Absence Of High-risk Human Papillomavirus Research Articles

Correlation of p53 Expression with Histopathological and Immunohistochemical Features of Human Papillomavirus in Oral Leukoplakia.

Background:Oral cancer is strongly associated with the habit of tobacco chewing, alcohol, and betel quid consumption in India. However, sometimes, majority of the population develop oral cancer without exposure to these risk factors and are sometimes cautious about their fitness, suggesting that additional causes such as genetic predisposition, diet, and viral agents may be associated which need to explored.Aims and Objectives:The aim of this study was to establish a possible correlation between clinical types of leukoplakia with their histopathological features of high-risk human papillomavirus (HPV) infection and the presence or absence of HPV and expression of p53through immunohistochemistry (IHC).Materials and Methods:Sample comprised of 40 cases of leukoplakia and 10 cases as control group. Three sections were prepared from each biopsy and subjected to IHC and hematoxylin and eosin (H and E) stain, respectively. IHC-stained slides were used to evaluate the expression of p53 and HPV and then correlated with the features of HPV infection using H and E staining. Chi-square test with a statistical analysis software package (SPSS software Version 20.0) was used.Observation and Results:The P value for p53 against HPV (IHC) was 0.012, which indicates a significant difference between positivity proportion of P53 and HPV (IHC), whereas the P value for koilocyte and HPV (IHC) is 0.311, which is nonsignificant and indicates no significance of difference between proportion of positivity between koilocyte and HPV (IHC).Conclusion:The expression of p53 was proportionally significant to the expression of positivity of HPV, but there was no significant association between koilocyte and p53 expression.

Gastric-type mucinous carcinoma of the cervix and its precursors - historical overview.

The emerging concept of gastric-type mucinous carcinoma (GAS) of the uterine cervix has been accepted worldwide because of its aggressive clinical behaviour and the absence of high-risk human papillomavirus (HPV). GAS is included as a variant of mucinous carcinoma in the 2014 World Health Organization classification, and its recognition has provoked a discussion on endocervical adenocarcinoma as a single entity such that endocervical adenocarcinoma is now divided into HPV-associated and HPV-independent groups. This article reviews historical and conceptual aspects of GAS and its precursors, starting with minimal deviation adenocarcinoma (MDA), through the ensuing confusion, up to the recent paradigm shift in cervical adenocarcinoma subclassification. The gastric immunophenotype of MDA was demonstrated by a Japanese group in 1998 using the HIK1083 antibody, which recognises gastric pyloric gland mucin, and this elucidated the pathogenesis of this particular tumour. However, this information resulted in overdiagnosis of lobular endocervical glandular hyperplasia (LEGH), first described in 1999 and which represents pyloric gland metaplasia (PGM), as malignant. In the early 2000s the relationship between MDA and LEGH/PGM became a matter of controversy. In 2007 HIK1083 immunohistochemistry extended the morphological spectrum of endocervical adenocarcinoma showing gastric differentiation beyond MDA, which resulted in the proposal of GAS as a distinct entity including MDA as its very well-differentiated subtype. GAS is now considered to be an aggressive and chemoresistant neoplasm that is not related to high-risk HPV. The LEGH/PGM-GAS sequence is currently regarded as an HPV-independent pathway of carcinogenesis. Understanding the underlying molecular events in this process is key to the development of biomarkers for early detection and molecular targeted therapy.

Identification of high-risk human papillomavirus and Rb/E2F pathway genomic alterations in mutually exclusive subsets of colorectal neuroendocrine carcinoma

Colorectal neuroendocrine carcinomas, both small cell and large cell types, are highly aggressive tumors with poor prognosis compared with colorectal adenocarcinoma. The molecular drivers of neuroendocrine carcinoma are best defined in small cell lung cancer, which shows near-universal genomic alterations in TP53 and RB1. The genetics of colorectal neuroendocrine carcinoma remain poorly understood; recent studies demonstrated infrequent RB1 alterations and genetics closely resembling colorectal adenocarcinoma. To better define the molecular pathogenesis of colorectal neuroendocrine carcinoma, we performed capture-based next-generation sequencing on 25 cases and evaluated for expression of p53, Rb, p16, and high-risk human papillomavirus (HR-HPV) subtypes using immunohistochemistry, in situ hybridization, and polymerase chain reaction. Rb/E2F pathway dysregulation was identified in nearly all cases (23/25, 92%) and occurred via three distinct mechanisms. First, RB1 genomic alteration was present in 56% (14/25) of cases and was accompanied by Rb protein loss, high p16 expression, and absence of HR-HPV; these cases also had frequent genomic alterations in TP53, the PI3K/Ras and Wnt pathways, as well as in DNA repair genes, with 4/14 cases being hypermutated. Second, 16% (4/25) of cases, all left-sided, had TP53 alteration without RB1 alteration; half of these harbored high-level amplifications in CCNE1 and MYC or MYCN and arose in patients with ulcerative colitis. Finally, 28% (7/25) of cases, all rectal or anal, lacked genomic alterations in RB1 or TP53 but were positive for HR-HPV. Our data demonstrate that Rb/E2F pathway dysregulation is essential in the pathogenesis of colorectal neuroendocrine carcinoma, akin to neuroendocrine carcinomas in other anatomic sites. Moreover, colorectal neuroendocrine carcinomas stratify into three distinct molecular subgroups, which can be differentiated based on Rb protein and HR-HPV status. HR-HPV infection represents a distinct mechanism for Rb and p53 inactivation in cases lacking genomic alterations in either gene. Differential treatment strategies for hypermutated and HPV-driven cases could improve patient outcomes.

The absence of high-risk human papillomavirus in Czech non-small cell lung cancer cases.

The purpose of our study was to examine the presence of human papillomavirus (HPV) DNA in Czech patients with non-small cell lung cancer (NSCLC). A highly sensitive quantitative polymerase chain reaction (qPCR) detecting the E6 gene of HPV16, 18, 31, and 56 was designed. The limit of detection was assessed using serial dilutions of HPV-positive plasmids. The qPCR was validated on a set of 402 cervical swabs where the qPCR, Cobas, and PapilloCheck methods were tested in parallel. Finally, qPCR was used for HPV detection in a set of 80 patients with primary NSCLC, both from formalin-fixed paraffin-embedded (FFPE) and fresh frozen (FF) tissue samples. The qPCR method was able to reliably detect at least 4 copies of the E6 gene per reaction in HPV16, 18, and 31, and 40 copies per reaction in HPV56. The sensitivity and specificity of the qPCR were 75.6-99.3% and 63.9-100% respectively, depending on the HPV genotype and reference method used. HPV DNA was not detected in the FFPE and FF samples from the set of 80 NSCLC patients. No hrHPV DNA was found in primary NSCLC tumors from a Czech population.

Comparison of the clinical performance of restriction fragment mass polymorphism (RFMP) and Roche linear array HPV test assays for HPV detection and genotyping

BackgroundThe need for accurate genotyping of human papillomavirus (HPV) infections is becoming increasingly important as HPV is the primary cause of cervical cancer worldwide. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry-based restriction fragment mass polymorphism (RFMP) assay provides accurate, broad-spectrum, high-throughput genotyping of HPV. ObjectivesWe evaluated the clinical performance of the RFMP assay compared to a commercially available Roche linear array HPV genotyping test (LA) for detecting and genotyping of HPV. Study designThe RFMP assay and the LA were compared for detecting and genotyping HPV among a cohort of 244 liquid-based cytology samples. ResultsOverall, 216 specimens (93.1%, κ=0.86) generated concordant results for the presence or absence of high-risk HPV (HR-HPV) by the two assays. The RFMP assay and the LA assay generated concordant, compatible, and discordant genotyping results for 79.3, 9.9, and 10.8%, respectively. The diagnostic sensitivity and specificity of RFMP and LA for the cervical lesions of squamous cell carcinoma (SCC) were similar, at 92.9 and 85.0% (RFMP) and 92.9 and 83.8% (LA), respectively. In addition, the odds ratio for SCC with HR-HPV positivity estimated by the RFMP assay (73.7, 95% CI: 8.9–3173.3) was higher than the LA assay (67.0, 95% CI: 8.2–2887.0). ConclusionsThe RFMP and the LA assays were highly comparable with regard to detection and genotyping analysis of HPV. The sensitivity and specificity of RFMP assay for the detection of HR-HPV in various levels of cervical lesions seems to be valuable in the monitoring of HPV-associated cervical cancer.

Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype

A subset of endocervical-type mucinous adenocarcinomas (ACs) of the uterine cervix exhibit a gastric phenotype and morphology, as reported in cases of minimal deviation AC in which the presence of human papillomavirus (HPV) has been rarely detected. To investigate the HPV-independent pathway of carcinogenesis in cases of gastric-type AC, we investigated the common high-risk HPV (hr-HPV) status in 52 nonsquamous cell carcinomas, using a PCR-based typing method and immunohistochemistry of p16INK4a (a cyclin-dependent kinase inhibitor that is overexpressed in both cancerous and precancerous cervical tissue, making it an ideal biomarker for cervical cancer cases). Using novel morphological criteria, seven of 52 (13.5%) carcinomas were designated as gastric-type ACs, all of which were negative for both hr-HPV DNA and p16INK4a. Nongastric-type ACs were frequently positive for both hr-HPV DNA (90%, 28/31) and p16INK4a (94%, 29/31) with adenosquamous and neuroendocrine carcinomas demonstrating the presence of hr-HPV DNA in 86% (6/7) and 83% (5/6) of cases, respectively. In these two types of carcinoma, 86% (6/7) and 100% (6/6) were positive for p16INK4a, respectively. Our data suggests that gastric-type AC appears to represent an oncogenic hr-HPV-independent neoplasm and therefore is a potential pitfall of HPV DNA testing and vaccination.

The Absence of High-risk HPV Combined With Specific p53 and p16INK4a Expression Patterns Points to the HPV-independent Pathway as the Causative Agent for Vulvar Squamous Cell Carcinoma and its Precursor Simplex VIN in a Young Patient

Simplex vulvar intraepithelial neoplasia (VIN) is an important precursor of vulvar invasive squamous cell carcinoma and characteristically occurs in postmenopausal women. In this report, the absence of high-risk human papillomavirus (HPV) combined with specific p53 and p16INK4a expression patterns points to the HPV-independent pathway as the causative agent for vulvar squamous cell carcinoma in a 28-year-old woman. Its precursor simplex VIN was initially interpreted as eczema. Although simplex VIN has a predilection for postmenopausal women, it can occur in young patients. The development of invasive vulvar squamous cell carcinoma underlines the importance of including simplex VIN in the differential diagnosis of vulvar lesions, even at a young age. Furthermore, knowledge about the HPV status in the tumor and thus the underlying causative pathway can alert the gynecologist for the presence or absence of multicentric lower genital tract disease, as this is frequent in the HPV-dependent and not in the HPV-independent pathway.

Should routine screening Papanicolaou smears be done for women older than 65 years?

O F ALL MEDICAL DEcisions, those regarding clinicianinitiated tests and trea tments in asymptomatic individuals require the most thoughtful consideration: as clinicians, we are careful to “do no harm” to healthy people. Populationbased preventive interventions fall in this category and include decisions about screening women older than 65 years for cervical cancer. As women age it becomes increasingly important to consider the benefits and harms that can be expected. With advancing age, the balance between benefit and harm continually changes: greater benefits and fewer harms can be expected in younger, healthy, at-risk women who have never been screened; older, infirmed women with prior normal test results and short life expectancies can expect fewer benefits and greater harms. Assessing where individual women reside at any one time on the balance provides the objective foundation of informed decision making regarding screening. Armed with the best quantitative information, clinicians can then incorporate individual women’s preferences to craft a screening strategy that is rational, safe, acceptable, and effective. A framework for cancer screening decisions in older individuals has recently been proposed. The quantitative information that clinicians need to consider are a woman’s likelihood of developing and dying from cervical cancer in her remaining lifetime, the potential benefits that will accrue from screening, and the potential harms directly related to the screening intervention. Much of the information, though difficult to estimate, is critical for optimal decision making. An unscreened woman’s lifetime risk of cervical cancer is estimated at 3.5% and can be reduced to 0.8% with screening. Throughout an average woman’s lifetime, events occur that modify her risk of developing cervical cancer. The most striking is surgical removal of the cervix by total hysterectomy. Up to 37% of women in the United States have had their cervix removed by the age of 65 years. Women who have had total hysterectomies for nonneoplastic conditions are no longer at risk of cervical cancer and should not be screened for this malignancy. Clinicians should be aware that some women may have had a supracervical hysterectomy in which the cervix was retained. As long as a woman has a cervix she will be at some risk, but these risks become smaller as the number of prior Papanicolaou tests (Pap smears) with normal results increases. By the age of 65 years, a woman with a long history of normal test results has an extremely high likelihood of being among the women who will not develop cervical cancer. Cumulative lifetime risks of incident cancers are more important for risk counseling, but these have not yet been well described in this group. Continued screening, however, can be expected to provide additional benefit in terms of cervical cancer prevention; but this relatively small additional benefit needs to be placed in the context of life expectancy. Women 90 years and older, for example, have average life expectancies of less than 5 years and are unlikely to benefit from cancer screening of any type. Younger women with severe medical conditions also may be expected to achieve marginal benefits from screening. Given that most cervical cancers diagnosed in older women occur among unscreened or poorly screened women, healthy women older than 65 years who have never been screened will probably achieve the greatest benefit. In the future, tests with more powerful predictive value, such as those screening for the presence or absence of highrisk human papillomavirus (HPV), may be more accurate than cytologic evaluation in risk-stratifying older women, though this strategy requires further study. No medical interventions are without harm, and the benefits of screening need to be weighed against harms of screening. Harms are easier to accept if patients are symptomatic than if they are not, as patients are more willing to accept risk, and From the Department of Obstetrics, Gynecology and Reproductive Sciences and the Department of Epidemiology and Biostatistics, University of California, San Francisco. The author has no relevant financial interest in this article. George F. Sawaya, MD CONTROVERSIES IN INTERNAL MEDICINE