RESUMO
Most nasopharyngeal carcinomas (NPCs) in a high-incidence population are driven by Epstein-Barr virus (EBV) infection. EBV-associated malignancies have increased expression of the programmed death-ligand 1 (PD-L1). Immunotherapy agents targeting the PD-1/PD-L1 pathway have achieved durable treatment effects in patients with various cancer types including EBV-associated malignancies. In this study, we sought to investigate PD-L1 expression in a cohort of patients with NPCs from the Philippines. Fifty-six NPCs were studied for PD-L1, p16, and DNA mismatch repair (MMR) deficiency by immunohistochemistry. One case with MMR deficiency was also assessed for microsatellite instability (MSI) by polymerase chain reaction. EBV and human papillomavirus (HPV) status were tested by in situ hybridization. All NPCs were p16 negative. Three of the 56 NPCs (5%) were EBV negative (EBV-) and HPV negative, while one NPC (1/56, 2%) was EBV positive and showed MSI (EBV+/MSI). Positive PD-L1 expression (PD-L1+), defined as membranous staining in ≥1% tumor cells, was seen in 64% (36/56) of NPCs. All three EBV- NPCs were PD-L1+ as was the EBV+/MSI NPC. PD-L1+ was seen significantly more often in NPCs from non-smokers than those from smokers (23/28, 82% vs 9/18, 50%; P = 0.047). PD-L1+ was not associated with pT, pN, distant metastasis, or clinical stage (P > 0.05). PD-L1+ was not associated with overall survival (P = 0.473). In summary, our results show frequent PD-L1 expression in NPCs regardless of EBV status and a preferential PD-L1 expression in non-smokers. MSI and HPV positivity are exceedingly rare in NPCs.
Assuntos
Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/análise , Carcinoma/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Adulto , Idoso , Antígeno B7-H1/análise , Carcinoma/genética , Carcinoma/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Filipinas , Estudos Retrospectivos , Adulto JovemRESUMO
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
Assuntos
Carcinoma/genética , Infecções por Vírus Epstein-Barr/genética , Exoma , Mutação , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/genética , Transdução de Sinais , Carcinoma/metabolismo , Carcinoma/fisiopatologia , Proliferação de Células , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/fisiopatologia , Infecções por Vírus Epstein-Barr/virologia , Genoma Humano , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/fisiopatologia , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo , Sequenciamento Completo do GenomaAssuntos
Artroplastia de Substituição/efeitos adversos , Embolia Gordurosa/etiologia , Embolia Pulmonar/etiologia , Fraturas do Ombro/cirurgia , Idoso , Diagnóstico Diferencial , Eletrocardiografia , Eletroencefalografia , Embolia Gordurosa/diagnóstico , Evolução Fatal , Feminino , Humanos , Embolia Pulmonar/diagnóstico , Fraturas do Ombro/diagnóstico por imagem , Síndrome , Tomografia Computadorizada por Raios X , Ultrassonografia DopplerRESUMO
While human papillomavirus (HPV)-positive squamous and adenosquamous carcinomas of the oropharynx have been well characterized, HPV-associated pure adenocarcinomas are exceptionally rare. Herein we report the clinicopathologic features of one such HPV-associated adenocarcinoma of the base of tongue (BOT). A 70 year-old male presented with a 2.8 cm base of tongue mass and lymphadenopathy. Immunohistochemically, the adenocarcinoma was p63 negative and p16 positive. HPV positivity was shown by in situ hybridization. Features of salivary type tumor or metastasis from a distant primary were absent. IonTorrent™ semiconductor sequencing analysis for 739 cancer-associated mutations in 46 actionable cancer genes was performed and PIK3CA exon 9 (p.E545K) and MET exon 2 (p.E168D) mutations were identified. No PIK3CA or MET amplification was identified by fluorescence in situ hybridization. A re-review of archival HPV-positive oropharyngeal squamous cell carcinomas (n = 89, 1983-2013) showed no additional cases of adenocarcinoma. The clinical follow-up for the three previously reported cases of HPV-associated adenocarcinoma of the BOT was updated. All previously reported cases were tested and were negative for PIK3CA exon 9 and 20 and MET exon 2 mutations. These findings offer a molecular basis for potential therapeutic use of PIK3CA inhibitors in a subset of patients with HPV-associated adenocarcinoma of BOT.
Assuntos
Adenocarcinoma/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias da Língua/genética , Adenocarcinoma/patologia , Adenocarcinoma/virologia , Idoso , Classe I de Fosfatidilinositol 3-Quinases , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Neoplasias da Língua/patologia , Neoplasias da Língua/virologiaRESUMO
OBJECTIVES: To evaluate the impact of margin sampling on local recurrence in patients with pT1-2 pN0 conventional squamous cell carcinoma of the oral tongue. MATERIALS AND METHODS: Based on margin sampling, 126 cases were divided into group 1 (margins sampled from the glossectomy specimen only), group 2 (with revision of glossectomy margins), and group 3 (margins primarily sampled from the tumor bed). RESULTS: The probability of local progression-free survival at 3years was .90, .76 and .73 (p=.0389) in groups 1, 2, and 3, respectively. Groups differed by frequency of positive glossectomy specimen margins (p=<.0001) and by the average distance from carcinoma to the closest margin (4.5, 2.4, and 3.0mm for Groups 1, 2, and 3, respectively; p=.0009). Tumor bed margin status (positive vs. negative) and other parameters (e.g., pattern and depth of invasion) did not correlate with local recurrence. Status of the glossectomy specimen margins did correlate with outcome. A positive glossectomy margin conferred a relative risk of 2.5 (95% confidence interval, CI, 1 - 6.3) for local recurrence. A proportional hazards regression model for margin width found a hazard ratio of 0.67 (95% CI=.57-.98) comparable to a 33% decrease in risk of local recurrence for an increase of 1mm of margin width (p=.0271). CONCLUSIONS: Status of the glossectomy specimen margins rather than that of tumor bed margins was prognostically relevant. Reliance on tumor bed margins appears to be associated with worse local control, perhaps due to the narrower initial resection.