RESUMO
INTRODUCTION: Patients with Human Papillomavirus (HPV+)-associated Laryngeal Squamous Cell Carcinoma (LSCC) exhibit dramatically improved survival relative to those with HPV-Negative (HPV-) tumors. In this study, the authors aimed to investigate the radiosensitivity of all available confirmed HPV+ and HPV-LSCC cells in vitro and in vivo. METHODS: Primary LSCC cells were generated from tumor specimens obtained from patients. Real-time PCR was performed to confirm HPV infection and the expression of HPV-related genes (E6 and E7), p53, and pRB. Clonogenic survival assays, western blotting, and flow cytometry were used to assess radiation sensitivity, apoptosis, and the expression of p53 and pRB. p53 and pRB knockout cells were generated using CRISPR/Cas9 technology. RESULTS: HPV+ LSCC cells displayed enhanced radiation sensitivity compared to HPV- cells. Radiation-induced apoptosis in HPV+ LSCC cells, accompanied by increased levels of p53 and pRB. Knockout of p53 or pRB led to radiation resistance and attenuated radiation-induced apoptosis in HPV+ LSCC cells. In vivo experiments showed similar results, where knockout of p53 or pRB decreased radiosensitivity in tumor-bearing mice. CONCLUSION: The present findings demonstrated that HPV+ LSCC cells displayed obvious inherent radiation sensitivity, corresponding to increased apoptosis following radiation exposure. Mechanism study showed that the expression of p53 and pRB in HPV+ cells are required for radiation sensitivity. These findings highlight a novel mechanism by which p53 and pRB play key roles in the radiation sensitivity of HPV+ LSCC compared to HPV-LSCC.
Assuntos
Apoptose , Carcinoma de Células Escamosas , Neoplasias Laríngeas , Infecções por Papillomavirus , Tolerância a Radiação , Proteína Supressora de Tumor p53 , Humanos , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/virologia , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/virologia , Proteína Supressora de Tumor p53/metabolismo , Infecções por Papillomavirus/radioterapia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/complicações , Apoptose/efeitos da radiação , Animais , Linhagem Celular Tumoral , Reação em Cadeia da Polimerase em Tempo Real , Masculino , Camundongos , Citometria de Fluxo , Western Blotting , Proteína do Retinoblastoma/metabolismoRESUMO
BACKGROUND: Merkel cell polyomavirus (MCPyV), a human polyomavirus that is unequivocally linked to merkel cell carcinoma (MCC), has been found in association with keratinocytes carcinomas (KC), especially basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Nevertheless, there is scarce information about the possible involvement of MCPyV in the development of KC. OBJECTIVES: To assess the presence of MCPyV DNA and Large-T Antigen (LT-Ag) via Polymerase Chain Reaction (PCR) and Immunohistochemistry (IHC) in cases of KC, and to correlate its presence with immunohistochemical markers p16, p53, and ki67, tumor type and subtype, sun-exposed location, and epidemiological data. METHODS: The prevalence of MCPyV DNA, LT-Ag, and immunohistochemical markers p16, p53, and ki67 was assessed by PCR and Immunohistochemistry (IHC) in 127 cases of KC, these results were correlated with tumor type and subtype, sun-exposed location, and epidemiological data. RESULTS: The MCPyV DNA was detected in 42.57% (43 of 101) cases by PCR, the LT-Ag was detected in 16.4% (20 of 122) of cases, p16 in 81.5% (97 of 119), p53 in 66.4% (83 of 125), ki67 in 89% (73 of 82). No correlation between MCPyV LT-Ag and DNA confronted with tumor type, subtype, location site, and immunohistochemical markers was found. A single correlation between the MCPyV LT-Ag and cSCC tumors and peri-tumoral lymphocyte cells was noted. STUDY LIMITATIONS: Further steps need to be taken to better evaluate the MCPyV influence and its possible role in KC carcinogenesis, as the evaluation of the virus genome state, the gene sequence that encodes LT-Ag in the KC tumor cells, and in situ hybridization for viral DNA or RNA in these cells. CONCLUSIONS: Despite the frequent detection of MCPyV in KC, the data available so far does not support the hypothesis of a causal relationship between them.
Assuntos
Antígenos Virais de Tumores , Biomarcadores Tumorais , Carcinoma de Célula de Merkel , Carcinoma de Células Escamosas , Antígeno Ki-67 , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Proteína Supressora de Tumor p53 , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos Virais de Tumores/análise , Biomarcadores Tumorais/análise , Carcinoma Basocelular/virologia , Carcinoma Basocelular/patologia , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Células Escamosas/virologia , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , DNA Viral/análise , Imuno-Histoquímica , Queratinócitos/virologia , Queratinócitos/patologia , Antígeno Ki-67/análise , Poliomavírus das Células de Merkel/isolamento & purificação , Reação em Cadeia da Polimerase , Infecções por Polyomavirus/virologia , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/patologia , Proteína Supressora de Tumor p53/análise , Infecções Tumorais por Vírus/virologiaRESUMO
BACKGROUND: The aim was to evaluate the frequency, clinicopathological features, and HPV status of oropharyngeal squamous cell carcinoma (OP-SCC) and benign HPV-related epithelial lesions of the oropharynx over the last 25 years. Moreover, a literature review was performed to investigate HPV frequency in OP-SCC samples diagnosed in Brazilian Centers. MATERIAL AND METHODS: A cross-sectional study analyzed OP-SCC, squamous papilloma, verruca vulgaris, and condyloma accuminatum, diagnosed from 1997 to 2021. HPV status of OP-SCC was determined by immunohistochemistry and "in situ" hybridization. Bivariate statistics were performed (p≤0.05). For the literature review, MEDLINE/PubMed, Web of Science, EMBASE, and Scopus were searched. Two independent reviewers assessed the studies for eligibility. RESULTS: Cross-sectional: 211 OP-SCC (63.0%) and 124 benign lesions (37.0%) were included. OP-SCC frequency increased gradually over time, whereas benign lesions had steady trends. OP-SCC affected more males (n= 171; 81.0%), though the relative frequency in females rose over time. Smoking (n= 127; 60.2%) was common in OP-SCC. Nineteen OP-SCC (13.0%) were positive for HPV. HPV-positive and HPV-negative tumors had similar clinicopathological features (p>0.05). Benign lesions predominated in middle-aged (n= 32; 26.7%) women (n= 71; 57.3%), in the soft palate (n=101; 81.5%). LITERATURE REVIEW: 32 studies were included, and in 60% of them, HPV frequency in OP-SCC was less than 25%. CONCLUSIONS: OP-SCC prevalence has been increasing, and it was mostly associated with smoking and alcohol rather than with HPV infection in Brazil. Benign lesions had a stationary frequency over the evaluated period.
Assuntos
Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Estudos Transversais , Brasil/epidemiologia , Neoplasias Orofaríngeas/virologia , Neoplasias Orofaríngeas/epidemiologia , Neoplasias Orofaríngeas/patologia , Infecções por Papillomavirus/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas/virologia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Adulto , Idoso , Fatores de Tempo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
INTRODUCTION: Metastatic disease to the breast is a rare condition, with contralateral breast metastasis being the most common primary site. CASE PRESENTATION: We present the case of a patient who underwent treatment for an HPV positive squamous cell carcinoma (SCC) of the cervix who, during follow-up, complained of a nodule in her left breast. Anatomopathological results indicating squamous carcinoma, which was not able to be differentiated from breast metaplastic carcinoma. Resection of the lesion was carried out, confirming carcinoma with squamous cell differentiation with negativity for GCDFP-15, mammaglobin, p63 and SOX10, but with positivity for p16 and for high risk HPV, confirming a single metastatic lesion of cervical carcinoma. DISCUSSION/CONCLUSION: In the presence of SCC in the breast, the differential diagnosis may consider the presence of primary lesion, metaplastic carcinoma with squamous cell differentiation or metastatic disease. The use of markers such as p63, SOX10 and p16, may help for a definitive diagnosis.
Assuntos
Neoplasias da Mama , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Mama/patologia , Neoplasias da Mama/secundário , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologiaRESUMO
INTRODUCTION: Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias. MATERIALS AND METHODS: A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed. RESULTS: Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival. CONCLUSION: PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.
Assuntos
Antígeno B7-H1/análise , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Neoplasias Penianas/química , Neoplasias Penianas/imunologia , Neoplasias Penianas/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/virologia , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Penianas/virologiaRESUMO
Introducción: el cáncer escamocelular (CEC) representa el 90-95% de todos los tipos de cáncer. En México, la frecuencia de CEC bucal (CECB) se ha incrementado y presenta una incidencia entre el 1 y el 5%. El CECB se asocia con sujetos en la quinta y séptima década de la vida, el sexo masculino, positivos a tabaquismo, alcoholismo, factores genéticos, inmunosupresión, infección por virus del papiloma humano (VPH) y estilos de vida poco saludables, entre otros. El objetivo de este trabajo fue presentar un caso clínico como ejemplo de las características emergentes en un paciente con CECB. Caso clínico: mujer de 38 años, con úlcera indurada, parcialmente adherida a planos profundos y dolorosa, asociada con un aumento de volumen, ubicada en vientre y borde lateral de lengua. Se realizó biopsia y con el diagnóstico histopatológico de carcinoma escamocelular invasor bien diferenciado, se procedió a determinar la presencia delVPH y resultó positivo a VPH 16. Se realizó tratamiento oncológico combinado (quirúrgico-radiación-quimioterapia), con buenos resultados para la paciente respecto a la estética y función. Conclusiones: se analizaron varios estudios que evalúan la presencia del VPH en lesiones de CECB, como un factor de riesgo que involucra con mayor frecuencia casos de pacientes jóvenes, la localización en lengua y antecedentes negativospara tabaquismo y alcoholismo frente a casos de CECB no asociados al VPH. Se requieren datos que contribuyan a dilucidar diversos aspectos aún desconocidos sobre la infección bucal por VPH y su relación con el CECB.
Background: Squamous cell cancer (SCC) represents 90-95% of all types of cancer. In Mexico, the frequency of oral SCC (OSCC) has increased, with an incidence between 1 and 5%. OSCC is associated with subjects in the 5 and 7th decade of life, males, positive for smoking, alcoholism, genetic factors, immunosuppression, human papillomavirus (HPV) infection, and unhealthy lifestyles, among others. Theobjectiveof thisworkwas to presenta clinical case as an example of the emerging characteristics in a patient with OSCC. Clinical case: 38-year-old female patient, with indurated ulcer, partially adhered to deep planes and painful, associated with an increase in volume, located on the belly and lateral edge of the tongue. A biopsy was performed and with the histopathological diagnosis of well differentiated invasive squamous cell carcinoma, the presence of HPV was determined, resulting positive for HPV-16. Combined cancer treatment was performed (surgical radiation-chemotherapy), with good results for the patient regarding aesthetics and function. Conclusions: We analyzed several studies evaluating the presence of HPV in lesions of OSCC, as a risk factor that involves more frequently cases of young patients, with location in tongue, and negative antecedents for smoking and alcoholism compared to cases of OSCC not associated with HPV. Data are required to help elucidate various still unknown aspects of oral HPV infection and its relationship with OSCC.
Assuntos
Humanos , Feminino , Adulto , Neoplasias da Língua/virologia , Carcinoma de Células Escamosas/virologia , Infecções por Papillomavirus/complicações , Alphapapillomavirus , Neoplasias da Língua/patologia , Carcinoma de Células Escamosas/patologia , Fatores de Risco , Estilo de VidaRESUMO
PURPOSE: To investigate the possibility of using the methylation level of PAX1/ZNF582 gene as molecular marker to differentiate the progression of cervical cancer. METHODS: From January 2016 to March 2018, 150 patients, who were admitted to Cervical Disease Diagnosis and Treatment Center of Xuzhu Maternity and Child Care Hospital, were enrolled in this study. Patients were classified into chronic cervicitis (for 19 cases), low-grade squamous intraepithelial lesion (LSIL) (18 cases), high-grade squamous intraepithelial lesion (HSIL) (37 cases) and squamous cell carcinoma (SCC) (31 cases). All patients underwent several tests including Thin-prep cytology test (TCT), HPV DNA detection and detection of methylation level of PAX1/ZNF582 genes. RESULTS: For diagnosis of HSIL, the area under curve (AUC) was 0.878 (95% CI 0.806 ~ 0.950); the threshold for PAX1 was 12.285, the sensitivity and specificity were 91.9% and 72.8%, respectively. The AUC of ZNF582 gene detection was 0.900 (95% CI 0.842 ~ 0.959), the threshold was 11.56, while the sensitivity and specificity were 97.3% and 76.7%, respectively. Among various tests we conducted, PAX gene detection methods showed the highest specificity (97.30%). PAX1/ZNF582 gene detection method demonstrated the highest accuracy. CONCLUSIONS: For patients with high-grade cervical lesion and cervical cancer, the methylation level of PAX1/ZNF582 gene could be applied as a noteworthy biomarker for diagnosis and for cervical cancer classification.
Assuntos
Carcinoma de Células Escamosas/genética , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Box Pareados/genética , Displasia do Colo do Útero/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Alphapapillomavirus/genética , Área Sob a Curva , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Doença Crônica , Metilação de DNA , DNA Viral/análise , Progressão da Doença , Feminino , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Sensibilidade e Especificidade , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Cervicite Uterina , Adulto Jovem , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
BACKGROUND/AIM: p16 and PTEN are tumor suppressor genes. Loss of these molecules in oral squamous cell carcinoma (OSCC) has been studied worldwide. In this study, we explored whether p16 cooperates with inactive PTEN during the pathogenesis of OSCC, especially in regard to tumor aggressiveness and proliferation. MATERIALS AND METHODS: Immunocytochemistry and western blot analysis were used to examine the levels of p16 and PTEN. Sequencing analysis was performed to identify mutations in the PTEN gene and HPV infection. Fluorescence in situ hybridization was used to examine the presence of the PTEN locus. RESULTS: PTEN analysis showed high positivity in T4 samples. HPV-positive tumors correlated with tabagism, tumor size 3 and 4, disease stages 3 and 4, presence of lymph node metastasis (N1) and poor differentiation. Immunoexpression of p16 was strongly correlated with the presence of HPV. CONCLUSION: PTEN demonstrated a higher reactivity in advanced disease stages and p16 was strongly associated with HPV. Viral presence decreases tumor aggressiveness. Patients with advanced stage lesions demonstrated lower survival rate.
Assuntos
Carcinoma de Células Escamosas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Perda de Heterozigosidade/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologiaRESUMO
Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient's recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11-14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.
Assuntos
Carcinoma de Células Escamosas/genética , Mutação/genética , Neoplasias Orofaríngeas/genética , Adulto , Idoso , Carcinoma de Células Escamosas/virologia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/virologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/virologia , Nicotiana/efeitos adversosRESUMO
Papillomaviruses (PVs) are circular double-stranded DNA virus belonging to Papillomaviridae family. During the infection cycle, PVs translate proteins that can influence cell growth and differentiation, leading to epidermal hyperplasia and papillomas (warts) or malignant neoplasms. Canis familiaris papillomaviruses (CPVs) have been associated with different lesions, such as oral and cutaneous papillomatosis, pigmented plaques, and squamous cell carcinomas (SCCs). Here, we report a clinical case of a mixed bred female dog with pigmented plaques induced by CPV16 (Chipapillomavirus 2) that progressed to in situ and invasive SCCs. Gross and histological findings were characterized, and the lesions were mainly observed in ventral abdominal region and medial face of the limbs. In situ hybridization (ISH) revealed strong nuclear hybridization signals in the neoplastic epithelial cells, as well as in the keratinocytes and koilocytes of the pigmented viral plaques. The full genome of the CPV16 recovered directly from the lesions was characterized, and the phylogenetic relationships were determined. The identification of oncoprotein genes (E5, E6, and E7) by high throughput sequencing (HTS) and their expected domains are suggestive of the malignant transformation by CPV16.