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1.
J Clin Oncol ; 40(2): 138-149, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-34699271

RESUMO

PURPOSE: Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC. METHODS: E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index. RESULTS: Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented. CONCLUSION: Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Cisplatino/uso terapêutico , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias Orofaríngeas/terapia , Papillomaviridae/isolamento & purificação , Faringectomia , Radioterapia de Intensidade Modulada , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Quimiorradioterapia Adjuvante , Cisplatino/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Faringectomia/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Radioterapia de Intensidade Modulada/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Fatores de Tempo
2.
BMC Cancer ; 21(1): 504, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957888

RESUMO

BACKGROUND: Lower prevalence HPV infection has been previously reported in Thai population when compared with Western countries. p16 expression indicates HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but not non-OPSCC. We therefore evaluated the characteristic and association of p16 and HPV in Thai patients with HNSCC. METHODS: We used immunohistochemistry and qPCR, respectively, to detect p16 and HPV DNA in archrival formalin-fixed paraffin-embedded HNSCC tissues. Patient characteristics and survival were analyzed. RESULTS: p16 expression was detected in tumors of 72 of 662 (10.9%) patients with HNSCC and was significantly associated with higher-grade histology, advanced nodal stage, and oropharynx. p16 was expressed in 28 and 6.5% of patients with OPSCC or non-OPSCC, respectively, and HPV DNA was detected in 15.6 and 1% of patients, respectively. Using p16 as a surrogate for HPV status, sensitivities were 80 and 25% in OPSCC and non-OPSCC, respectively. Positive and negative predictive rates of OPSCC were 38 and 95%. Discordance rates between HPV and p16 were 23 and 7% in OPSCC and non-OPSCC, respectively. Overall survival (OS) were significantly longer in both p16-positive OPSCC (p = 0.049), and non-OPSCC (p = 0.003). CONCLUSIONS: Low prevalence of p16 and HPV associated OPSCC and non-OPSCC were confirmed in Thai patients. High discordance and low positive predictive rates of p16 were observed in HPV-associated OPSCC. p16 was a significant prognostic factor for OS for patients with OPSCC or non-OPSCC. Therefore, HPV testing should be performed to assess the association of HPV with HNSCC regardless of p16 expression.


Assuntos
Alphapapillomavirus/isolamento & purificação , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias Orofaríngeas/química , Infecções por Papillomavirus/complicações , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Viral/análise , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Adulto Jovem
3.
Am J Surg Pathol ; 45(7): 951-961, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739785

RESUMO

Early studies estimate that 5% to 10% of oropharyngeal squamous cell carcinomas overexpress p16 but are unassociated with transcriptionally-active high-risk human papillomavirus (HPV). Patients with discordant HPV testing may experience clinical outcomes that differ from traditional expectations. To document the rate of p16 and HPV mRNA positivity, characterize patients with discordant testing, and identify features that may warrant selective use of HPV-specific testing after p16 IHC, a multi-institutional, retrospective review of oropharyngeal squamous cell carcinoma patients with p16 IHC and HPV mRNA testing by reverse transcriptase polymerase chain reaction was performed. Of the 467 patients, most had T1 or T2 tumors (71%), 82% were p16 positive, and 84% were HPV mRNA positive. Overall, most tumors were nonkeratinizing (378, 81%), which was strongly associated with p16 and HPV positivity (93% and 95%, respectively). Overall, 81% of patients were double positive, 14% double negative, and 4.9% discordant (3.4% p16 negative/HPV mRNA positive and 1.5% p16 positive/HPV mRNA negative). The survival rates of these discordant patient groups fell squarely between the 2 concordant groups, although in multivariate analysis for both disease-free survival and overall survival, discordant patients were not found to have statistically significantly different outcomes. Reclassifying patients by applying HPV mRNA testing when p16 results and morphology do not match, or when p16 results are equivocal, improved prognostication slightly over p16 or HPV mRNA testing alone. Patients with discordant testing demonstrate a borderline significant trend toward survival differences from those with concordant tests. When evaluated independently, patients who were p16 negative but HPV mRNA positive had a prognosis somewhat closer to double-positive patients, while those who were p16 positive, but HPV mRNA negative had a prognosis closer to that of double-negative patients. We suggest an algorithm whereby confirmatory HPV mRNA testing is performed in patients where p16 status is not consistent with tumor morphology. This captures a majority of discordant patients and improves, albeit modestly, the prognostication.


Assuntos
Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Imuno-Histoquímica , Neoplasias Orofaríngeas/química , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , RNA Mensageiro/genética , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Adulto , Idoso , Algoritmos , Técnicas de Apoio para a Decisão , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/virologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Estados Unidos/epidemiologia
4.
Pathol Res Pract ; 216(12): 153243, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33113454

RESUMO

In a retrospective review, we identified 332 patients with 338 pathologically diagnosed primary oropharyngeal carcinomas (OPC) between January 2013 and March 2020 with known p16/HPV status from a tumor registry at Northwestern Memorial Hospital. The tumors predominantly involved the palatine tonsil (51 %) and the base of the tongue/lingual tonsil (38 %). The most common type of cancer was non-keratinizing squamous cell carcinoma (60 %), and the majority of primaries were p16 positive/HPV-mediated (86 %). A cohort of p16 positive/HPV mediated OPC (27/283, 9.5 %) presented with aggressive clinical behavior, including multiple distant metastases at unusual sites. Tumor size >2 cm and the presence of tumor anaplasia/multinucleation were significantly associated with an increased rate of distant metastases in p16 positive/HPV mediated cases, both in unadjusted and adjusted analyses (all P < 0.05). Of the 332 individuals in the overall cohort, 38 individuals died due to their disease within the observed follow-up time. Among the 283 patients with p16 positive/HPV mediated tumors, survival was estimated at 97 % (95 % CI 95 %, 100 %) at 1 year, 95 % (95 % CI 92 %, 98 %) at 2 years, and 80 % (95 % CI 72 %, 89 %) at 5 years. The presence of tumor anaplasia/multinucleation and distant metastasis were both significantly associated with poorer disease-specific survival in p16 positive/HPV mediated cases (both P < 0.05), with the survival effect of tumor anaplasia/multinucleation likely mediated in part through its association with distant metastasis. For p16 positive/HPV-mediated OPC, age, smoking status, tumor status, and lymph node status were not significantly associated with disease-specific survival in our study.


Assuntos
Carcinoma de Células Escamosas/secundário , Neoplasias Orofaríngeas/patologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/virologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/virologia , Núcleo Celular/patologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Progressão da Doença , Feminino , Humanos , Illinois , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/mortalidade , Intervalo Livre de Progressão , Sistema de Registros , Estudos Retrospectivos , Carga Tumoral
5.
Br J Cancer ; 123(7): 1114-1122, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32624580

RESUMO

BACKGROUND: A remarkably better prognosis is associated with oropharyngeal squamous cell carcinomas (OPSCC) driven by human papillomaviruses (HPV) compared with HPV-negative OPSCC. Consequently, de-escalation of standard treatment has been suggested. Due to modest specificity rates, debates are ongoing, whether p16INK4a, a surrogate marker for HPV-driven OPSCC, is sufficient to correctly identify those tumours and avoid substantial HPV misattribution and thus undertreatment of patients by de-escalation. Robust data estimating the proportion of potentially undertreated patients are missing. METHODS: We assessed a large-scale cohort of consecutively included OPSCC diagnosed between 2000 and 2017 for HPV-DNA, HPV genotypes, p16INK4a expression and multiple tumour- and patient-related risk factors, and investigated their impact on patients' survival in comprehensive uni- and multivariate analyses. RESULTS: Aetiological relevance of HPV (p16INK4a- and high-risk HPV-DNA-positivity) was detected in 27.1% (n = 192) of OPSCC, with HPV16 being the most abundant HPV type (94.6%). In 5.5% patients (n = 39), p16INK4a overexpression but no HPV-DNA was detected. Principal component and survival analyses revealed that 60.6% of these p16INK4a-positive OPSCC lacking HPV-DNA did not resemble HPV16-driven but HPV-negative OPSCC regarding risk-factor profile and overall survival. Notably, this group represented 10.6% of all p16INK4a-overexpressing OPSCC. CONCLUSIONS: p16INK4a as a single marker appears insufficient to indicate OPSCC patients suitable for treatment de-escalation.


Assuntos
Alphapapillomavirus/isolamento & purificação , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias Orofaríngeas/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Biomarcadores Tumorais/análise , Estudos de Coortes , DNA Viral/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/virologia , Análise de Componente Principal , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
6.
Acta Oncol ; 59(6): 666-672, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32079442

RESUMO

Background: Incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly in many western countries due to Human papillomavirus (HPV) and tobacco smoking, with a considerable overlap. Immunotherapy directed at the PD1/PD-L1 axis have shown promise in head and neck cancer and other cancer types. PD-L1 expression may indicate a poorer prognosis, and at the same time indicate a possible benefit of anti-PD-L1 immunotherapeutic agents. The primary aim of this study was to establish the prognostic effect of PD-L1 expression after primary curative radiotherapy alone.Material and methods: A cohort of 303 OPSCC patients treated with primary, curative intended radiotherapy was established. PD-L1 expression was evaluated by immunohistochemistry on formalin fixed, paraffin embedded tissue sections. PD-L1 positivity was defined as a Combined Positive Score (CPS) ≥1, indicating staining of either tumor cells, lymphocytes or macrophages.Results: Median follow-up was 5.3 years. With 199 deaths, there was no difference in overall survival between patients with PD-L1+ and PD-L1- tumors (adjusted hazard ratio [aHR] and 95% confidence interval [CI]: 1.0 [0.71-1.4]). Also, locoregional failure was similar between the two groups (aHR 1.1 [CI: 0.68 - 1.7]). Tumors were PD-L1+ in 76% of cases, significantly more among HPV p16+ tumors (82% vs. 70%, p = .01). Interestingly, higher prevalence of PD-L1+ expression was seen in HPV p16+ patients with <10 pack-years of tobacco-smoking (93%) compared to HPV p16+ smokers (76%) or HPV p16-negative patients (70%) (p = .003).Conclusion: PD-L1 expression had no prognostic significance in OPSCC patients treated with primary radiotherapy alone. A substantial proportion of OPSCC tumors show PD-L1 overexpression, especially in HPV p16+ tumors in patients with little or no smoking history.


Assuntos
Alphapapillomavirus , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/radioterapia , Neoplasias Orofaríngeas/radioterapia , Infecções por Papillomavirus/complicações , Fumar Tabaco/efeitos adversos , Idoso , Antígeno B7-H1/análise , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/mortalidade , Intervalos de Confiança , Feminino , Seguimentos , Papillomavirus Humano 16 , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/metabolismo , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/etiologia , Neoplasias Orofaríngeas/mortalidade , Infecções por Papillomavirus/metabolismo , Prognóstico , Fumar Tabaco/metabolismo
7.
Strahlenther Onkol ; 196(6): 552-560, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32080773

RESUMO

PURPOSE: A 15-gene hypoxia classifier has been developed and validated as a predictive factor for patients with head and neck squamous cell carcinoma treated with radiotherapy and nimorazole. This paper aimed to investigate the role of this hypoxia classifier as a prognostic factor for patients with oropharyngeal cancer (OPC) treated with accelerated chemoradiotherapy. METHODS: P16 and 15-gene hypoxia classifier status, categorising tumours as more or less hypoxic, were determined for 136 OPC patients. Locoregional recurrence rate (LRR) and overall survival (OS) were estimated with cumulative incidence function and Kaplan-Meier method, respectively, stratified according to p16 and hypoxia status. RESULTS: P16-positive patients (34.6%) had significantly better LRR and OS than p16-negative patients. The 5­year LRR of patients with more hypoxic OPC was similar to those with less hypoxic OPC in the overall patient population (27.3% versus 25.1%; p = 0.98; HR = 1.01 [CI95% 0.47;2.17]) and in the p16-negative OPC (36.4% versus 30.1%; p = 0.70; HR = 1.17 [CI95% 0.53;2.56]). No significant OS differences could be observed in neither p16-negative nor p16-positive subgroup with a 5-year OS for p16-negative more hypoxic OPC of 44.2% versus 49.0% in the less hypoxic OPC (p = 0.92; HR 0.97 [CI95% 0.51;1.84]). CONCLUSION: No significant outcome differences were observed between more or less hypoxic tumours, as determined by the 15-gene hypoxia classifier. These results suggest that the 15-gene hypoxia classifier may not have prognostic value in an OPC patient cohort treated with accelerated chemoradiotherapy.


Assuntos
Carcinoma de Células Escamosas/terapia , Hipóxia Celular/genética , Quimiorradioterapia , Imagem de Difusão por Ressonância Magnética , Genes p16 , Neoplasias Orofaríngeas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Cetuximab/uso terapêutico , Quimiorradioterapia/métodos , Cisplatino/uso terapêutico , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/mortalidade , Oxigênio/análise , Prognóstico , Resultado do Tratamento
8.
Hum Pathol ; 95: 1-23, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31449826

RESUMO

The field of head and neck pathology was just developing 50 years ago but has certainly come a long way in a relatively short time. Thousands of developments in diagnostic criteria, tumor classification, malignancy staging, immunohistochemistry application, and molecular testing have been made during this time, with an exponential increase in literature on the topics over the past few decades: There were 3506 articles published on head and neck topics in the decade between 1969 and 1978 (PubMed source), with a staggering 89266 manuscripts published in the most recent decade. It is daunting and impossible to narrow the more than 162000 publications in this field and suggest only a few topics of significance. However, the breakthrough in this anatomic discipline has been achieved in 3 major sites: oropharyngeal carcinoma, salivary gland neoplasms, and sinonasal tract tumors. This review will highlight selected topics in these anatomic sites in which the most profound changes in diagnosis have occurred, focusing on the information that helps to guide daily routine practice of surgical pathology.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/história , Difusão de Inovações , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/história , Neoplasias de Cabeça e Pescoço/virologia , História do Século XX , História do Século XXI , Humanos , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/história , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Neoplasias dos Seios Paranasais/química , Neoplasias dos Seios Paranasais/história , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/virologia , Patologia/história , Patologia/tendências , Neoplasias das Glândulas Salivares/química , Neoplasias das Glândulas Salivares/história , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/virologia
9.
J Clin Pathol ; 72(8): 542-549, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31113825

RESUMO

AIMS: Limited information is available regarding the precise differences in the tumour immune microenvironment (TIM) of patients with human papilloma virus (HPV)-associated and non-HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Here, we retrospectively reviewed 137 patients with OPSCC treated with a definitive treatment to identify molecular relationships in the TIM. MATERIALS AND METHODS: We used immunohistochemical analysis to assess p16 status, programmed death ligand 1 (PD-L1) level, and/or CD8+ tumour-infiltrating lymphocyte (TIL) density, followed by prognostic evaluation of these immune-related parameters. RESULTS: Multivariate analyses demonstrated that PD-L1 level on immune cells but not on tumour cells or CD8+ TIL density was a significant predictive factor of disease-free survival (DFS) and overall survival (OS). Additionally, subgroup analyses demonstrated that patients positive for p16 and PD-L1 expression on immune cells had favourable DFS and OS, whereas patients negative for p16 and PD-L1 expression on immune cells showed worse DFS and OS. CONCLUSIONS: We demonstrated that PD-L1 expression on immune cells but not tumour cells might represent a useful prognostic biomarker in patients with OPSCC receiving a definitive treatment. We propose that a co-assessment of p16 and PD-L1 expression on immune cells would have greater prognostic potential compared with evaluation of each factor alone in patients with OPSCC.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias Orofaríngeas/química , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/química , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/imunologia , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/terapia , Intervalo Livre de Progressão , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Fatores de Tempo , Microambiente Tumoral
10.
PLoS One ; 13(9): e0204249, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30235319

RESUMO

Oral cavity squamous cell carcinoma (OCC) and oropharyngeal squamous cell carcinoma (OPC) are among the most common cancers worldwide and are associated with high mortality and morbidity. The purpose of this study is to identify potential biomarkers to distinguish OCC/OPC from normal controls and to distinguish OCC patients with and without nodal metastasis. We tested saliva samples from 101 OCC, 58 OPC, and 35 normal controls using four analytical platforms (NMR, targeted aqueous by LC-MS/MS, global aqueous and global lipidomics by LC-Q-TOF). Samples from OCC and normal controls were divided into discovery and validation sets. Using linear regression adjusting for age, sex, race and experimental batches, we found the levels of two metabolites (glycine and proline) to be significantly different between OCC and controls (FDR < 0.1 for both discovery and validation sets) but did not find any appreciable differences in metabolite levels between OPC and controls or between OCC with and without nodal metastasis. Four metabolites, including glycine, proline, citrulline, and ornithine were associated with early stage OCC in both discovery and validation sets. Further study is warranted to confirm these results in the development of salivary metabolites as diagnostic markers.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Metabolômica/métodos , Neoplasias Bucais/diagnóstico , Neoplasias Orofaríngeas/diagnóstico , Saliva/química , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/química , Carcinoma de Células Escamosas/química , Cromatografia Líquida , Citrulina/química , Detecção Precoce de Câncer , Feminino , Glicina/química , Humanos , Modelos Lineares , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/química , Estadiamento de Neoplasias , Ornitina/química , Neoplasias Orofaríngeas/química , Prolina/química , Espectrometria de Massas em Tandem
11.
Acta Cytol ; 62(5-6): 339-345, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29966127

RESUMO

OBJECTIVE: High-risk human papilloma virus (HPV) testing should be performed on all patients with newly diagnosed oropharyngeal HPV-associated squamous cell carcinoma (OPHPVSCC), and p16 immunostaining can be used as a surrogate marker. Although in surgical pathology specimens p16 staining in > 70% of the tumor cells is considered a positive result, the interpretation in fine-needle aspiration (FNA) specimens has remained controversial. STUDY DESIGN: FNA of neck lymph nodes and corresponding surgical specimens from 42 patients with OPHPVSCC were reviewed. RESULTS: In FNA specimens, 38 cases (90.5%) had viable tumor cells, 32 (76.2%) had keratin debris, and 36 (85.7%) had degenerated keratinized tumor cells. Twenty-seven of 27 (100%) had positive p16 staining in > 70% of viable tumor cells, while the degenerated tumor cells were negative. Twenty of 24 (83.3%) primary OPHPVSCC exhibited focal degenerated keratinized tumor cells and/or keratin debris. CONCLUSIONS: This study showed that the majority of the OPHPVSCC metastases in lymph nodes had degenerated keratinized tumor cells and keratin debris. Many primary OPHPVSCC also demonstrated focal keratinization and/or degeneration. The degenerated tumor cells showed no immunoreactivity to p16. The same 70% cutoff used in histologic specimens should be applied in cytologic specimens, but only the viable tumor cells should be counted.


Assuntos
Biomarcadores Tumorais/análise , Biópsia por Agulha Fina , Inibidor p16 de Quinase Dependente de Ciclina/análise , Imuno-Histoquímica , Queratinas/análise , Linfonodos/química , Neoplasias Orofaríngeas/química , Infecções por Papillomavirus/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Sobrevivência Celular , Feminino , Humanos , Linfonodos/patologia , Linfonodos/virologia , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
12.
J Natl Cancer Inst ; 110(1)2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922779

RESUMO

Background: Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed. Methods: CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4's role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9-15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided. Results: Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69-7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65-0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%-79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%-64.0% decrease across different models, P ≤ .04). Conclusions: These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types.


Assuntos
Adenocarcinoma/tratamento farmacológico , Fibroblastos Associados a Câncer/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Colorretais/química , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Bucais/química , Miofibroblastos/patologia , NADPH Oxidases/antagonistas & inibidores , Neoplasias Orofaríngeas/química , Actinas/análise , Adenocarcinoma/química , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Fibroblastos Associados a Câncer/química , Fibroblastos Associados a Câncer/fisiologia , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/genética , Contagem de Células , Transdiferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Neoplasias Esofágicas/química , Neoplasias Esofágicas/genética , Feminino , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Miofibroblastos/química , NADPH Oxidase 4 , NADPH Oxidases/análise , NADPH Oxidases/genética , Transplante de Neoplasias , Neoplasias Orofaríngeas/patologia , Fenótipo , Pirazóis/uso terapêutico , Pirazolonas , Piridinas/uso terapêutico , Piridonas , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Taxa de Sobrevida , Regulação para Cima
13.
Hum Pathol ; 76: 149-155, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29208563

RESUMO

Perivascular epithelioid cell tumors (PEComas) in the head and neck region are rare, with 26 cases described in literature. These distinct mesenchymal tumors normally express both myoid and melanocytic markers. We here report an interesting and challenging case of malignant PEComa that showed transcription factor E3 (TFE3) protein expression and rearrangement, paucity of muscle and melanocytic marker expression, and morphologically mimicked alveolar soft part sarcoma. Awareness of this morphologic pitfall and recognition of TFE3 gene-rearranged PEComa, as a distinct subtype of PEComa, is essential to avoid misdiagnosis.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/análise , Biomarcadores Tumorais/análise , Neoplasias Orofaríngeas/química , Neoplasias de Células Epitelioides Perivasculares/química , Sarcoma Alveolar de Partes Moles/química , Adulto , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/terapia , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patologia , Neoplasias de Células Epitelioides Perivasculares/terapia , Valor Preditivo dos Testes , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia , Tomografia Computadorizada por Raios X
14.
Am J Surg Pathol ; 41(12): 1722-1728, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28877058

RESUMO

The oral cavity and oropharynx have historically been viewed as a single anatomic compartment of the head and neck. The practice of combining the oral cavity and oropharynx has recently been revised, largely owing to the observation that human papillomavirus (HPV)-related carcinogenesis has a strong predilection for the oropharynx but not the oral cavity. The purpose of this study was to determine whether HPV is evenly distributed across squamous cell carcinomas of the oropharynx including those sites that do not harbor tonsillar tissues such as the soft palate. A search of the medical records of the Johns Hopkins Hospital identified 32 primary squamous cell carcinomas of the soft palate (n=31) and posterior pharyngeal wall (n=1). All were evaluated with p16 immunohistochemistry and high-risk HPV in situ hybridization (ISH) (29 by RNA ISH and 3 by DNA ISH). For comparison, we also reviewed the medical records to obtain the HPV status of patients who had undergone HPV testing of primary tonsillar carcinomas over the same time interval as part of their clinical care. High-risk HPV as detected by ISH was present in just 1 (3.1%) of the 32 oropharyngeal squamous cell carcinomas, including 1 of 2 p16-positive carcinomas. The difference in HPV detection rates between tonsillar and nontonsillar sites was significant (1/32, 3.1% vs. 917/997, 92%; P<0.0001). HPV is not frequently detected in squamous cell carcinomas arising from nontonsillar regions of the oropharynx. Indeed, squamous cell carcinomas of the soft palate more closely resemble those arising in the oral cavity than those arising in areas of the oropharynx harboring tonsillar tissue. This finding not only further sharpens our understanding of site-specific targeting by HPV, but may have practical implications regarding HPV testing and even the way the oral vault is oncologically compartmentalized to partition HPV-positive from HPV-negative cancers.


Assuntos
Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/virologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Idoso , Baltimore , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , DNA Viral/genética , Feminino , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/patologia , Interações Hospedeiro-Patógeno , Testes de DNA para Papilomavírus Humano , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/patologia , Palato Mole/patologia , Palato Mole/virologia , Tonsila Palatina/patologia , Tonsila Palatina/virologia , Papillomaviridae/genética , Infecções por Papillomavirus/patologia , RNA Viral/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
15.
Mod Pathol ; 30(9): 1194-1203, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28621317

RESUMO

High-risk human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas have a more favorable prognosis than HPV-negative ones. p16 immunohistochemistry has been recommended as a prognostic test in clinical practice. Several p16 antibodies are available, and their performance has not been directly compared. We evaluated three commercially available p16 antibody clones (E6H4, JC8 and G175-405) utilizing 199 cases of oropharyngeal squamous cell carcinoma from a tissue microarray, read by three pathologists with three different cutoffs for positivity: any staining, >50% and >75%. Positive predictive values for high-risk HPV status by RNA in situ hybridization for the E6H4, JC8 and G175-405 clones were 98%, 100% and 99% at the 75% cutoff, but negative predictive values were much more variable at 86%, 69% and 56%, respectively. These improved using the 50% cutoff, becoming similar for all three antibodies. Intensity varied substantially, with 85% of E6H4, 72% of JC8 and 67% of G175-405 showing strong (3+) intensity. With Kaplan-Meier survival plots at the 75% cutoff, the E6H4 clone showed the largest differential in disease specific and overall survival between p16-positive and -negative results. Decreasing the cutoff to 50% increased correlation with HPV in situ hybridization and improved the survival differential for the JC8 and G175-405 clones without worsening of performance for the E6H4 clone. Interobserver agreement was also assessed by kappa scores and was highest for the E6H4 clone. Overall, these study results show modest but important performance differences between the three different p16 antibody clones, suggesting that the E6H4 clone performs best because of strongest staining intensity, greatest differential in outcomes between positive and negative results, lowest interobserver variability, and lowest background, nonspecific staining. The results also suggest that a 75% cutoff is very functional but that, in this patient population with high HPV incidence, 50% and any staining cutoffs may be more effective, particularly for the non-E6H4 clones.


Assuntos
Anticorpos/imunologia , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias de Cabeça e Pescoço/química , Imuno-Histoquímica , Neoplasias Orofaríngeas/química , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , RNA Viral/genética , Biomarcadores Tumorais/imunologia , Biópsia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virologia , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/virologia , Interações Hospedeiro-Patógeno , Humanos , Hibridização In Situ , Estimativa de Kaplan-Meier , Variações Dependentes do Observador , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/terapia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise Serial de Tecidos
16.
Hum Pathol ; 66: 40-47, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28554574

RESUMO

Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm that most commonly occurs in cervical lymph nodes. It has histologic and clinical overlap with the much more common p16-positive human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx, which characteristically has nonkeratinizing morphology and often presents as an isolated neck mass. Not surprisingly, follicular dendritic cell sarcomas are commonly misdiagnosed as squamous cell carcinoma. Immunohistochemistry is helpful in separating the 2 entities. Follicular dendritic cell sarcoma expresses dendritic markers such as CD21 and CD23 and is almost always cytokeratin negative. However, in many cases of HPV-related oropharyngeal carcinoma, only p16 immunohistochemistry as a prognostic and surrogate marker for HPV is performed. p16 expression in follicular dendritic cell sarcoma has not been characterized. Here, we investigate the expression of p16 in follicular dendritic cell sarcoma and correlate it with retinoblastoma protein expression. A pilot study of dendritic marker expression in HPV-related oropharyngeal squamous cell carcinoma was also performed. We found that 4 of 8 sarcomas expressed p16 with strong and diffuse staining in 2 cases. In 2 of the 4 cases, p16 expression corresponded to loss of retinoblastoma protein expression. Dendritic marker expression (CD21 and CD23) was not found in HPV-related oropharyngeal squamous cell carcinomas. As such, positive p16 immunohistochemistry cannot be used as supportive evidence for the diagnosis of squamous cell carcinoma as strong and diffuse p16 expression may also occur in follicular dendritic cell sarcoma. Cytokeratins and dendritic markers are critical in separating the two tumor types.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Inibidor p16 de Quinase Dependente de Ciclina/análise , Sarcoma de Células Dendríticas Foliculares/metabolismo , Neoplasias de Cabeça e Pescoço/química , Neoplasias Orofaríngeas/química , Infecções por Papillomavirus/metabolismo , Adulto , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Sarcoma de Células Dendríticas Foliculares/patologia , Diagnóstico Diferencial , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Missouri , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Projetos Piloto , Valor Preditivo dos Testes , Receptores de Complemento 3d/análise , Receptores de IgE/análise , Proteína do Retinoblastoma/análise , Carcinoma de Células Escamosas de Cabeça e Pescoço , Tennessee
17.
Otolaryngol Head Neck Surg ; 157(2): 239-251, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28397583

RESUMO

Objectives We analyze the relationship between CD44, epidermal growth factor receptor (EGFR), and p16 expression in oral cavity and oropharyngeal cancers in a diverse population. We also describe whether particular patterns of staining are associated with progression-free survival and overall survival. Study Design Prospective study, single-blind to pathologist and laboratory technologist. Setting Hospital based. Subjects and Methods Immunohistochemistry, comprising gross staining and cellular expression, was performed and interpreted in a blinded fashion on 24 lip/oral cavity and 40 oropharyngeal cancer specimens collected between 2007 and 2012 from participants of a larger study. Information on overall survival and progression-free survival was obtained from medical records. Results Nineteen cases were clinically p16 positive, 16 of which were oropharyngeal. Oral cavity lesions were more likely to exhibit strong CD44 membrane staining ( P = .0002). Strong CD44 membrane and strong EGFR membrane and/or cytoplasmic staining were more common in p16-negative cancers ( P = .006). Peripheral/mixed gross p16 staining pattern was associated with worse survival than the universal staining on univariate and multivariate analyses ( P = .006, P = .030). This held true when combining gross and cellular localization for p16. For CD44, universal gross staining demonstrated poorer overall survival compared with the peripheral/mixed group ( P = .039). CD44 peripheral/mixed group alone and when combined with universal p16 demonstrated the best survival on multivariate analysis ( P = .010). Conclusion In a diverse population, systematic analysis applying p16, CD44, and EGFR gross staining and cellular localization on immunohistochemistry demonstrates distinct patterns that may have prognostic potential exceeding current methods. Larger studies are warranted to investigate these findings further.


Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/análise , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Receptores ErbB/análise , Receptores de Hialuronatos/análise , Boca/química , Neoplasias Orofaríngeas/química , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Boca/patologia , Proteínas de Neoplasias/análise , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Prognóstico , Estudos Prospectivos , Método Simples-Cego , Taxa de Sobrevida
18.
Int J Cancer ; 140(5): 1186-1198, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27859245

RESUMO

The accurate diagnosis of human papillomavirus (HPV) causality in oropharyngeal squamous cell carcinomas (OPSCC) is likely to influence therapeutic decisions in affected patients in the near future. We conducted a systematic review and meta-analysis to determine the diagnostic accuracy of p16INK4a immunohistochemistry (IHC) to identify HPV-induced OPSCC. We identified all studies that performed p16INK4a IHC (index test) and HPV E6/E7 mRNA detection using an amplification-based method (gold standard to indicate a transforming relevance of HPV) in OPSCC. Testing with one or more comparator tests (HPV DNA PCR, HPV DNA in situ hybridization (ISH) and p16INK4a IHC/HPV DNA PCR combined testing) was an optional criterion for inclusion. Among 1,636 retrieved studies 24 fulfilled the inclusion criteria. The pooled sensitivity of p16INK4a IHC, HPV DNA PCR, HPV DNA ISH and p16INK4a IHC/HPV DNA PCR combined testing was 94% (95%-confidence interval (CI) 91-97%), 98% (CI 94-100%), 85% (CI 76-92%) and 93% (CI 87-97%), respectively. The pooled specificity was 83% (CI 78-88%), 84% (CI 74-92%), 88% (CI 78-96%) and 96% (CI 89-100%), respectively. p16INK4a IHC/HPV DNA PCR combined testing was as sensitive as either p16INK4a IHC or HPV DNA PCR alone but significantly more specific than either separate test. In conclusion, p16INK4a IHC is highly sensitive but moderately specific to diagnose HPV-transformed OPSCC when used as a single test. Combined p16INK4a IHC and HPV DNA PCR testing significantly enhances specificity while maintaining high sensitivity. This diagnostic test combination thus represents an attractive testing strategy for the reliable diagnosis of HPV-induced OPSCC in the clinical setting and may constitute an inclusion criterion for future therapeutic trials.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/diagnóstico , Inibidor p16 de Quinase Dependente de Ciclina/análise , Proteínas de Neoplasias/análise , Neoplasias Orofaríngeas/diagnóstico , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/virologia , Transformação Celular Viral , DNA Viral/análise , Humanos , Hibridização In Situ , Proteínas Oncogênicas Virais/genética , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/virologia , Papillomaviridae/genética , Infecções por Papillomavirus/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Viral/análise , Sensibilidade e Especificidade
20.
Hum Pathol ; 50: 51-61, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26997438

RESUMO

Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P < .0001). HPV infection and EGFR gene copy number gain (EGFR CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P < .0001 and P < .0001, respectively). The EGFR CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/virologia , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Variações do Número de Cópias de DNA , DNA Viral/genética , Feminino , Amplificação de Genes , Dosagem de Genes , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Testes de DNA para Papilomavírus Humano , Humanos , Imuno-Histoquímica , Hibridização In Situ , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/terapia , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/mortalidade , Prevalência , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Tempo , Resultado do Tratamento
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