Expression of Ki-67 can assist in predicting recurrences of low-grade anal intraepithelial neoplasia in AIDS

The objective of this study was to define the colposcopic features of the normal anal canal and of anal human papillomavirus (HPV)-associated lesions, including anal intraepithelial neoplasia (AIN), and to correlate the colposcopic impression with the final histopathologic diagnosis. A controled colposcopic screening study of women considered at risk for HPV-associated anal epithelial abnormalities was carried out. All colposcopic assessments included a biopsy with matching histopathologic diagnosis. The study group consisted of 213 women who were considered at risk of anal HPV infection and AIN. A further group of 50 women, who had no previous history of ano-genital HPV infection or AIN and whose recent cervical smear was negative were recruited as controls. Informed consent was obtained from all patients, and the study was approved by the local ethical committee. In the control group of 50 women no AIN was detected. Normal histology was obtained in 45/50 (90%) biopsies where normality had been predicted on colposcopy. Histologic diagnosis in the at-risk group was normal in 143 (67%), subclinical papillomarvirus infection (SPI) in 24 (11%), and AIN of all grades (including three cases of early invasive squamous cancer in a field change of AIN III) in 46 (22%) patients. Nineteen of 24 (79%) cases of SPI were incorrectly predicted as normal on colposcopy, and another one (4%) as AIN I–II. Only four (17%) cases of SPI were correctly predicted at colposcopy. Of the 46 cases of histologically proven AIN, 26 (56%) were AIN I–II, and 20 (44%) were AIN III. Some 50% of AIN I–II were incorrectly predicted as SPI on colposcopy. Of the 20 AIN III lesions, 15 (75%) were correctly predicted by colposcopy. Three (20%) of these lesions contained foci of early invasion, of which in only one case (33.3%) was invasive disease suspected at colposcopy. Some 25% (5/20) of AIN III lesions were incorrectly diagnosed as AIN I–II at colposcopy. As is the experience with colposcopic assessment of the cervix, anal colposcopy predictions correlated well with the final histologic diagnosis, at the normal and high-grade AIN ends of the spectrum. The colposcopic predictive distinction between SPI and low-grade AIN (I–II) was less accurate. It was difficult to distinguish early invasive lesions within a field change of AIN III, from pure AIN III. In these studies there were three cases of early anal squamous carcinoma arising in AIN III lesions, two of which were unsuspected clinically.

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Ki-67 expression in anal intraepithelial neoplasia in AIDS

Sao Paulo Medical Journal ◽

10.1590/s1516-31802001000300007 ◽

2001 ◽

Vol 119 (3) ◽

pp. 119-121 ◽

Cited By ~ 7

Author(s):

Edenilson Eduardo Calore ◽

Carmen Ruth Manzione ◽

Sidney Roberto Nadal ◽

Maria José Cavalieri ◽

Nilda Maria Perez Calore ◽

...

Keyword(s):

Lower Layer ◽

Intraepithelial Neoplasia ◽

Cell Counting ◽

Biological Behavior ◽

Low Grade ◽

High Grade ◽

Ki 67 ◽

Staining Techniques ◽

The Mean ◽

Group 2

CONTEXT: AIDS is one of the most important risk factors for progression and recurrence of anogenital condyloma. In a previous work, we observed that patients with warts and high-grade AIN (HAIN) had recurrences more frequently than did patients with warts without AIN. The mechanisms of this increased incidence of high-grade lesions in AIDS are not known. OBJECTIVE: We studied the expression of the proliferative marker Ki-67 by immunohistochemical methods, in specimens of anal condyloma from HIV+ patients to clarify whether its expression can be associated to the grade of AIN. DESIGN: A retrospective study of hiltological specimens. SETTING: University referral unit. SAMPLE: 34 patients were divided into two groups: (1) condylomas with low grade AIN (LAIN), with 25 patients; and (2) condylomas with HAIN, with 9 patients. In this latter group we examined two areas: 2A (HAIN area) and 2B (LAIN area). MAIN MEASUREMENTS: The immunohistochemical reaction for Ki-67 was done on histological sections. Slices were lightly stained with hematoxylin, to help us in Ki-67 positive cell counting. The percentage of Ki-67 marked nuclei was calculated. We applied one-way variance analysis for statistics. RESULTS: The mean number of Ki-67 positive cells in group 1 was 19.68 ± 10.99; in group 2 (area A) it was 46.73 ± 10.409; and in area B it was 36.43 ± 14.731. There were statistical differences between groups 1 and 2A and between groups 1 and 2B. Ki-67 positive cells predominated in the lower layer in LAIN. Positive Ki-67 cells were found in all layers in group 2A, and in group 2B they predominated in the two lower or in all layers of the epithelium. CONCLUSIONS: Our results suggest that LAIN areas (using routine staining techniques) in HAIN can have a biological behavior more similar to HAIN.

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9. Cellular immune response to anal dysplasia in HIV-positive men on highly active antiretroviral therapy

Sexual Health ◽

10.1071/shv10n6ab9 ◽

2013 ◽

Vol 10 (6) ◽

pp. 574

Author(s):

Nada Farhat ◽

Nora Laver ◽

José Caro

Keyword(s):

Immune Response ◽

Cellular Immune Response ◽

Antitumour Activity ◽

Intraepithelial Neoplasia ◽

Anal Intraepithelial Neoplasia ◽

Low Grade ◽

Cd4 Cells ◽

Cd8 Cells ◽

Anal Dysplasia ◽

Cellular Immune

Background The role of the cellular immune response to anal dysplasia progression is poorly understood. Extrapolated from the cervical model, CD4+ (killed by HIV) and CD8+ cells may have crucial anti-tumour activity. We report pilot data on key immune responses in HIV+ patients on HAART with anal dysplasia. Methods: High-resolution anoscopy and biopsies were performed. Ten tissue biopsies with high-grade anal intraepithelial neoplasia (HGAIN) were stained with immunohistochemistry for CD4+, CD8+, CXCL12+ and FOXP3+, and compared with 10 samples with low-grade anal intraepithelial neoplasia (LGAIN). Serum CD4+ and CD8+ counts were available. Tissue photographs were obtained and analysed utilising MetaXpress software. Results: In all dysplastic tissue, we found a higher number of CD4+, CD8+ and FOXP3+ cells in the subepithelium than epithelium. In HGAIN, the number of FOXP3+, intraepithelial CD4+ cells, and the ratio of intraepithelial to serum CD4+ were higher than in LGAIN. CXCL12+ staining was more abundant in HGAIN. CD4+ cells outnumbered CD8+ cells in all dysplastic tissue. Conclusions: The higher CD4+ to CD8+ ratio in HGAIN may be explained by the excess demand for antitumour activity, which is known to be a function of CD4+ cells against HPV-dysplasia in the analogous cervical dysplasia model. Cytotoxic CD8 cells, although known to have an important anti-tumour role, were less abundant in our study. The pro-tumour FOXP3+ cells, being more abundant in HGAIN, may have a key role in the progression of anal dysplasia. Strategies to block CXCL12+ may be useful in the treatment of HPV-related dysplasia.

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The Accuracy of Anal Swab–Based Tests to Detect High-Grade Anal Intraepithelial Neoplasia in HIV-Infected Patients: A Systematic Review and Meta-analysis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz191 ◽

2019 ◽

Vol 6 (5) ◽

Cited By ~ 3

Author(s):

Fernando Dias Gonçalves Lima ◽

Janine D Viset ◽

Mariska M G Leeflang ◽

Jacqueline Limpens ◽

Jan M Prins ◽

...

Keyword(s):

Anal Cancer ◽

Predictive Value ◽

Dna Detection ◽

Intraepithelial Neoplasia ◽

Anal Intraepithelial Neoplasia ◽

Hiv Positive ◽

High Grade ◽

Ki 67 ◽

Hpv Dna ◽

Anal Swab

Abstract Background The incidence of high-risk human papillomavirus (HR-HPV)–induced anal cancer is increasingly problematic among HIV-positive patients. Anal cancer is preceded by precursor lesions, anal intraepithelial neoplasia (AIN). AIN detection requires high-resolution anoscopy, a cumbersome and time-consuming procedure. We aggregated evidence on anal swab–based tests to detect AIN in HIV-positive patients. Methods We searched MEDLINE and EMBASE for cross-sectional studies on AIN detection with anal cytology, HR-HPV DNA detection, HPV E6/E7 mRNA analysis, and P16INK4a and Ki-67 immunostaining. Summary estimates of sensitivity and specificity were calculated using bivariate logistic regression. Cytology was reported using the terms squamous intra-epithelial lesion (SIL) for AIN and high-grade SIL (HSIL) for high-grade AIN (HGAIN). Results We included 22 studies. Using cytology with a cutoff of any SIL to detect HGAIN, we detected a sensitivity of 82% (95% CI, 74%–87%) and specificity of 45% (95% CI, 44%–66%); with the cutoff of HSIL, the sensitivity was 44% (95% CI, 45%–67%) and the specificity was 79% (95% CI, 69%-87%). The sensitivity of HPV DNA to detect HGAIN was 91% (95% CI, 82%–95%) and the specificity was 27% (95% CI, 21%–33%). For MSM, the positive predictive value (PPV) of cytology with a cutoff of any SIL was 36% (95% CI, 23%–50%) and the negative predictive value (NPV) was 87% (95% CI, 78%–93%), whereas cytology with a cutoff of HSIL had a PPV of 62% (95% CI, 50%–73%) and an NPV of 78% (95% CI, 65%–87%). The PPV of HR-HPV DNA detection was 37% (95% CI, 20%–57%) and the NPV was 87% (95% CI, 79%–93%). Conclusions Given its sensitivity, cytology with a cutoff of any SIL could be considered as a triaging method, whereas cytology with a cutoff of HSIL had better specificity and could be used for quality assurance. HR-HPV DNA detection had poor specificity and PPV, making it unsuitable for triage.

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HER2 Status in Premalignant, Early, and Advanced Neoplastic Lesions of the Stomach

Disease Markers ◽

10.1155/2015/234851 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

A. Ieni ◽

V. Barresi ◽

L. Rigoli ◽

R. A. Caruso ◽

G. Tuccari

Keyword(s):

Current Knowledge ◽

Intraepithelial Neoplasia ◽

Disease Recurrence ◽

Her2 Status ◽

Her2 Overexpression ◽

Low Grade ◽

High Grade ◽

Gastric Lesions ◽

Ki 67 ◽

Gastric Type

Objectives. HER2 expression in gastric cancer (GC) has received attention as a potential target for therapy with Trastuzumab. We reviewed the current knowledge on HER2 status in premalignant gastric lesions and in early (EGC) and advanced (AGC) GC to discuss the possible pathogenetic and prognostic roles of HER2 overexpression in GC.Results. HER2 overexpression was documented in gastric low-grade (LG) and high-grade intraepithelial neoplasia (HG-IEN), with higher frequency in gastric type dysplasia. HER2 overexpression was significantly associated with disease recurrence and poor prognosis in EGC representing an independent risk factor for lymph node metastases. HER2 overexpression was more frequent in AGC characterized by high grade, advanced stage, and high Ki-67 labeling index. The discordance in HER2 status was evidenced between primitive GC and synchronous or metachronous metastases.Conclusions. HER2 overexpression in premalignant gastric lesions suggests its potential involvement in the early steps of gastric carcinogenesis. The assessment of HER2 status in EGC may be helpful for the identification of patients who are at low risk for developing nodal metastases. Finally, the possible discordance in HER2 status between primary GC and its synchronous metastases support routine assessment of HER2 both in the primary GC and in its metastatic lesions.

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Presence or Absence of Significant HPVE4 Expression in High-grade Anal Intraepithelial Neoplasia With p16/Ki-67 Positivity Indicates Distinct Patterns of Neoplasia

The American Journal of Surgical Pathology ◽

10.1097/pas.0000000000000984 ◽

2018 ◽

Vol 42 (4) ◽

pp. 463-471 ◽

Cited By ~ 6

Author(s):

Annemiek Leeman ◽

Edyta C. Pirog ◽

John Doorbar ◽

Miekel M. van de Sandt ◽

Folkert J. van Kemenade ◽

...

Keyword(s):

Intraepithelial Neoplasia ◽

Anal Intraepithelial Neoplasia ◽

High Grade ◽

Ki 67

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Evaluation of biomarkers p16ink4a/ki-67 in cervical cytology for diagnosis of cervical intraepithelial neoplasia

10.1055/s-0039-1685267 ◽

2016 ◽

Author(s):

P. K. Sathija ◽

S. Rajaram ◽

V. K. Arora ◽

B. Gupta ◽

N. Goel

Keyword(s):

Diagnostic Accuracy ◽

Cervical Intraepithelial Neoplasia ◽

Intraepithelial Neoplasia ◽

Cervical Cytology ◽

Low Grade ◽

Nuclear Staining ◽

Care Hospital ◽

High Grade ◽

Ki 67 ◽

Good Diagnostic Accuracy

Background: Novel biomarkers, P16INK4a/Ki-67 are disease specific and identify risk of progression to cervical cancer. Aim: To test the clinical utility of biomarkers p16INK4a/Ki-67 in cervical intraepithelial neoplasia. Methodology: Experimental study was conducted over an 18 month period at a tertiary care hospital. 3500 sexually active women between 30-55 years were screened by VIA/VILI, Pap test & HPV-DNA PCR. All screen positive women (n=280) underwent colposcopy and biopsy if required. At the time of colposcopy repeat cervical smear were taken for evaluation of p16INK4a/Ki-67. Immunocytochemistry for p16INK4A and Ki-67 was done by partitioning one slide into two parts for each biomarker. For p16INK4A positivity, nuclear +/- cytoplasmic scoring and intensity score was calculated and final score obtained. For Ki-67 staining was exclusively nuclear. Staining patterns were categorized as negative, intermediate or strongly positive. Results: 86 women with abnormal cytology were evaluated with p16INK4A/Ki-67 immunocytochemistry and 20.9% (n=18) and 18.6% (n=16) were positive for each biomarker. For ASCUS (n=42) and LSIL (n=23) smears, specificity and NPV were 100% with a likelihood ratio (LR+) of 27 and 25 respectively suggesting good diagnostic accuracy. The combined sensitivity and specificity of p16INK4a/Ki-67 in detecting CIN-2+ lesion was 76.9% and 95.8% respectively with LR+ of 18.72 in high grade smears. Conclusions: p16INK4A/Ki-67 evaluation in cervical cytology are valuable biomarkers in ruling out or detecting CIN2+ in ASCUS and LSIL smears. Unnecessary intervention in large number of low grade smears can be avoided by applying these biomarkers. In high grade smears detection rate of biomarkers p16INK4A/Ki-67 was high and had a good diagnostic accuracy.

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Abstract LB-177: HPV16 CpG and de novo-cytosine methylation is differentially associated with low-grade versus high-grade anal intraepithelial neoplasia in HIV-infected men

10.1158/1538-7445.am2011-lb-177 ◽

2011 ◽

Author(s):

Dorothy J. Wiley ◽

Emmanuel V. Masongsong ◽

Provaboti Barman ◽

Mina Kalantari ◽

Hans Ullrich Bernard ◽

...

Keyword(s):

Cytosine Methylation ◽

De Novo ◽

Intraepithelial Neoplasia ◽

Anal Intraepithelial Neoplasia ◽

Low Grade ◽

High Grade ◽

Grade Versus

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P16/Ki-67 Immunostaining is Useful in Stratification of Atypical Metaplastic Epithelium of the Cervix

Clinical medicine Pathology ◽

10.4137/cpath.s522 ◽

2008 ◽

Vol 1 ◽

pp. CPath.S522 ◽

Cited By ~ 3

Author(s):

Ann E. Walts ◽

Shikha Bose

Keyword(s):

Squamous Epithelium ◽

Squamous Metaplasia ◽

Intraepithelial Neoplasia ◽

Low Grade ◽

Serial Sections ◽

Broad Distribution ◽

Ki 67 ◽

Associated Lesions ◽

Metaplastic Epithelium

Cervical metaplastic squamous epithelium exhibiting atypia insufficient for a diagnosis of cervical intraepithelial neoplasia (CIN) is usually reported as “atypical squamous metaplasia” (ASM). Stratification impacts treatment since the differential is often between reactive and high grade CIN (CIN II, III). Diagnosis with H&E is associated with low intra/interobserver concurrence. P16/Ki-67 immunostains are helpful to assess cervical biopsies for HPV-associated lesions but staining in metaplastic squamous epithelium has received little attention. This study aims to establish staining characteristics of metaplastic squamous epithelium and determine if p16/Ki-67 is useful in ASM stratification. 80 cervical biopsies containing morphologically normal and dysplastic squamous metaplasia were retrieved to determine the staining characteristics of metaplastic epithelium utilizing p16/Ki-67 immunostains. These included 21 benign squamous metaplasia (BSM) from benign cervices, 15 BSM present adjacent to HPV/CIN lesions, and 44 CIN involving squamous metaplasia. Serial sections with controls were stained for p16 and Ki-67 and in-situ hybridization (ISH) for low-risk (LR) and high-risk (HR) HPV was performed. P16 was recorded as negative, spotty, or band-like. Ki-67 was recorded as positive when present in >50% of lesional nuclei. Results were correlated with H&E diagnosis. 95% of the BSMs, whether from normal cervices or adjacent to HPV/CIN were p16/Ki-67 negative. 81% HG CINs involving squamous metaplasia were p16 band/Ki-67 positive. Low grade CIN (CIN I) involving metaplastic epithelium showed a broad distribution of p16/Ki-67 staining patterns. Based on these criteria, 20 ASM were evaluated. 10% of the ASM cases were p16 band/Ki-67 positive indicating HG CIN. 60% of the ASMs were p16/Ki-67 negative indicating reactive change (all with the exception of one case being HPV negative). The remaining 30% of the ASM cases showed variable positivity for p16 and Ki-67 and could not be stratified into the two categories. Thus p16/Ki-67 staining is helpful in stratification of ASM as reactive or CIN.

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