Expression of p16INK4a in relation to histopathology and viral load of ‘high-risk’ HPV types in cervical neoplastic lesions (original) (raw)
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Brazilian Journal of Medical and Biological Research, 2008
The purpose of the present study was to identify the expression of p16 INK4 in cervical cancer precursor lesions by immunohistochemistry and to correlate it with lesion grade and presence of human papillomavirus (HPV) infection. Cervical specimens from 144 women seen consecutively at the gynecology outpatient clinic of our institution from December 2003 to May 2005 were analyzed by cytopathology, histopathology, polymerase chain reaction for HPV-DNA, and p16 INK4 immunostaining. Histologically normal biopsies, HPV-DNA negative by polymerase chain reaction, were used as control. HPV-DNA prevalence, including the control group, was 68.1% and the prevalence of p16 INK4 expression was 55.0%. The percentage of cells stained by p16 INK4 ranged from 10 to 100%, both in the group consisting of cervical intraepithelial neoplasia (CIN)1/HPV specimens and in the group of CIN2/CIN3 specimens with P value of 0.0001. p16 INK4 expression was 48.3% in the CIN1/HPV group, as opposed to 94.3% in the CIN2/CIN3 group (P = 0.001), showing a statistically significant difference between the two groups. The quantitative method used here is simple and less subjective than the different semiquantitative methods described in the literature. In view of the different definitions of a p16 INK4 -positive case, it is almost impossible to compare the findings reported by different investigators. This study confirms the association between p16 INK4 and CIN2 and CIN3 lesions. Moreover, it shows that some low grade lesions expressed high levels of this protein. This may indicate that such low grade lesions may be predisposed to progress to high grade lesions. This means that p16 INK4 may be a strong marker for "neoplastic lesions" induced by HPV and not just an infection marker.
Cureus
Introduction Cervical cancer is the fourth most frequent cancer in women worldwide, and it continues to be a big issue in developing countries. The current case-control study sought to determine the presence of high-risk human papillomaviruses (hr-HPV) in the development of cervical cancer, as well as their relationship with the cell cycle inhibitor gene p16INK4A in cervical cancer. Methods The association between p16INK4A protein and the presence of hr-HPV DNA in cervical lesions was explored in this study, which included 150 cervical cancer patients and 100 normal cervix samples. The immunohistochemistry approach was used to identify the expression of the p16INK4A protein, while the semi-quantitative polymerized chain reaction (PCR) method was used to identify the genomic identity of hr-HPV. Results About 90.67% (n=136) of the 150 case samples were found to be hr-HPV positive. Within the 136 HPVpositive samples, 45 (33.08%) show moderate expression of the p16INK4A protein, whereas 91 (66.91%) show overexpression, which is statistically significant (0.05). Among the 136 HPV-positive samples, 22.08% (N=30) were classified as having cervical intraepithelial neoplasia (CIN), with 56.66% (n=17) having CIN3, 36.66% (n=11) having CIN2, and 6.67% (n=2) having CIN1. Conclusion Based on the semi-quantitative immune staining scoring method of p16INK4A protein, genomic expression of HPV demonstrates that the expression of p16INK4A protein increases with the infectious load of the hr-HPV genome in the host cell. The result directly shows that immunostaining of the p16INK4A protein, in conjunction with the assessment of high-risk HPV in the host genome, will aid in the identification of cervical cancer in the cervix.
Journal of cancer prevention, 2016
Cervical cancer is a major public health problem in Morocco. The cervical cancer has a long precancerous period that provides an opportunity for the screening and treatment. Improving screening tests is a priority goal for the early diagnosis of cervical cancer. This study was conducted to evaluate the combination of p16 INK4a protein expression, human papillomavirus (HPV) typing, and histopathology for the identification of cervical lesions with high risk to progress to cervical cancer among Moroccan women. A total of 96 cervical biopsies were included in this study. Signal amplification in situ hybridization with biotinylated probes was used to detect HPV. Immunohistochemistry was used to evaluate the expression of p16 INK4a protein. HPV DNA was detected in 74.0% of the biopsies (71/96). Of the seventy-one positive HPV cases, we detected 67.6% (48/71) of high risk (HR)-HPV (HPV 16 and 18), 24% of low risk-HPV (HPV 6 and 11), 1.4% intermediate risk-HPV (HPV 31, 33, and 35), and 7% coinfections (HPV 6/11 and 16/18). Overexpression of p16 INK4a protein was observed in 72.9% (70/96) of the biopsies. In addition, p16 INK4a protein detection was closely correlated with recovery of HR HPV. Our result showed that p16 INK4a expression level is correlated with HR-HPV status.
Human papillomavirus detection and p16INK4a expression in cervical lesions: a comparative study
Human Pathology, 2014
p16 INK4a expression in dysplastic cervical lesions is related to high-risk human papillomavirus (HR-HPV) infection. The immunohistochemical expression of this protein in these lesions allows an increase in diagnostic reproducibility in biopsies and the introduction of prognostic factors in low-grade lesions. Here, we studied the immunohistochemical expression of p16 in 86 dysplastic cervical lesions, 54 cervical intraepithelial neoplasms-grade 1 (CIN-I), 23 CIN-II, and 9 CIN-III. In addition, we performed HPV detection and genotyping. We detected HR-HPV in 19/54 CIN-I, 21/23 CIN-II and 9/9 CIN-III cases. p16 INK4a immunoreactivity was observed in 7/19 CIN-I HR-HPVpositive, 17/21 CIN-II HR-HPV-positive and all CIN-III cases. Immunoreactivity for p16 INK4a was found in 7/54 CIN-I and in 17/23 CIN-II cases. In the follow-up, we detected 3 p16-positive high-grade squamous epithelial lesions (CIN-II and CIN-III) in the CIN-I/p16-negative group and 5 p16-positive high-grade squamous epithelial lesions cases in the CIN-II/p16-negative group. We conclude that p16 negativity in CIN-I and CIN-II biopsies does not always imply regression of the lesion and that the diagnosis of CIN-II should not be based solely on p16 results.
South Asian Journal of Cancer, 2018
Introduction: Human papilloma virus (HPV) which is causative factor for cervical cancer may interact with p16 leading to malignant transformation of cervical epithelial cells. The present study was conducted to assess the immunoexpression of p16 INK4a in premalignant and malignant lesions of cervix and to correlate it with HPV 16 expression. It was also intended to study the various risk factors which may be associated with cervical cancer in this north Himalayan region of India. Material and Methods: The study included 50 cases of premalignant and malignant cervical lesions and 50 controls diagnosed on histopathology over a period of one year. All the relevant clinical details were noted and both cases and controls were subjected to HPV 16 and p16 INK4a immunohistochemical staining. Results: 67% of subjects (including cases and controls) and 94% of the cases were positive for HPV 16 expression. p16 INK4a expression was negative in all the controls, positive in 96% of invasive cance...
Diagnostic Pathology, 2014
Background: Cervical cancer is one of the most common cancers affecting women worldwide. It is well established that human papilloma virus (HPV) infection is the prime risk factor in the development of cervical cancer. The current screening and diagnostic tests have limitations in identifying the range of lesions caused by HPV. The current study aims to evaluate the diagnostic value of p16 immunohistochemical (IHC) investigation in high-risk human papillomavirus (HR-HPV) related lesions of the uterine cervix in Hospital Tuanku Jaafar, Seremban, Malaysia. Methods: A total of 75 cases were selected from the records of Pathology services, Hospital Tuanku Ja'afar, Seremban. The samples were collected in three separate groups (n = 25 per group) as Carcinoma cervix, Carcinoma in situ and Chronic cervicitis. The demographic data of the patients and the representative paraffin blocks were retrieved from Hospital Tuanku Ja'afar, Seremban. The immunohistochemical staining with p16 and HPV 16 L1 were done on all cases. The staining intensity and density were observed and compared among the three groups of cases. Results: Immunohistochemistry of p16INK4A staining shows nil (0/25) expression in the cervicitis patients, 72% (18/25) in CIN patients and 100% (25/25) in cervical carcinoma. HPV 16 L1 was positive in 100% (25/25) of cervicitis patients, 96% (24/25) of CIN patients and 40% (10/25) of cervical cancers patients. A chi square test was used to analyze the result and the obtained p value was <0.05. Conclusion: p16 expression was strongly observed in cervical cancer and minimally observed in cervicitis. Thus indicating p16 immunohistochemistry investigations can aid in diagnosing the different categories of cervical lesions into benign, insitu and malignant.
… -Research and Practice, 2006
An immunohistochemical analysis with monoclonal antibody p16 INK4a was performed in formalin-fixed, paraffinembedded samples of 60 cases. The aim was to investigate in biopsies the expression of p16 INK4a of normal uterine cervical tissue, pre-cancerous and cancerous lesions, and their relation with human papilloma virus (HPV) and HIV status. Three parameters were evaluated: percentage of p16 INK4a positive cells, reaction intensity, and cell staining pattern. All of these parameters were statistically different when compared among different histological groups. However, logistic regression model showed that the reaction intensity was the best indicator of the expression of p16 INK4a . This expression increases from normal to invasive squamous carcinoma. Sixty-six percent of the patients with CIN grade 1 (CIN1) expressed p16 INK4a (all these cases were infected with high risk HPV). Our study supports the hypothesis that p16 INK4a expression in pre-cancerous lesions and cancers can be used to identify HPV-transformed cells. Of great interest for routine diagnostic use is the fact that immunohistochemical testing for p16 INK4a seems to be capable of identifying HPV-positive cells and potentially recognizing those lesions with an increased risk of progression to high-grade lesions.
Modern Pathology, 2005
Adolescents have high rates of human papillomavirus (HPV) infection, and persistent high-risk HPV infection can lead to the development of cervical cancer. The cyclin-dependent kinase inhibitor, p16 INK4a is overexpressed in cervical intraepithelial neoplasia (CIN), probably due to a persistent and integrated HPV infection. This study investigated p16 INK4a expression, grades of CIN, and high-risk HPV infection in adolescent cervical biopsies. Biopsies were immunohistochemically stained for p16 INK4a. The presence of wide-spectrum, low-risk, or highrisk HPV was determined by amplifying DNA extracted from the cervical biopsies. Biopsies were classified as cervicitis, 15 cases; CIN 1, 48 cases; CIN 2, 46 cases, and CIN 3, 52 cases. The distribution of p16 INK4a staining was graded as patchy, diffuse basal, and diffuse full thickness. Pearson's v 2 tests analyzed the relationships between p16 INK4a staining, HPV infection, and CIN. Biopsies of cervicitis were negative for HPV and for p16 INK4a expression. High-risk HPV 16, 18, and 31 increased from 18% in CIN 1 to 66% in CIN 2/3 (Po0.001). In CIN 1, p16 INK4a was positive in 44% of biopsies with 35% showing patchy, 7% diffuse basal, and one case (2%) showing diffuse full thickness staining. In CIN 2/3, p16 INK4a was positive in 97% of biopsies with 23% showing patchy, 21% diffuse basal, and 53% diffuse full thickness staining. The difference in the proportions of biopsies showing patchy p16 INK4a staining in CIN 1 and diffuse full thickness staining in CIN 2/3 was significant (Po0.001). In CIN 1, 61% of high-risk HPV-positive biopsies were p16 INK4a negative, while all high-risk HPV-positive CIN 2/3 biopsies were p16 INK4a positive. Diffuse, full thickness p16 INK4a expression discriminated low-grade from high-grade CIN and appears to be a marker of persistent high-risk HPV infection.
Cancer detection and prevention, 2005
Human papillomavirus (HPV) infection plays a crucial role in cervical carcinogenesis. Apart from the detection of p16 protein in cervical tissues, the feasibility of the presence of HPV DNA in peripheral blood being an auxiliary marker of cervical lesions was examined. Peripheral blood samples and cervical tissues, from 36 cervical tissues from high-grade squamous intraepithelial lesions (HSIL) and 31 early invasive cervical cancers (EICC), were analyzed for HPV 16/18 DNA and HPV 16/18 E7 mRNA expression, as well as the in situ expressions of p16 and pRb to investigate the in-between associations. The prevalence of HPV 16/18 DNA in patients with EICC was relatively higher than those of HSIL, in both of cervical tissues and peripheral blood. The presence of HPV 16/18 DNA in peripheral blood was positively correlated with that in cervical tissue, as well as with p16 overexpression in cervical tissues together with a significant correlation between E7 mRNA and pRb and p16 protein expre...
International Journal of Gynecological Pathology, 2004
The role of p16 INK4a as a marker of HR-HPV and in the diagnosis of CIN has been well established, but its predictive value in the clearance of the virus after CIN treatment and its use as a prognostic marker of cervical cancer has not been studied. A series of 302 archival samples, including 150 squamous cell carcinomas (SCCs) and 152 CIN lesions, were subjected to immunohistochemical staining for p16 INK4a and HPV testing using PCR with three primer sets (MY09/11, GP5 + /GP6 + , SPF). Follow-up data were available of 88 SCC patients, and 67 of the CIN lesions had been followed-up with serial PCR after conization. HR-HPV types were closely associated with CIN (OR 19.12; 95%CI 2.31-157.81) and SCC (OR 27.25; 95%CI 3.28-226.09). There was a significant linear relationship between the lesion grade and intensity of p16 INK4a staining (p ס 0.0001). The expression of p16 INK4a was also closely related to HR-HPV (p ס 0.0001). p16 INK4a staining was a 100% specific indicator of CIN, with 100% PPV, and showed 83.5% sensitivity and 80.1% PPV in detecting HR-HPV. However, p16 INK4a staining did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, despite a slightly more favorable survival in women with strong/intense p16 INK4a staining in univariate analysis, p16 INK4a expression was not an independent prognostic predictor in multivariate survival (Cox) analysis. After adjustment for p16 INK4a staining, HR-HPV, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and age, only the last two were significant prognostic predictors (p ס 0.0001 and p ס 0.003, respectively). The present data confirm the role of p16 INK4a as a highly specific marker of CIN and HR-HPV type, but expression of this protein does not seem to be of any prognostic value in cervical cancer or in predicting the clearance of HR-HPV after treatment of CIN. We speculate that different subgroups of cervical cancer are characterized by aberrant p16 INK4a /cyclin D/Rb pathways that are due to different mechanisms that can be mutually exclusive.