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Objectives: This study examined the effects of various factors on survival in hypopharyngeal cancer, involving a total of 100 patients. Methods: Comorbidities, treatment modalities, survival times, and potential factors affecting survival were retrospectively analysed. The expression of p16 was also examined. A statistical analysis was conducted using IBM SPSS V25 software. Results: The mean overall survival time was determined to be 30.8 months. Smoking was observed in 95%, and regular alcohol consumption was reported in 75% of the cases. The expression of p16 did not significantly affect survival (p = 0.74) or the maximum tumour size (p = 0.21). The Kaplan-Meier method demonstrated significantly longer survival times (p = 0.047 *) in the group that underwent partial pharyngolaryngectomy with or without adjuvant therapy (median: 75.25 months, 95% CI: 31.57-118.93), compared to the other four treatment groups (i.e., total laryngectomy with pharyngectomy with or without adjuvant therapy, chemoradiation, chemotherapy, and radiotherapy). Conclusions: The study found that factors such as sex, comorbidities (e.g., type 2 diabetes and chronic obstructive pulmonary disease), TNM and stage, weight loss, smoking, and alcohol consumption did not have a significant effect on survival. In conclusion, the longest survival was observed after partial pharyngolaryngectomy with or without adjuvant therapy. Risk factors and comorbidities did not show a significant effect on survival. p16 expression was not a factor that affected either survival or tumour size.
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BACKGROUND/AIM: The expression of the cyclin-dependent kinase inhibitor p16 correlates with the presence of human papillomavirus. The purpose of this investigation was to assess the prognostic relevance of p16 expression in patients with vulvar squamous cell carcinoma (VSCC) treated with radical surgery followed by adjuvant (chemo) radiation in selected cases. PATIENTS AND METHODS: Seventy-eight patients were analyzed retrospectively. RESULTS: Positive p16 immunostaining was detected in 19 (24.4%) patients. Five-year disease-free survival (DFS) and 5-year overall survival (OS) were better in p16-positive compared to p16-negative patients (83.9% versus 37.3% p=0.002 and 91.7% versus 57.6%, p=0.003, respectively). p16 expression retained prognostic relevance at multivariate analysis for both DFS and OS. CONCLUSION: p16 expression was detected in 24.4% of patients with VSCC and was found to be an independent prognostic variable for both DFS and OS.
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Carcinoma de Células Escamosas , Infecciones por Papillomavirus , Neoplasias de la Vulva , Femenino , Humanos , Pronóstico , Estudios Retrospectivos , Supervivencia sin Enfermedad , Vulva/química , Vulva/metabolismo , Vulva/patología , Neoplasias de la Vulva/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Carcinoma de Células Escamosas/metabolismo , Escisión del Ganglio LinfáticoRESUMEN
Detection of p16 through immunohistochemistry (IHC) is the standard for determining the HPV status of the tumor according the TNM eighth edition released in 2017 and has become crucial for determining the HPV status of oropharyngeal squamous cell carcinomas (OPSCC) with direct impact on staging and prognostication. In recent years, detection of HPV DNA in mouthwashes has been proposed as a noninvasive alternative, both for OPSCCs and for other head and neck squamous cell carcinomas (HNSCCs). However, the prospect of using the mouthwashes to monitor the response to therapy is unclear. To evaluate the effect of curative therapy on the detection of HPV DNA, we performed a prospective study comparing the detection frequency of high-risk HPV DNA (HR-HPV-DNA) in pre- and post-therapy mouthwashes. We collected 137 mouthwashes from 88 pathologically confirmed HNSCC patients for DNA isolation and HPV genotyping with the Inno-LiPA assay. We show that HPV DNA in pretherapeutic mouthwashes can detect HPV-driven HNSCCs with a sensitivity of 50.0% and specificity of 85.4%, alongside a high negative predictive value of 79.5% and an accuracy of 74.5%. Furthermore, we observed a notable decrease in the detection frequency of HR-HPV-DNA after successful treatment (pre-therapy 50.0% (9/18) versus post-therapy 9.7% (3/28)). However, the comparatively low sensitivity regarding detection of HPV-driven OPSCC argues against its use in clinical routine.
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Aims: The present study evaluated the frequency of micronuclei in oral potentially malignant disorders (OPMDs) and their association with the presence of dysplasia on cytology and biopsy as well as their association with p53 mutation and p16 expression. Cytological findings of dysplastic changes in OPMDs were compared to histological diagnoses. Material and Methods: This was a cross-sectional, observational, descriptive study. Scrape smears (n = 74) were collected from lesions in patients with OPMDs. Punch biopsy was collected in patients showing dysplastic changes. Tissue microarray for p53 mutation and p16 expression was performed using paraffin embedded blocks. Cases were classified into grades of dysplasia using both scrape smears and biopsy. Micronuclei frequency was calculated per 100 cells using scrape smears. Mann-Whitney U test was used for correlation of cytology and histology for grade of dysplasia as well as micronuclear frequency with p53 mutation and p16 expression. Results: Micronuclear frequency was found to be increased in patients with dysplasia. A significant association of micronuclear frequency with dysplastic changes was seen on cytology. Sensitivity of cytological evaluation was found to be 64.7%. The association of the micronuclear frequency of samples with p53 mutation and p16 expression was nearly significant (n = 28, P = 0.069 and 0.095, respectively). Conclusion: Micronuclear frequency can be a reliable marker of mutagenic change in OPMDs. Cytological assessment of micronuclei can serve as useful, non-invasive, and relatively inexpensive tool to predict cancerous changes in OPMDs.
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PURPOSE: Despite many studies attributing HPV infection to oropharyngeal tumorigenesis, its involvement in non-oropharyngeal cancers is ambiguous. We have evaluated the mutation profile of p16 along with protein expression and correlated it with the HPV status in oral cancers. METHODS: Somatic mutations in p16 were studied by exome sequencing (n=25) and validated by Sequenom Mass spectrometry (n=50). Expression of p16 was studied by immunohistochemistry (IHC) and correlated with HPV16/18 status evaluated by PCR, and IHC (n=221) in oral cancers. RESULTS: Out of 25 oral cancer patients' samples sequenced by Exome sequencing, p16 mutations were found in 4 samples (16%). All the p16 mutations were identified in patients with cancers in the site of gingivobuccal complex and not tongue subsite. All the 4 patients with p16 mutations had failed treatment, and showed a significantly poor disease-free survival. Insilico analysis of the types of p16 mutations showed mutated, truncated p16 protein having an increased intrinsic disorder, and all the mutations involved truncation post arginine. Validation of the p16 mutations by mass spectrometry showed 8/50 (16%) of patients harbouring pArg80Ter mutation, of which 7/8 (87.5%) had failed treatment. Overexpression of p16 in >70% of the tumour cells was found in 21.4% (26/121) OSCC patients, 6.75% (5/74) OPML patients and p16 expression was significantly correlated (p=0.001; χ2 = 25.601) to the grade. All the samples were studied for HPV presence by PCR and IHC. We found that none of the p16 positive tumours showing expression in >70% of the tumour cells harbored HPV both by PCR as well as IHC. CONCLUSION: Our study emphasises the importance of p16 in oral cancers, and shows that oral cancer is not HPV associated and p16 expression is not a surrogate marker for HPV.
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Alphapapillomavirus , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Genes p16 , Neoplasias de la Boca/genética , Mutación/genética , Biomarcadores de Tumor/genética , Humanos , Inmunohistoquímica , Neoplasias de la Boca/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: Decisions regarding the staging, prognosis, and treatment of patients with head and neck squamous cell carcinomas (HNSCCs) are made after determining their p16 expression levels and human papillomavirus (HPV) infection status. METHODS: We investigated the prognostic roles of p16-positive and p16-negative circulating tumor cells (CTCs) and their cell counts in HNSCC patients. We enrolled patients with locally advanced HNSCCs who received definitive concurrent chemoradiotherapy for final analysis. We performed CTC testing and p16 expression analysis before chemoradiotherapy. We analyzed the correlation between p16-positive and p16-negative CTCs and HPV genotyping, tissue p16 expression status, response to chemoradiotherapy, disease-free survival, and overall survival. RESULTS: Forty-one patients who fulfilled the study criteria were prospectively enrolled for final analysis. The detection rates of p16-positive (>0 cells/mL blood) and p16-negative (≥3 cells/mL blood) CTCs were 51.2% (n = 21/41) and 70.7%, respectively. The best responses of chemoradiotherapy and the p16 positivity of CTCs are independent prognostic factors of disease progression, with hazard ratios of 1.738 (95% confidence interval (CI): 1.031-2.927), 5.497 (95% CI: 1.818-16.615), and 0.176 (95% CI: 0.056-0.554), respectively. The p16 positivity of CTCs was a prognostic factor for cancer death, with a hazard ratio of 0.294 (95% CI: 0.102-0.852). CONCLUSIONS: The p16-positive and p16-negative CTCs could predict outcomes in HNSCC patients receiving definitive chemoradiotherapy. This non-invasive CTC test could help stratify the risk and prognosis before chemoradiotherapy in clinical practice and enable us to perform de-intensifying therapies.
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OBJECTIVES: Human papillomavirus (HPV) is a risk factor for head and neck squamous cell carcinoma (HNSCC), which is currently increasing worldwide. We evaluated the prevalence of HPV DNA and p16 expression in HNSCC patients age <45 years compared with patients aged ≥45 years. METHODS: Thirty-nine patients aged <45 years who presented at Besançon University Hospital with HNSCC since 2005 were included in this retrospective study. HPV DNA was detected by HPV genotyping and p16 expression was determined by immunohistochemistry using paraffin-embedded tissues. A matched-group of 38 patients aged ≥45 years from Besançon University Hospital was included. RESULTS: The overall prevalence of HPV infection was 11.7%. HPV16 was the only genotype detected in 4/39 and 5/38 patients, and p16 was expressed in 6/39 and 4/38 patients aged <45 years and ≥45 years, respectively. CONCLUSIONS: HPV-positivity and p16 expression were similar in both age groups. The results suggest that p16 immunohistochemistry may provide a prognosis biomarker for all HNSCCs, not only oropharyngeal cancers, and this should be addressed in large clinical trials.
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Alphapapillomavirus , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Alphapapillomavirus/genética , Carcinoma de Células Escamosas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , ADN Viral/genética , Neoplasias de Cabeza y Cuello/genética , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/genética , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/genéticaRESUMEN
The expression of p16 is a good surrogate of human papillomavirus (HPV) infection in HPV-associated cancers. The significance of p16 expression, HPV genotype and genera in the outcome of patients with HPV-associated cervical cancer (CC) is unclear. Our aim is to ascertain the prognostic significance of these factors. Data from 348 patients (median age: 47.5 years old) with CC, diagnosed in two referral centers, were retrospectively collected. Advanced disease (FIGO2018 IB2-IV) was present in 68% of patients. A single HPV genotype was identified in 82.8% of patients. The most common HPVs were HPV16 (69%) and HPV18 (14%). HPV genera reflected this distribution. HPV16 tumors presented at an earlier stage. P16 was negative in 18 cases (5.2%), 83.3% of which were squamous cell carcinomas. These cases occurred in older patients who tended to have advanced disease. In the univariate analysis, HPV16 (HR: 0.58; p = 0.0198), α-9 genera (HR: 0.37; p = 0.0106) and p16 overexpression (HR: 0.54; p = 0.032) were associated with better survival. HPV16 (HR: 0.63; p = 0.0174) and α-9 genera (HR: 0.57; p = 0.0286) were associated with less relapse. In the multivariate analysis, only the International Federation of Gynecology and Obstetrics (FIGO) stage retained an independent prognostic value. HPV16, α-9 genera and p16 overexpression were associated with better survival, although not as independent prognostic factors. Patients with p16-negative HPV-associated CC were older, presented with advanced disease and had worse prognosis.
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Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Papillomaviridae/genética , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/virología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Estudios de Cohortes , Femenino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Centros de Atención Terciaria , Regulación hacia Arriba , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Adulto JovenRESUMEN
OBJECTIVES: There is an increasing number of oral squamous cell carcinoma (OSCC) associated with HPV-16. However, p16 expression by immunohistochemistry as the current gold standard for a surrogate marker for virus infection reveals unsatisfying diagnostic accuracy. The aim of this study was to investigate a new rapid test for L1 antibody detection (Prevocheck®) and to validate its diagnostic performance. MATERIALS AND METHODS: In a prospective study, the HPV 16 association of all consecutive patients with an OSCC treated between 2015 and 2019 were analyzed by L1 seropositivity (via PrevoCheck®), p16 immunostaining, and partly multiplex PCR for subtype analysis. RESULTS: Overall (n = 107), p16 expression was positive in 17 cases (15.9%), and L1 antibody seropositivity in 7 cases (6.5%). In PCR analysis, two cases of HPV35 and 50 were found. Total HPV prevalence was 8.4% overall and 6.5% for HPV-16. An inferior diagnostic accuracy for HPV-16-associated OSCC in comparison to PrevoCheck® was revealed. CONCLUSION: The rapid test for L1 antibodies showed an optimal sensitivity and specificity, positive and negative predictive value, and an overall diagnostic accuracy of 100%. However, HPV prevalence seems low in OSCC. CLINICAL RELEVANCE: L1 rapid test may represent an additional diagnostic staging method to detect HPV-16 association rather than p16 immunohistochemistry.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Infecciones por Papillomavirus , Carcinoma de Células Escamosas/diagnóstico , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Humanos , Papillomaviridae , Infecciones por Papillomavirus/diagnóstico , Estudios Prospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death and in most cases it is often diagnosed at an advanced stage. Many genetic and microenvironmental factors are able to modify the cell cycle inducing carcinogenesis and tumor growth. Among the metabolic and genetic factors that come into play in carcinogenesis and tumor cell differentiation and growth there are two different proteins that should be considered which are glucose transporters (GLUTs) and p16INK4 The first are glucose transporters which are strongly involved in tumor metabolism, notably accelerating cancer cell metabolism both in aerobic and anaerobic conditions. There are different subtypes of GLUT family factors of which GLUT 1 is the most important and widely expressed. By contrast, p16 is mainly a tumor-suppressor protein that acts on cyclin-dependent kinase favoring cell cycle arrest in the G1 phase. Our search focused on the action of the aforementioned factors.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Neoplasias Pulmonares/genética , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , PronósticoRESUMEN
INTRODUCTION: Human papillomavirus (HPV) infection plays an important role in the etiopathogenesis of oropharyngeal squamous cell carcinomas. HPV detection in these tumours is a positive prognostic marker. The p16 protein expression, which is detected immunohistochemically, is an indirect marker of active HPV infection. Unlike in oropharyngeal carcinoma, in oral carcinoma, the prognostic significance of HPV/p16 positivity is unclear. Some studies even show a worse prognosis in patients with HPV/p16 positive oral carcinoma. The aim of our study is to consider the significance of p16 protein expression in relation to clinicopathological parameters and prognosis in patients with oral squamous cell carcinomas. Methods: One hundred and twenty patients treated surgically for oral carcinoma were enrolled in the study. The most common anatomical sites of oral carcinoma were the tongue body (54; 45% of cases) and floor of mouth (35; 29.2% of cases). All tumours were analysed immunohistochemically for p16 protein expression. The results were correlated with the clinicopathological parameters and analysed statistically. RESULTS: Ten patients (8.3%) tested positive for p16 expression. In the study cohort, p16 expression was identified as the most significant factor with a negative effect on survival (p=0.019). Based on the Cox proportional hazard model, the p16-positive patients had four times worse survival than the p16-negative ones. Other factors with a statistically significant effect on survival were T status, N status, and recurrence. CONCLUSION: The significance of p16 expression differs between oral and oropharyngeal carcinomas. The p16 positivity seems to be a negative prognostic factor in oral carcinomas. Nevertheless, the significance of HPV presence in tumours outside the oropharyngeal area remains unclear.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Humanos , Recurrencia Local de NeoplasiaRESUMEN
OBJECTIVES: We assessed the periodontal situation radiologically according to tumour p16 status. MATERIALS AND METHODS: Patients with a diagnosis of tonsillar cancer and availability of a digital panoramic radiograph (DPR) during a 5-year period were included in this retrospective study. The predictor variables were periodontal stability, marginal bone loss, marginal bone loss without periodontal stability and total number of teeth. Periodontal status was compared with p16 status, age, gender, smoking and alcohol use. RESULTS: Among 115 patients included in the analyses (p16-negative, n = 24; p16-positive, n = 91), smoking (p < .0001), heavy alcohol use (p < .0001) and total number of teeth (p = .0001) were significantly associated with p16 status. Current smoking (OR = 7.3) and heavy alcohol use (OR = 10.1) increased the risk of p16-negative cancer. CONCLUSIONS: Patients with p16-negative tonsillar carcinoma had less teeth than patients with p16-positive tumours. Other periodontal findings were common in both groups without statistical significance. Heavy alcohol use and smoking were the most important risk factors for p16-negative tonsillar carcinoma.
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Carcinoma de Células Escamosas , Infecciones por Papillomavirus , Periodontitis , Neoplasias Tonsilares , Humanos , Pronóstico , Estudios Retrospectivos , Neoplasias Tonsilares/diagnóstico por imagenRESUMEN
BACKGROUND: Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinomas (OPSCCs) demonstrate superior outcome compared with HPV-negative OPSCCs. The eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, lymph node, metastasis (TNM) classification (TNM 2017) modifies OPSCC staging based on p16 positivity as a surrogate for HPV-driven disease. In p16-negative OPSCCs, lymph node (N) categories include extracapsular/extranodal extension (ECE); and, in p16-positive OPSCCs, N categories are based on the number of positive neck lymph nodes omitting ECE status. The objective of the current study was to assess the prognostic impact of positive ECE status and the detection of HPV16 DNA in patients with p16-positive OPSCC. METHODS: In a cohort of 92 patients with p16-positive, lymph node (N)-positive (stage III-IVB) OPSCC who underwent surgery and neck dissection, allowing for a pathologic examination of positive lymph nodes, 66 of 92 patients (71.4%) were p16-positive/HPV16 DNA-positive, 62 of 92 (67%) were ECE-positive, and 45 of 62 (72.6%) were ECE-positive, p16-positive, and HPV16 DNA-positive. Differences in outcome were assessed using Kaplan-Meier plots and Cox proportional hazard regression (CoxR) for tumor-specific survival and overall survival (OS). RESULTS: The mean numbers of positive lymph nodes in ECE-positive patients (5.0 positive lymph nodes; 95% CI, 3.8-6.4 positive lymph nodes) and ECE-negative patients (2.4 positive lymph nodes; 95% CI, 1.8-2.9 positive lymph nodes) were different (P = .0007). ECE affected OS and tumor-specific survival in p16-positive patients (P = .007 and P = .047, respectively) and in p16-positive/HPV16 DNA-positive patients (P = .013 and P = .026, respectively). Related to the unequal distributions of ECE-positive/HPV16 DNA-negative tumors, the TNM 2017 failed to discriminate OS in patients with UICC stage I, II, and III disease (mean OS, 54.5, 73.4, and 45 months, respectively; median OS, 64.7 months, not reached, and 41.1 months, respectively). According to a univariate CoxR, the presence of ECE predicted impaired OS in patients with p16-positive OPSCC (hazard ratio, 3.40; 95% CI, 1.17-9.89; P = .025) and even greater impaired OS in those with p16-positive/HPV16 DNA-positive OPSCC (HR, 8.64; 95% CI, 1.12-66.40; P = .038). Multivariate CoxR confirmed ECE and HPV16 DNA detection as independent predictors. CONCLUSIONS: ECE and HPV16 DNA status should be included in the prognostic staging of patients with p16-positive OPSCC because several lines of evidence demonstrate their impact on survival.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Extensión Extranodal/patología , Papillomavirus Humano 16/genética , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Adulto , Anciano , ADN Viral/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patología , Infecciones por Papillomavirus/patología , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Análisis de SupervivenciaRESUMEN
OBJECTIVE: To identify the expression of the molecular markers p53 and p16INK4A in head and neck squamous cell carcinoma (HNSCC) and to assess their impact on its clinical and morphological characteristics and overall survival (OS) rates in patients with HNSCC. MATERIAL AND METHODS: Histological blocks were immunohistochemically studied using anti-p16 and p53 monoclonal antibodies in Krasnodar Clinical Oncology Dispensary One in 2011 to 2016. Overexpression of p16INK4A was established in the presence of 3 and 4 staining points (nuclear and/or cytoplasmic staining in 40% or more tumor cells). That of p53 was determined in the presence of nuclear staining (3+) in more than 50% of tumor cells. RESULTS: Overexpression of p16 was found in 15 (27%) patients (9 (60%) men and 6 (40%) women). The p16-positive tumor status was associated with the female sex (p=0.023), which was characteristic of tonsil cancer (p<0.001) and represented by the nonkeratinizing type (p=0.008). Overexpression of p16 was associated with more frequent regional lymph node metastases (p=0.029). Overexpression of p53 was related to G2 tumor (p=0.021) and expression of p53 was less than 50% associated with tongue body cancer (p=0.004). Kaplan-Meier analysis showed that the 3-year OS in p16-positive HNSCC patients was significantly higher than that in p16-negative ones (p=0.048). Significantly higher OS rates were observed in p16-positive HNSCC patients than in p16INK4A-negative ones for Stage III-IV (p=0.021). OS rates in HNSCC patients with co-expression of p16INK4A (3 and 4 points) and p53 (3+) were significantly higher than in the absence of a combination of these molecular markers (p=0.049). At the same time, OS in HNSCC patients with co-expression of p16INK4A (3 and 4 points), p53 (3+) was significantly higher than in the absence of a set of these molecular markers for stage III-IV (p=0.01). OS in patients with Stages I-II HNNSCC and co-expression of p16INK4A (3 and 4 points) and p53 (3+) did not significantly differ from that in the absence of a set of these molecular markers (p=0.960). CONCLUSION: Overexpression of p16INK4A (3 and 4 points) can be used as a prognostic marker to divide patients into subgroups with different clinical and morphological characteristics. The data on the correlation of p53 overexpression as a marker of mutations in the TP53 gene are contradictory and the study has not revealed the worst overall survival rates. A set of markers for the expression of p16 (≥40%) and p53 (≥50%) has been proposed for use as a favorable prognostic sign.
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Biomarcadores de Tumor , Carcinoma de Células Escamosas , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Genes p53 , Neoplasias de Cabeza y Cuello , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Células Epiteliales , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Pronóstico , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Oral field cancerization describes a multifocal development process involving many cells at once in response to prolong exposure to carcinogens. This case demonstrated differential p16 expression in different sections of the same HPV negative tumor on the floor of mouth in a patient with history of prolonged smoking. METHODS: Histological examination, presence of HPV infection and OncoScan analysis of DNA extracted from two well-defined areas with different p16 expression profiles were performed. RESULTS: Histological and immunochemical analysis revealed the presence of a dual architectural pattern squamous cell carcinoma with a p16 negative and a p16 positive component. OncoScan analysis showed genetic changes that define field cancerization of the p16 negative tumor as revealed by mosaicism in both loss of heterozygosity and copy number alterations in cancer-associated genes located on 3p, 7p, 9p 11q, and 17p. CONCLUSION: These changes were indicative of field cancerization in response to tobacco exposure.
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Carcinoma de Células Escamosas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Variaciones en el Número de Copia de ADN , Pérdida de Heterocigocidad , Neoplasias de la Boca/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Fumar Cigarrillos/efectos adversos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Genoma , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patologíaRESUMEN
AIM: To evaluate cyclin-dependent kinase inhibitor 2A (CDKN2A) and cytokeratin 7 (CK7) expression in cervical intraepithelial neoplasia (CIN) formalin-fixed samples. MATERIALS AND METHODS: Staining with antibody clones G175-405 for CDKN2A and OV-TL 12/30 for CK7 were evaluated and the detection of protein expressions were compared in 147 patients with CIN. RESULTS: Clinical follow-up of patients with CIN1 and CIN2 showed that most patients had a favorable outcome. Single CDKN2A or CK7 expression and their combined expression had a greater sensitivity and negative predictive value in CIN1, corresponding to the non-development of the disease. The positive predictive value of CDKN2A was greater than that of CK7. Combined expression of CDKN2A and CK7 showed that the sensitivity, specificity, positive predictive values, and negative predictive values had their maximum index in the CIN1 group. Analysis of combined expression of CDKN2A and CK7 showed that 85.7% of patients presented unfavorable clinical outcomes, with positive expression for both markers identified in CIN2. CONCLUSION: Combined expression of CK7 and CDKN2A was associated with a better diagnosis of CIN, and negative expression in CIN1/2 groups had a greater negative predictive value for patient clinical outcome.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Queratina-7/metabolismo , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/metabolismo , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/metabolismo , Adolescente , Adulto , Biomarcadores de Tumor/metabolismo , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Lesiones Intraepiteliales Escamosas de Cuello Uterino/diagnóstico , Lesiones Intraepiteliales Escamosas de Cuello Uterino/metabolismo , Lesiones Intraepiteliales Escamosas de Cuello Uterino/patología , Neoplasias del Cuello Uterino/patología , Adulto Joven , Displasia del Cuello del Útero/patologíaRESUMEN
PURPOSE: To evaluate the impact of HPV16 load (VL-the number of virus genome copies per cell) and P16 expression on prognosis of patients with squamous cell carcinomas (SCCs) of head and neck (HN). MATERIALS AND METHODS: HPV16 presence was assessed in the group of 109 patients with HNSCCs by quantitative polymerase chain reaction (qPCR). VL (assessed by qPCR) and P16 expression (evaluated by immunohistochemistry) were analysed only in the subgroup of HPV16-positive tumours. These features were correlated with 5-year overall survival (OS) and disease-free survival (DFS). RESULTS: HPV16 infection was found in 36 tumours (33.0%). Virus-positive patients had better OS and DFS than those without infection (P = 0.041 and 0.005). Among HPV16-positive HNSCCs, 18 (50.0%) had higher VL (median value > 6764.3 copies/cell) and 25 (73.5%) P16 over expression. The significant differences in OS and DFS (P = 0.008 and 0.004) were noticed according to VL, wherein 100% DFS was found for patients with higher VL. According to P16 expression, significant difference was found only for OS (P = 0.020). In multivariate analysis, VL (P = 0.045; HR = 2.795; CI 0.121-1.060) and the level of smoking (P = 0.023, HR = 2.253; CI 1.124-4.514) were independent factors affecting DFS of HPV16-positive patients. CONCLUSION: On the basis of viral load, it is possible to differentiate prognosis of patients with HPV16-positive HNSCCs. In this subgroup, viral load has stronger prognostic potential than P16 expression.
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Carcinoma de Células Escamosas/virología , Neoplasias de Cabeza y Cuello/virología , Papillomavirus Humano 16/aislamiento & purificación , Infecciones por Papillomavirus/virología , Carcinoma de Células Escamosas/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Dosificación de Gen , Genoma Viral , Neoplasias de Cabeza y Cuello/patología , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Infecciones por Papillomavirus/patología , Reacción en Cadena de la Polimerasa , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello , Carga ViralRESUMEN
Overexpression of the p16 tumor suppressor, but also deletion of its gene locus 9p21, is linked to unfavorable tumor phenotype and poor prognosis in breast cancer. To better understand these contradictory observations, and to clarify the prognostic impact of p16 expression and 9p21 deletion, a tissue microarray (TMA) with 2,197 breast cancers was analyzed by fluorescence in-situ hybridization and immunohistochemistry (FISH) for 9p21 deletion and p16 expression. p16 immunostaining was weak in 25.6%, moderate in 7.1%, and strong in 12.7% of 1,684 evaluable cancers. Strong p16 staining was linked to advanced tumor stage (p = 0.0003), high-grade (p < 0.0001), high tumor cell proliferation (p < 0.0001), negative hormone receptor (ER/PR) status (p < 0.0001 each), and shorter overall survival (p = 0.0038). 9p21 deletion was found in 15.3% of 1,089 analyzable breast cancers, including 1.7% homozygous and 13.6% heterozygous deletions. 9p21 deletion was linked to adverse tumor features, including high-grade (p < 0.0001) and nodal positive cancers (p = 0.0063), high cell proliferation (p < 0.0001), negative hormone receptor (ER/PR) status (p ≤ 0.0006), and HER2 amplification (p = 0.0078). Patient outcome was worse in 9p21 deleted than in undeleted cancers (p = 0.0720). p16 expression was absent in cancers harboring homozygous 9p21 deletions, but no difference in p16 expression was found between cancers with (59.2% p16 positive) and without heterozygous 9p21 deletion (51.3% p16 positive, p = 0.0256). In summary, p16 expression is unrelated to partial 9p21 deletion, but both alterations are linked to aggressive breast cancer phenotype. High-level p16 expression is a strong predictor of unfavorable disease course in breast cancer.
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Biomarcadores de Tumor , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 9 , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Eliminación de Gen , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Proliferación Celular , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Metástasis Linfática , Clasificación del Tumor , Fenotipo , Modelos de Riesgos Proporcionales , Factores de Riesgo , Análisis de Matrices Tisulares , Regulación hacia ArribaRESUMEN
The aim of the study was to assess regional control and survival in primary irradiated oropharyngeal cancer patients with advanced neck disease (≥cN2a) receiving planned neck dissection (PND) irrespective of the nodal response compared to salvage neck dissection (SND) in case of regional persistence or reccurence in relation to tumoral p16 overexpression. 96 consecutive patients treated at the University Hospital of Zurich, Switzerland were included. Tissue microarray-based scoring of p16 expression was obtained. 5 years overall (OS) and disease-specific survival (DSS) in the PND and SND cohort were 70 vs. 57 % (p = 0.20) and 80 vs. 65 % (p = 0.14), respectively. Regional control in PND and SND achieved 95 vs. 87 % (p = 0.29), respectively. There was no statistically significant impact of neck treatment (PND vs. SND) on regional control or survival among patients with p16-negative tumors (5 years OS 59 vs. 50 %, p = 0.66; 5 years DSS 59 vs. 57 %, p = 0.89) nor among patients with p16-positive tumors (5 years OS 84 vs. 67 %, p = 0.21; 5 years DSS 95 vs. 81 %, p = 0.24). The type of neck dissection after primary intensity-modulated radiotherapy (IMRT) had no impact on regional control and survival even in human papillomavirus (HPV)-associated disease. Therefore we are convinced that based on the accuracy of newer diagnostic modalities the surveillance of a radiologically negative neck after primary chemoradiation (CRT) is oncologically safe irrespective of p16 expression of the tumor.
Asunto(s)
Carcinoma de Células Escamosas/terapia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Regulación Neoplásica de la Expresión Génica , Disección del Cuello/métodos , Estadificación de Neoplasias , Neoplasias Orofaríngeas/terapia , ARN Neoplásico/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Quimioradioterapia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/patología , Radioterapia de Intensidad Modulada , Tasa de Supervivencia/tendencias , Suiza/epidemiologíaRESUMEN
BACKGROUND: A germline mutation in the 3'-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: We conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings. RESULTS: KRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04). CONCLUSIONS: The TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients. CLINICAL TRIAL REGISTRATION NUMBERS: NCT00503997, NCT00425750, NCT00003809.