5%, with 2.4% cervical cancers) but higher rates than LSIL (80.2% and 12.9%) or atypical squamous cells/cannot exclude HSIL (ASC-H) (54.3% and 17.2%). Whereas CIN 2/3 detection rates were similar in HPV-positive LSIL-H and HPV-positive ASC-H, CIN 2/3 findings were more likely with HPV-negative LSIL-H than with HPV-negative ASC-H., Conclusions: LSIL-H is a unique category of cytologic abnormality associated with distinctive hrHPV and CIN 2/3+ diagnostic rates.

Background: Studies of the performance of the automated FocalPoint Guided Screening (FPGS) imaging system in gynecologic cytology screening relative to manual screening have yielded conflicting results. In view of this uncertainty, a validation study of the FPGS was conducted before its potential adoption in 2 large laboratories in Ontario., Methods: After an intense period of laboratory training, a cohort of 10,233 current and seeded abnormal slides were classified initially by FPGS. Manual screening and reclassification blinded to the FPGS results were then performed. Any adequacy and/or cytodiagnostic discrepancy between the 2 screening methods subsequently was resolved through a consensus process (truth). The performance of each method's adequacy and cytodiagnosis vis-a-vis the truth was established. The sensitivity and specificity of each method at 4 cytodiagnostic thresholds (atypical squamous cells of undetermined significance or worse [ASC-US+], low-grade squamous intraepithelial lesion or worse [LSIL+], high-grade squamous intraepithelial lesion or worse [HSIL+], and carcinoma) were compared. The false-negative rate for each cytodiagnosis was determined., Results: The performance of FPGS in detecting carcinoma, HSIL+, and LSIL+ was no different from the performance of manual screening, but the false-negative rates for LSIL and ASC-US were higher with FPGS than with manual screening., Conclusions: The results from this validation study in the authors' laboratory environment provided no evidence that FPGS has diagnostic performance that differs from manual screening in detecting LSIL+, HSIL+, or carcinoma., (Copyright © 2012 American Cancer Society.)

Background: The 2001 Bethesda System for gynecologic cervical cytology reporting classifies squamous intraepithelial lesions into low-grade (LSIL) and high-grade (HSIL) lesions. An intermediate term, "low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion (LSIL-H)," has been used in a small percentage of LSIL cases. To the authors' knowledge, little is known regarding the human papillomavirus (HPV) status in patients with LSIL-H., Methods: A total of 808 SurePath specimens obtained between December 2009 and April 2011 were tested for 40 HPV genotypes using DNA microarray, followed by a confirmatory DNA sequencing assay., Results: The infection rate for high-risk HPV in women with LSIL-H (92%) was strikingly close to that for women with HSIL (91%), which was higher than that for those with LSIL (74%); atypical squamous cells, cannot rule out high-grade lesion (ASC-H) (78%); or LSIL and ASC-H combined (74%). HPV type 16, the most common carcinogenic HPV genotype, was detected in 36% of women with LSIL-H, which was significantly higher than that in women with LSIL and ASC-H combined (13.8%), but less than that in women with HSIL (44.6%). Patients with LSIL-H and HSIL had similar infection rates for low-risk/intermediate-risk HPV genotypes, which were lower than those in LSIL or LSIL and ASC-H combined., Conclusions: Women found to have LSIL-H on a Papanicolaou test appear to have a unique HPV distribution pattern that clearly differs from LSIL and is comparable to that for HSIL, suggesting an increased risk of high-grade lesions over that of women with LSIL. Recognizing LSIL-H as an independent diagnostic category may help in the early identification of the high-risk subgroup that may require a management algorithm comparable to that for patients with HSIL. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society., (Copyright © 2012 American Cancer Society.)

Objective: To analyze the correlation and accuracy between Reid's colposcopic index (RCI) and histologic results from colposcopically directed biopsy (CDB) in differentiating high-grade squamous intraepithelial lesion (HSIL) from low-grade squamous intraepithelial lesion (LSIL)., Materials and Method: A retrospective analysis of medical records of women who had abnormal Pap smear and underwent colposcopy, RCI scoring and CDB from January 1st, 2003 to December 31st, 2006 at Rajavithi Hospital was conducted., Results: One hundred women were included in the present study. Compared with histological diagnosis from CDB, accuracy for four colposcopic criteria: margin pattern, color, vascular pattern and iodiness staining were 73.0%, 79.0%, 75.0% and 69.2%, respectively. Combining these variables into RCI showed 89.0% overall accuracy. Color and vascular pattern showed a good agreement with histologic results from CDB (Kendall's tau C = 0.68 and 0.63; p < 0.05). Overall, RCI yielded a good agreement (Kendall's tau C = 0.66; p < 0.05)., Conclusion: RCI yields a good correlation with histology from CDB and it has high accuracy in differentiating HSIL from LSIL.

Objective: To evaluate the histopathology of women who had "atypical squamous cells of undetermined significance" (ASC-US) on cervical cytology in a region with high incidence of cervical cancer., Material and Method: Retrospective case-record review of 254 women with ASC-US cytology undergoing colposcopic examination at Nakornping Hospital between October 2003 and September 2007., Results: Of the 254 patients who had ASC-US smears underwent colposcopic and histopathologic evaluation. The mean age was 45.3 years (range, 18-72 years). The histologic diagnoses, obtained from colposcopically directed biopsy or endocervical curettage or loop electrosurgical excision procedure or cold knife conization after initial colposcopy, showed that 47 (18.5%) women had histologically confirmed high-grade lesions and 20 (7.9%) women had invasive cancers. There was no statistically significant difference in the incidence of high-grade or invasive lesions between who were 50 years old or more and those who were younger (50.0% and 50.5%, respectively, p = 0.39)., Conclusion: Reporting ASC-US cytology in our population is obviously associated with significant cervical pathology, particularly invasive cancer that is possible at a rate higher than previously reported. Women who have ASC-US smears should therefore be referred for immediate colposcopy regardless of age.

Background and Aim: Confocal endomicroscopy is ultra-high-magnification endoscopy with histological observation during ongoing endoscopy. We planned a pilot study of the diagnosis of the depth of esophageal cancer using confocal endomicroscopy for treatment strategies., Methods: Patients had 14 superficial esophageal cancers and one dysplasia. The depth of neoplasms in 15 lesions was confirmed by endoscopic mucosal resection or surgery. We examined the rate of delineation and compared results of confocal imaging with histological findings. We classified two cellular and three microvascular patterns on confocal endomicroscopic images: CP-N for normal squamous mucosa and CP-Ca for cancerous lesion; VP-type A for normal squamous mucosa; VP-type B for T1a-EP and T1a-LPM cancers; and VP-type C for T1a-MM or a more invasive cancer pattern. We measured diameters of microvessels for the three patterns of confocal endomicroscopic images and histological specimens., Results: The rate of delineation was 73.3% (11/15) for esophageal cancer. The results of confocal imaging coincided well with microvessel distribution on horizontal histology. Two endoscopists blindly diagnosed the two types by cellular pattern and the three types by vascular pattern: their overall accuracies were 96% and 89% for the cellular pattern and 85% and 85% for the vascular pattern, respectively. The k value of the cellular pattern and the vascular pattern diagnosis was 0.84 and 0.75, respectively., Conclusion: Scoring and quantification of confocal endomicroscopic images may be useful for the differential diagnosis and diagnosis of superficial invasion by squamous cell carcinoma.

Squamous intraepithelial lesions (SILs) of the larynx, clinically usually defined as leukoplakia and chronic laryngitis, have remained the main controversial topic in laryngeal pathology for decades as regards classification, histological diagnosis and treatment. SILs are caused by smoking and alcohol abuse. There is also mounting evidence that gastroesophageal reflux is a potential aetiological factor. Human papillomavirus infection seems to play little if any role in laryngeal carcinogenesis. Histological classification of SILs is the central disputed aspect of these lesions. There are as yet no generally accepted criteria for histological grading of laryngeal SILs. Three currently used classifications of SILs are reviewed here: the dysplasia system, the Ljubljana classification and the binary system of squamous intraepithelial neoplasia. One of the most important issues of SILs is the risk of malignant transformation. Data in the literature are controversial because of inconsistent use of morphological criteria in different classifications. It is often difficult for clinicians to agree on the most appropriate therapeutic option for a particular grade of SIL that has been diagnosed. Transition from normal epithelium to SILs and squamous cell carcinoma is related to progressive accumulation of genetic changes leading to a clonal population of transformed epithelial cells. Despite extensive research into these genetic changes in laryngeal carcinogenesis, reliable genetic markers with diagnostic and prognostic value are still lacking.

We undertook this study to assess the characteristics of smears with features intermediate between high-grade squamous intraepithelial lesion (HSIL) and low-grade squamous intraepithelial lesion (ISIL). We also wanted to determine how these smears correlate with high risk biopsy diagnosis and to compare this with the biopsy correlation of LSIL and HSIL. Seventy-four squamous intraepithelial lesion (SIL) smears were identified as intermediate-grade SIL smears taken at colposcopy in a 1 year period. They were correlated with concurrent colposcopically guided biopsies. Thirty-five percent of cases with intermediate-grade SIL smears had a biopsy diagnosis of moderate dysplasia or higher as compared with 12% for LSIL 74% for HSIL. This confirmed our hypothesis that intermediate-grade SIL smears have a rate of biopsy diagnosis of moderate dysplasia or higher intermediate to that of LSIL and HSIL.

Objective: This study evaluated the impact of the Bethesda System (TBS) 2001 in reporting of atypical glandular cells (AGC) when using conventional Pap smears (CS) and liquid-based cytology preparations (LBC)., Study Design: Follow-up information for all atypical glandular cells of undetermined significance (AGUS)/ AGC cases encountered in Queen Mary Hospital from July 2000 to June 2004 was analyzed. The difference in percentages associated with certain end points when using different reporting systems and preparation methods were compared. The age trends and time interval between cytologic diagnosis and detection of positive end points were studied., Results: More than half of these cases turned out to be "negative." The majority with "negative" end points belonged to the "not otherwise specified" (NOS) groups (including atypical endometrial cells) in TBS 2001. The connotation of "favor neoplastic" carried a high positive predictive value for significant lesions. Most of the significant outcomes were discovered within the subsequent 6 months. A decreased reporting of "AGC, NOS" and an increased reporting of "atypical endocervical cells, NOS" were noted when using LBC., Conclusion: Subcategorization of AGC in TBS 2001 according to cellular origin and risk of malignancy, which is further enhanced by application of LBC, is useful.

Objective: In the current study, we explore the diagnostic parameters and pitfalls in the follow-up of 123 cases of Pap smears diagnosed as high-grade atypical squamous cells (ASC-H) at our institution., Study Design: A computer database search was performed from the archives of the Ottawa Hospital Cytopathology Service for cases diagnosed with ASC-H between January 2003 and July 2005., Results: Follow-up of the 123 cases of ASC-H showed high grade squamous intraepithelial lesion (HSIL) in 73 patients (59.4%), low grade squamous intraepithelial lesion (LSIL) in 11 (8.9%), immature squamous metaplasia in 23 (18.7%), reactive squamous cell changes in 12 (9.8%), benign glandular lesions (endocervical atypia, degenerated glandular cells) in 2 (1.6%) and atrophy in 2 (1.6%). In our study, 83 patients were younger than 40 years (67.4%), with biopsy-proven HSIL found in 54 patients (65.1%). The remaining 40 patients (32.6%) were older than 40 years of age, and follow-up biopsies showed HSIL in 19 patients (47.5%)., Conclusion: In our study, 59.4% of the cases that were diagnosed cytologically as ASC-H were found to have HSIL on subsequent biopsies. This correlation was stronger in patients below the age of 40 years (65.1% vs. 47.5%). The cytopathologic feature most strongly associated with HSIL was the presence of coarse nuclear chromatin (84%).

We evaluated the impact of the Bethesda System (TBS) 2001 in cytology reporting of atypical squamous cells (ASC) when using conventional Pap smears and liquid-based cytology preparations (LBC). Follow-up information for all ASC cases encountered in Queen Mary Hospital, Hong Kong, China, from July 2000 to June 2004 (using TBS 1991 in the first 2-year period and TBS 2001 in the second) was analyzed. Among 4, 089 ASC cases studied, more than 50% had negative follow-up; this percentage was lower with TBS 2001. The percentage of ASC cases with a low-grade cervical intraepithelial neoplasia (CIN) end point was higher with TBS 2001, especially after application of LBC. There was also a decreasing trend of having this low-grade CIN end point with advancing age. Most clinically significant outcomes occurred after 6 months and before 1 year post-ASC diagnosis. With TBS 2001, more than 50% of ASC, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) were associated with high-grade CIN on follow-up. TBS 2001 improves the positive predictive value of ASC for clinically significant lesions. Introduction of dichotomous subcategorization of ASC is relevant, with ASC-H associated with a much higher risk of subsequent high-grade squamous lesions.

Background: The Bethesda System (TBS) along with its companion atlas was updated in 2001 to improve standardization, clarity, and reproducibility of cervical cytology reporting., Methods: The authors used a novel web-based format to compare assessments of 77 images demonstrating a range of classical and borderline cytologic changes by a self-selected group of United States cytotechnologists (n = 216) and pathologists (n = 185)., Results: Participants were highly experienced, with 71.2% of cytotechnologists and 53.0% of pathologists reporting >10 years of practice. The mean percentage of exact agreement with the panel was slightly though significantly higher for cytotechnologists (57.0%) compared with pathologists (53.4%), adjusted for experience (P = .004); cervical cytology percentage effort (P = .0005); or cervical accession volume (P = .0002). Compared with the TBS panel, exact agreement was achieved for 55.1% of image ratings compared with 82.3% agreement at the level of Negative vs non-Negative for images with a single-panel interpretation. Agreement with the panel was highest for images classified as Low-Grade Squamous Intraepithelial Lesion and lowest for Atypical Squamous Cells qualified as either of Undetermined Significance or Cannot Exclude a High-Grade Squamous Intraepithelial Lesion. Reviewers were less sensitive in identifying high-grade glandular lesions than they were in identifying high-grade squamous lesions at any threshold (P < .001)., Conclusions: Morphologic appearances of images were more important determinants than participants' academic or professional degrees with regard to interobserver reproducibility in classifying cervical cytology images. Experienced cytotechnologists and pathologists performed similarly. Participants achieved higher sensitivity for identifying high-grade squamous lesions than they did for high-grade glandular lesions. These findings demonstrated that web-based studies may be useful in assessing interobserver agreement in classifying images., (Published 2006 by the American Cancer Society.)

Head and Neck Squamous Cell Carcinoma (HNSCC) are generally similar in their clinical features, epidemiology and etiology although their natural and clinical history and treatment differ. Despite lot of improvement in diagnostic and management technique, there is little improvement in survival rate over the last few decades. This study was carried-out in a multidisciplinary tertiary level hospital (BSMMU), with a country-wide catchment area to see the burden of HNSCC existing in our country and their clinical pattern. The overall incidence rate of HNSCC in this study was (0.15%) i.e. 150 person in 1,00,000 population. Male incidence (0.19%) was higher than female (0.12%). This study revealed that carcinoma of the larynx (25.22%) and pyriform fossae (20.57%) were the main culprit, whereas buccal carcinoma was the main component (37.70%) in the female series. Highest incidence was found in the 6th decade in both sexes. As the treatment of HNSCC may be time consuming, requires multidisciplinary approach, demands lot of clinical, social and financial consideration, therefore, the best treatment can be offered through a combined board consisting of Surgical, Radiation, Medical oncologists, Histopathologist and Speech therapist as required.

We compared the overall ASC rate and the outcomes for women with different categories of ASC before and after TBS 2001 to evaluate the impact of TBS 2001. Our laboratory reported ASC in four subcategories before TBS 2001; ASC, favor reactive (ASC-R), favor low-grade squamous intraepithelial lesion (SIL) (ASC-L), undetermined significance (ASC-US), and ASC-H. Since the implementation of TBS 2001, we have been reporting ASC as ASC-US and ASC-H. After TBS 2001, our ASC rate decreased from 6.2% to 4% (P < 0.0001). Before TBS 2001, ASC-R carried the same risk as ASC-US for underlying condyloma/CIN 1. Moreover, ASC-R was rarely associated with CIN 2 or 3. Before TBS 2001, ASC-H captured more low-grade (condyloma/CIN 1) and less high-grade (CIN 2, 3, and SCC) lesions compared to after TBS 2001. More women with ASC-H after TBS 2001 underwent colposcopy (80% vs. 71%, P < 0.05). Twenty-two percent of women with ASC-H required 2-4 colposcopies to identify the high-grade lesion. Our results confirm that consistent application of TBS 2001 terminology for ASC reduces the ASC rate, and better identifies women at high risk for CIN 2, 3, and SCC. In addition, ASC-H requires very close clinical follow-up as a significant percentage of women require more than one colposcopy to identify the high-grade lesion.

Background: Transmission over the Internet of low-resolution images acquired by automated screening of cervical cytology specimens has the potential to provide remote interpretation and, hence, centralization of a cytology workforce., Methods: Liquid-based cervical cytology slides were scanned using the FocalPoint(R) System. Ten black-and-white images that had the greatest probability of containing abnormality were acquired from each of 32 reference slides (16 negative samples, 3 samples of atypical squamous cells of uncertain significance, 5 samples of low-grade squamous intraepithelial lesions [LSIL], 5 samples of high-grade squamous intraepithelial lesions [HSIL], 1 adenocarcinoma in situ sample, and 2 carcinoma samples) and were transmitted as e-mail attachments in JPEG format to remote reading stations. The slides were interpreted independently by two pathologists and were assigned to either of two groups: 1) suspicious for >or=HSIL or 2)

The diagnosis of atypical squamous epithelial cells, borderline nuclear changes, is associated with some controversy, as it encompasses benign, reactive, as well as possible neoplastic conditions. The aim of this study was to evaluate the follow-up diagnoses of cytological atypia in conventional Papanicolaou smears (CP) and liquid-based samples by the ThinPrep Pap Test (TP). A total of 1607 CP smears from 1 January 2000 to 31 December 2000 and 798 TP samples from 1 January 2002 to 31 December 2002 diagnosed as atypia were included. The results show that the detection rate of atypia in cervical cytological samples was reduced by 41.3% (P < 0.001) in TP compared with CP. Cytological and histological follow-up data showed the presence of neoplastic lesions in 34.7% of patients screened by TP versus 22.3% of patients screened by CP, corresponding to a 55.6% increase in TP (P < 0.001). Follow-up diagnosis of mild dysplasia was seen more than twice as often in TP than in CP (12.8% versus 5.0%, P < 0.001). The prevalence of moderate and severe dysplasia was significantly increased with 26.7% in TP compared with CP (21.9% versus 17.2%, P < 0.01). In conclusion, the ThinPrep Pap Test yielded a significant decrease in atypia rates compared with the conventional Papanicolaou test. In subsequent follow-up the percentage of neoplastic lesions was significantly increased in the ThinPrep Pap Test samples.

Recent revisions of the Bethesda System (TBS III) did not modify the original two-tiered low-grade and high-grade squamous intraepithelial lesion (LSIL/HSIL) terminology and continued to offer the option of subclassifying HSIL into moderate dysplasia/cervical intraepithelial neoplasia (CIN II) and severe dysplasia/CIN III. The purpose of this study is to evaluate the significance of the HSIL moderate dysplasia/CIN II subclassification and the causes of Pap test-biopsy discordance for this subclassification. HSIL/moderate dysplasia/CIN II Pap tests were identified from the University of California Davis Medical Center laboratory file for a 5-yr period (1997-2001) and correlated with follow-up cervical biopsies. Cervical biopsies with CIN II diagnoses were identified from the laboratory file for the same time period, and correlated with their preceding Pap test. Discordant Pap test-biopsy pairs from either group were reviewed by two pathologists for the following causes for discordance: cytologic overcall or undercall, biopsy overcall or undercall, and sampling error or possible lesion regression. During the review period, 161 of 378 total HSIL Pap tests had a HSIL/CIN II result (42%), and 81/161 (50%) had a follow-up cervical biopsy. 38/81 (47%) were concordant, and 43 (53%) were discordant; 39/43 discordant cases had both Pap test and biopsy slides available for review. CIN I was the most common discordant biopsy diagnosis. Sampling error was the most common cause of discordance and was three times more common than the other causes; 536 CIN cervical biopsies with CIN were identified in the laboratory files during this review period, and 108/536 (20%) received a diagnosis of CIN II. Sixty-seven of 108 (62%) had a preceding Pap test result available; 32 of the 67 (48%) had a concordant preceding Pap test with a HSIL/CIN II result, and 35 (52%) were discordant; 32/35 discordant cases had both Pap test and biopsy slides available for review. LSIL was the most common discordant Pap test diagnosis. Sampling error was also the most common cause of discordance, and was also three time more frequent than any other cause for discordance. HSIL/CIN II is a meaningful subclassification in our laboratory. We support the TBS III recommendation for optional subclassification of HSIL and suggest that individual laboratories may wish to monitor use of this subclassification through internal correlation studies., (Copyright 2004 Wiley-Liss, Inc.)

Objective: To evaluate the criteria for diagnosis of atypical squamous cells (ASC) and its two subtypes: undetermined significance ASC (ASC-US) and atypical squamous cells-cannot exclude high-grade intraepithelial lesion (HSIL, ASC-H) defined in 2001 the Bethesda system (TBS)., Method: One thousand one hundred and eighty six pap smears and liquid-based thin-layer preparations with diagnosis of atypical squamous cells of undetermined signification (ASCUS) according to TBS 1991 criteria, were re-classified by a cytopathologist using TBS 2001 criteria., Results: The cytologic diagnosis according to TBS 2001 criteria was: negative in 285 cases (24.0 %), ASC-US in 627 cases (52.9%), ASC-H in 254 cases (21.4%), low-grade intraepithelial lesion (LISL) in 16 cases (1.3%), and HISL in 4 cases (0.3%), respectively. Out of 1186 cases, 168 received histological examination. Cervical intra-epithelial neoplasia (CIN) II-III were diagnosed in 18.9 % of patients with ASC-H, 5.2% of patients with ASC-US, and 14.3% of patients with ASCUS defined by using TBS 1991 criteria, respectively (P < 0.05). During the follow-up of 6 months, 4 cases of ASC-US changed to LSIL, one ASC-US changed to HSIL, 2 ASC-US changed to LSIL, and 2 ASC-US to HSIL., Conclusions: New classification of ASC recommended by 2001 TBS has apparent clinical significance. Colposcopically directed cervical biopsy should be performed immediately if ASC-H is diagnosed. In ASC-US patients, checking of cervical smear in an interval of 3 approximately 6 months is necessary. It is suggested to use ASC-US and ASC-H instead of ASCUS in cytological diagnosis.

Objectives: The cytologic report written by a cytopathologist on the basis of smears from the cervix and cervical canal ought to give detailed and worthwhile information which allows making appropriate diagnostic and therapeutic decisions. The diagnosis of atypical cells of unspecified importance (ASCUS and AGUS) ought to have clinicians to carry out further diagnostic histopathologic procedures in order to explain the pathologic character of processes going on in the female reproductive organ. This is because such pathological states may as well spell could mean reactive, preinvasive as neoplastic changes of invasive character., Design: This problem has led to carry out a research in order to examine the proliferative potential of cells in cytological smears (Ki-67, AgNORs) and to answer whether this potential allows us to qualify atypical cells as changes of reactive or neoplastic type., Materials: In our study there were estimated 97 cases of cytological smears from the cervix and cervical canal. In this paper, immunohistochemical methods, and staining techniques developed by Ploton et al. in the detection of AgNORs and in the examination of Ki-67 antigen were used., Conclusions: 1. The average number of AgNORs in cell nucleus was highest in ASCUS cells and exceedingly higher in CIN 1 and CIN 3.2. The areal ratio of AgNORs to that of the cell nucleus was highest in HSIL and cancer cells, least in ASCUS. 3. In ASCUS and LSIL, AgNORs were minute and scattered whereas they were large and centrally located in HSIL and cancer cells., Results: We found that analysis of AgNORs makes easier the differentiation of ASCUS and LSIL cells from HSIL and neoplastic ones according to the classification system of Bethesda.

Aims: Although many workers have graded pre-invasive squamous lesions arising in the bronchus, there has been no consensus classification system until the latest edition of the WHO/IASLC histological classification of pulmonary and pleural tumours. Because the value of any such system is dependent on its reproducibility, we have circulated a series of such lesions to a panel of histopathologists to assess interobserver and intra-observer variation when the WHO/IASLC classification was applied., Methods and Results: Colour transparencies of 28 pre-invasive squamous lesions were assessed by six histopathologists (two with a special interest in pulmonary pathology, two generalists and two trainees) on three separate occasions over a period of 3 months, using the criteria of the WHO/IASLC (mild, moderate and severe dysplasia, and in-situ carcinoma). An additional category of metaplasia was added for those cases that showed no dysplasia. Weighted kappa coefficents of agreement (K(w)) were used to evaluate paired observations with a standard quadratic weighting being employed, such that kappa coefficients corresponded to intra-class correlation coefficients. Wilcoxon's sign-ranked test was used to measure the statistical significance of group trends, when comparing kappa values for the three grading systems. Various 3-point systems were also assessed, through combination of the above groups. Intra-observer agreement was substantially better than interobserver variation (mean: 0.71 vs. 0.55). Between the various pathologist groups, inter-observer variation was relatively minor, although intra-observer variation was higher within the trainee pathologist group. Using weighted kappa values, there was no significant difference in either inter-observer or intra-observer agreement between the five point grading system and a 3-point system of metaplasia/mild, moderate and severe/in-situ grades. However, there was a significant increase in variation when a 3-point system of metaplasia/mild, moderate/severe and in-situ carcinoma was used., Conclusion: This study shows levels of interobserver and intra-observer variation similar to those found in other grading systems in histopathology, with no significant decrease in variability found by abridging the system. The WHO/IASLC system is therefore recommended for future use in both clinical and research fields.

The presence of human papillomavirus (HPV) and Epstein-Barr virus (EBV) was sought in cervical scrapings from 110 human immunodeficiency virus (HIV)-infected women to evaluate the role of these viruses as risk factors for squamous intraepithelial lesions of the cervix. By using PCR, presence of HPV-DNA and EBV-DNA was found in 60.9% (67/110) and in 10% (11/110) of clinical samples, respectively. Identification of oncogenic group of HPV by hybrid capture (HC II, Murex-Digene) indicated the presence of low-risk HPV in 13 (19.4%) patients, high-risk HPV in 28 (41.8%), and both types of HPV in 26 (38.8%) patients. Squamous intraepithelial lesions were present in 59 cases, being low-grade (n = 52) and high-grade (n = 7) lesions. HPV was detected in 84.7% of patients with lesions, in association with low-grade (43/52) and high-grade lesions (7/7), and in 33% of patients without lesions. EBV-DNA was detected in 8 patients with low-grade lesions and in 3 patients without lesions. Concurrent genital HPV and EBV infection was observed in 9 cases. HPV was associated with detection of squamous intraepithelial lesions [OR = 3.55; 95% CI = (1.96; 6.48)]. No significant association was found between presence of EBV and detection of lesions, both in case of EBV infection alone [OR = 1.4; 95% CI = (0. 93; 2.12)] and in case of HPV/EBV combined infection [OR = 0.87; 95%CI = (0.54; 1.42)]. These data confirm the significant role of HPV as risk factor for squamous intraepithelial lesions and suggest that EBV could not be involved in the pathogenesis of the lesions that arise in the cervix of HIV-positive women., (Copyright 2000 Wiley-Liss, Inc.)

The objectives of this study were to evaluate 1) the detection rate of atypical glandular cells of undetermined significance of endocervical cell type (AGUS-EC) and 2) the correlation between AGUS-EC on cytology and biopsy results using the conventional Papanicolaou (Pap) smear test vs. the ThinPrep Pap test (TPPT). Cervical-vaginal samples processed by the conventional Pap smear for 11 mo in 1996-1997 were identified, as were TPPTs collected for the same interval in 1997-1998. Biopsy results were compared after a 9-mo follow-up for both groups. There were 112 AGUS-EC cases from 82,754 conventional Pap smears (detection rate, 0.14%) compared with 58 cases from 82,252 TPPTs (detection rate, 0.07%) (P < 0.01). Biopsies were available in 72 of 112 patients from the conventional Pap smear group and 35 of 58 patients from the TPPT groups. Five dysplastic glandular lesions/ AIS were diagnosed by biopsy in the 35 patients (14.3%)from the TPPT group, compared with 2 of the 72 patients (2.8%) from the conventional Pap smear group (P < 0.05). There were no statistically significant differences between other follow-up diagnoses for the two methods. The use of TPPT resulted in fewer cases of AGUS-EC and better correlation with histology. The TPPT appears to be as sensitive as and more specific than the conventional Pap smear for detection of endocervical glandular lesions.

Objective: A new terminology for cytologic diagnosis of cervical lesions has been introduced by Bethesda System. This includes: 1) Atypical squamous cells of undetermined significance (ASCUS), 2) Low-grade squamous intraepithelial lesion (LSIL), 3) High-grade squamous intraepithelial lesion (HSIL), 4) squamo-cellular carcinoma. The aim of this study was to assess the correlation between the colpocytologic test (Pap psmear), the histologic response and colposcopy., Methods: We re-examined the cytologic results of 447 patients who underwent routine cytologic tests, with a diagnosis of various grades of atypia, from ASCUS to HSIL. A histologic test was carried out on a colposcopic basis in 210 cases and cytologic results were correlated with the histologic and colposcopic pictures., Results: For ASCUS the histology was positive in 19.1% (31/163) of cases and negative in 10.4% of the colposcopically positive cases (17/163), while in the remaining 70.5% (115/163) the colposcopy resulted negative. In LSIL with the presence of human papillomavirus (HPV) the histologic findings, confirmed the cytologic result in 35.8% (48/134) while in the group of cervical intraepithelial neoplasia (CIN I) results corresponded in 40.6% (41/101). In high squamous intraepithelial lesions there was an histologic confirmation in 59.2% (29/49)., Conclusions: The data obtained indicate an increase in positive histology results from the types of low grade (ASCUS-LSIL) to those of a high grade (HSIL). Our results indicate that the presence of ASCUS should be assessed colposcopically and histologically, where indicated.

Background: Squamous cancers of the upper aerodigestive tract (UADT) are related to the use of tobacco and/or alcohol, and in North America they are more common among the poor. They are usually locoregionally confined at diagnosis, and local treatment with surgery and/or radiation therapy is often curative. This study compares the incidence and survival of this group of diseases in Canada and the U.S., two North American neighbors with many cultural similarities but significant differences in their health care and social programs., Methods: To describe and compare the case mix, incidence, and outcome of squamous cancers of the UADT in Ontario, Canada, and the U.S., we used the Ontario Cancer Registry (OCR) and the Surveillance, Epidemiology, and End Results (SEER) registries in the U.S. to identify all cases of cancer with International Classification of Disease (ICD) codes 141, 143-9, 160-1, and a subset of 140, which were diagnosed between 1982 and 1994. ICD-O histology codes were placed into clinically relevant groupings, and ICD-9 site codes were grouped into sites as defined by the International Union Against Cancer and the American Joint Committee on Cancer. Age-adjusted incidence rates were calculated for each site. For the SEER registry, race specific incidence rates were also calculated. Observed and expected survival were plotted by site and registry, and from these, relative survival was calculated. Survival was compared during the first 5 years after diagnosis and during the next 5 years among patients who had survived the first 5 years., Results: Of the 16,577 and 42,990 cases identified in the OCR and SEER registries, respectively, squamous cancer was by far the most common histology (94.1% in OCR, 94.6% in SEER) and will form the main subject of this report. The distribution of squamous cancers by site, subsite, age, and gender were remarkably similar in the two populations. Overall, the incidence was about 17% higher in the U.S. than in Ontario, and this difference was seen for all sites except the nasopharynx, which was more common in Ontario. The higher incidence in the U.S. in part reflects the much higher rate for African Americans than for Americans of other ethnic backgrounds. During the first 5 years after diagnosis, when most deaths from UADT cancer occur, there was a significant relative survival difference in favor of the U.S. for cancer of the supraglottis, and in favor of Ontario for cancer of the oral cavity. There was a nonsignificant trend in favor of Ontario for cancer of the nasopharynx. Within the SEER population, for all sites except the nasopharynx, 5-year relative survival was considerably worse for African Americans than for Americans of other ethnic backgrounds. Examination of survival beyond 5 years after diagnosis for patients who had survived the first 5 years revealed that for all sites, the observed survival continued to diverge markedly from the expected survival. The excess mortality ranged from less than 20% for glottic and nasopharyngeal cancers to about 30-40% for oropharyngeal and supraglottic cancers., Conclusions: Despite remarkable similarities in case mix between the two countries, UADT cancers were more frequent in the SEER population of the U.S. than in Ontario, and this was partly attributable to the much higher incidence among African Americans. Significant differences between the registries in 5-year survival were seen for several sites. African Americans with UADT cancers had much worse prognoses than did Americans of other ethnic backgrounds. Patients who survive their UADT cancer remain at a higher-than-expected risk of death even after they have been cured., (Copyright 2000 American Cancer Society.)

Exophytic and papillary squamous cell carcinomas (SCCs) are uncommon variants of SCC of the upper aerodigestive tract mucosa. The histomorphologic distinction between these variants has not been previously attempted or correlated with prognostic outcome. One hundred four cases of exophytic and papillary SCCs of the larynx were identified in the files of the Armed Forces Institute of Pathology from 1971 to 1991. The patients included 25 women and 79 men, aged 27 to 89 years (average 60.7 years). Patients had hoarseness at presentation, and many patients were using tobacco (n = 87) and/or alcohol (n = 49). Tumors measured up to 6 cm in greatest dimension. The larger tumors were associated with vocal cord impairment (n = 39). Histologically, the SCCs were divided into 2 growth patterns: papillary-frond (n = 12) or broad-based, exophytic (n = 92). Patients were treated with excisional biopsy, vocal cord stripping, and/or laryngectomy, in conjunction with radiation therapy (n = 70). Eighty-seven patients had no evidence of disease at last follow-up (average follow-up 8.6 years). Seventeen patients with an exophytic pattern died with disease (10 disseminated disease; 7 local disease). No patients with papillary patterns died of disease, although there had been 4 recurrences. In conclusion, patients with papillary and exophytic SCCs have a better prognosis than those with conventional SCCs, and the prognosis for those with papillary SCCs is even better.

Objective: To demonstrate empirically that the efficiency of rescreening to discover false negative cytologic diagnoses is greatly enhanced by prospectively stratifying accessions according to risk level., Study Design: We stratified accessions from 11 clinical sources and established the rate of diagnoses according to three categories: (1) "within normal limits"/"benign cellular changes" (WNL/BCC), (2) "atypical squamous/glandular cells of undetermined significance" (ASCUS/AGCUS) and (3) "squamous intraepithelial lesion/invasive carcinoma" (SIL/CA). We then prospectively rescreened all negative smears from sources with rates of positive diagnoses (ASCUS/AGCUS and SIL/CA) in excess of 20% and 5% of negative smears from sources with rates of positive diagnoses < 20%. We compared the detection rates of false negatives on rescreening target groups with random rescreening of 10% of all negative smears., Results: The rates of SIL/CA, ASCUS/AGCUS and WNL/BCC varied from 0 to 43%, 4% to 14% and 46% to 94%, respectively. Rescreening 10% of all negative smears revealed a false negative fraction of 3%; rescreening target groups revealed a false negative fraction of 5.9%., Conclusion: The yield of prospectively detected false negative diagnoses was significantly increased by targeting high-risk accession groups. When cytology laboratories serve diverse populations, stratifying accessions by risk to permit increased sampling from the proportionately higher risk categories is a simple and effective device to maximize the yield and benefit from rescreening.

Precise regulation of cell organization results in well-differentiated tissue structures and continuous renewal of the oral epithelium maintaining a highly ordered tissue architecture. Here we demonstrate that FT-IR microspectroscopy, performed on sections of cancerous tissue biopsies, is capable of generating biochemical maps that show the distribution and any abnormal concentration of individual classes of biomolecules. Oral epithelia affected by cancer (squamous cell carcinoma) show many abnormal changes in morphology, of which the formation of keratin pearls is only one. Spectra from selected pearl areas demonstrate that these structures contain not only abnormal keratin concentrations but also seem to be stabilized by surrounding collagen fibers. Infrared image maps reveal that in the center of keratin pearls the concentration of protein (cytokeratins) is abnormally high, that DNA is absent and that the cell membrane fluidity is reduced. This suggests that cells are structurally destroyed and transformed into nuclei-free horny cells, simulating normal differentiation and epithelial growth. We also introduce a new analysis modality, two-dimensional (2D) tissue classification, and apply it to establish spectral similarities between different tissue structures. A total of 315 spectra, recorded for the original map, were analyzed by pattern recognition methods, classified and re-assembled into new maps based on their spectral similarities. The re-assembled maps clearly indicate significant tissue changes outside the pearls, suggesting early biochemical changes that accompany abnormal growth. Employing this 2D analysis modality in combination with infrared histopathology may be relevant to tumor diagnosis and prognosis.

Detection of potential pitfalls for the ASCUS interpretation is essential for appropriate patient management. Between 1991-1994, 50 cervicovaginal specimens with Candida spp. were submitted for pathologists' review because of a possible ASCUS diagnosis. None had been preceded by abnormal smears, and all were followed by one or more benign smears and/or biopsy. Candida-associated changes included nuclear enlargement with focal hyperchromasia and cytoplasmic changes of orangeophilia, vacuoles, and perinuclear rings. Initially, 16 cases had been interpreted as ASCUS and 34 as benign. Upon review, utilizing strict Bethesda System criteria for ASCUS and awareness of Candida-associated changes, 10 of the 16 ASCUS cases were reclassified as benign. Knowledge of Candida-associated changes which may mimic ASCUS can prevent overuse of the ASCUS term, providing optimal, cost-effective management.