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1.
Clin Cancer Res ; 30(13): 2764-2771, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38669077

RESUMO

PURPOSE: Human papillomavirus (HPV) is the cause of the majority of cervical cancer cases and has been showed to be released as cell-free tumor DNA (ctHPV DNA) into the circulation. Here, we analyze if ctHPV DNA could be used as a prognostic biomarker and/or to detect relapse earlier than traditional methods in locally advanced cervical cancer (LACC). EXPERIMENTAL DESIGN: A total of 74 patients with LACC were included; 66of 74 were positive for 13 high-risk HPV types on a bead-based assay of tumor biopsy samples. HPV-type-specific droplet digital PCR assays were developed. Longitudinal plasma samples were then analyzed for the biopsy-verified HPV type for each patient. In total, 418 plasma samples were analyzed. Patients were followed for a median of 37 months. Results were correlated to tumor and clinical characteristics. RESULTS: Of the pretreatment plasma samples, 92.4% were positive for ctHPV DNA. Persistent ctHPV DNA in end-of-treatment, early follow-up (1-2 months after end-of-treatment), or tumor evaluation (3-4 months after end-of-treatment) plasma was correlated with worse progression-free survival (P < 0.001) compared with if ctHPV DNA was not found. The positive predictive value of ctHPV status at early follow-up for predicting disease progression was 87.5%, and the negative predictive value was 89.3%. ctHPV DNA was found in plasma before relapse was diagnosed using radiology in all patients (n = 10) who experienced relapse after complete clinical response to treatment with a median 315 days lead time. CONCLUSIONS: ctHPV DNA in follow-up plasma is a promising prognostic biomarker in patients with LACC, useful for analysis of response to therapy and for early detection of relapse.


Assuntos
Biomarcadores Tumorais , DNA Viral , Detecção Precoce de Câncer , Recidiva Local de Neoplasia , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/mortalidade , Biomarcadores Tumorais/sangue , Prognóstico , Pessoa de Meia-Idade , DNA Viral/sangue , Recidiva Local de Neoplasia/virologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/sangue , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/sangue , Infecções por Papillomavirus/complicações , Adulto , Idoso , Detecção Precoce de Câncer/métodos , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Ácidos Nucleicos Livres/sangue , Estadiamento de Neoplasias , Papillomavirus Humano
2.
Oral Oncol ; 151: 106749, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38461771

RESUMO

OBJECTIVE: Patients with human papillomavirus DNA positive (HPVDNA+) and p16ink4a overexpressing (p16+) oropharyngeal squamous cell carcinoma (OPSCC), especially those with cancer in the tonsillar and base of tongue subsites as compared to other OPSCC subsites have a better outcome than those with only HPVDNA+ or only p16+ cancer. Likewise having a high viral load has been suggested to be a positive prognostic factor. We therefore hypothesized, that HPV viral load could vary depending on OPSCC subsite, as well as with regard to whether the cancer was HPVDNA+ and p16+, or only HPVDNA+, or only p16+ and that this affected outcome. MATERIAL AND METHODS: To address these issues HPV viral load was determined by HPV digital droplet (dd) PCR in tumor biopsies with previously known HPVDNA/p16 status from 270 OPSCC patients diagnosed 2000-2016 in Stockholm, Sweden. More specifically, of these patients 235 had HPVDNA+/p16+, 10 had HPVDNA+/p16-, 13 had HPVDNA-/p16+ and 12 had HPVDNA-/p16- cancer. RESULTS: We found that HPVDNA+/p16+ OPSCC had a significantly higher viral load than HPVDNA+/p16- OPSCC. Moreover, there was a tendency for a higher viral load in the tonsillar and base of tongue OPSCC subsites compared to the other subsites and for a low viral load to correlate to a better clinical outcome but none of these tendencies reached statistical significance. CONCLUSION: To conclude, the mean viral load in HPVDNA+/p16+ OPSCC was higher than in HPVDNA+/p16- OPSCC, but there was no statistically significant difference in viral load depending on OPSCC subsite or on clinical outcome.


Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Papillomavirus Humano , Infecções por Papillomavirus/patologia , DNA Viral/análise , Inibidor p16 de Quinase Dependente de Ciclina , Prognóstico , Papillomaviridae/genética
3.
Acta Oncol ; 62(12): 1649-1652, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37793801

RESUMO

BACKGROUND: The prevalence of different HPV types, especially HPV16 and 18 in cervical cancer in patients diagnosed 2019-2023 in Stockholm was compared to corresponding data from 2003-2008 before the introduction of HPV vaccination in Sweden. MATERIAL AND METHODS: Cervical cancer samples from 125 patients diagnosed 2019-2023 in Stockholm were analysed for 27 HPV types by multiplex assay and the HPV type prevalence data was compared to data obtained in 154 cervical samples from 2003-2008. RESULTS: Patient median age was higher 2019-2023 compared to 2003-2008 (55-years vs. 42-years, p = 0.046). Overall HPV prevalence was 93.6%, HPV16 and 18 accounted for 62.2% of all squamous cell carcinoma cases (SCC) and 63.6% of all adenocarcinoma cases (ADC) vs. 92.9%, 69.7% and 88.6% respectively 2003-2008. CONCLUSION: The joint prevalence of HPV16 and 18 in SCC and ADC tended to be slightly lower in 2019-2023 as compared to 2003-2008, but the difference was not statistically significant.


Assuntos
Adenocarcinoma , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/patologia , Papillomavirus Humano 16 , Papillomavirus Humano , Suécia/epidemiologia , Prevalência , Carcinoma de Células Escamosas/epidemiologia , Adenocarcinoma/epidemiologia , Papillomaviridae
4.
Int J Cancer ; 152(11): 2232-2242, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36274628

RESUMO

Tumor cells release fragments of their DNA into the circulation, so called cell-free tumor DNA (ctDNA), allowing for analysis of tumor DNA in a simple blood test, that is, liquid biopsy. Cervical cancer is one of the most common malignancies among women worldwide and high-risk human papillomavirus (HR-HPV) is the cause of the majority of cases. HR-HPV integrates into the host genome and is often present in multiple copies per cell and should thus also be released as ctDNA. Such ctHPV DNA is therefore a possible biomarker in cervical cancer. In this review, we first give a background on ctDNA in general and then a comprehensive review of studies on ctHPV DNA in cervical cancer and pre-malignant lesions that may develop in cervical cancer. Furthermore, studies on ctHPV DNA in other HPV related malignancies (eg, head-and-neck and anogenital cancers) are briefly reviewed. We conclude that detection of ctHPV DNA in plasma from patients with cervical cancer is feasible, although optimized protocols and ultra-sensitive techniques are required for sufficient sensitivity. Results from retrospective studies in both cervical cancer and other HPV-related malignancies suggests that ctHPV DNA is a promising prognostic biomarker, for example, for detecting relapses early. This paves the way for larger, preferably prospective studies investigating the clinical value of ctHPV DNA as a biomarker in cervical cancer. However, there are conflicting results whether ctHPV DNA can be found in blood from patients with pre-malignant lesions and further studies are needed to fully elucidate this question.


Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Papillomavirus Humano , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Estudos Retrospectivos , Estudos Prospectivos , Recidiva Local de Neoplasia , DNA Viral/genética , DNA Viral/análise , Biomarcadores Tumorais/genética , Papillomaviridae/genética
5.
Gynecol Oncol ; 167(1): 107-114, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35918201

RESUMO

OBJECTIVES: Tumor cells release fragments of their DNA into the circulation, so called cell-free tumor DNA (ctDNA) or liquid biopsy. Here, we analyze if cell-free human papillomavirus DNA (ctHPV DNA) is detectable before, during and after treatment, in patients with cervical cancer or pre-malignant lesions that may develop into cervical cancer, and whether ctHPV DNA levels were correlated to patient or tumor characteristics and outcome. Furthermore, total cell-free DNA load is studied using cfAlbumin DNA as a surrogate marker. METHODS: 18 patients with locally advanced CC (LACC), 15 patients with early stage CC (ESCC) and 21 patients with pre-malignant lesions, all with verified HPV16, 18 or 45-positive lesions, were included. Pre- during- and post-treatment plasma were tested for HPV16, 18 & 45 and total cfDNA load using droplet digital PCR. RESULTS: ctHPV DNA was found in 94.4% and 26.7% of pre-treatment plasma of patients with LACC and ESCC respectively, while all samples from patients with pre-malignant lesions were negative. Higher levels of ctHPV DNA were correlated to higher FIGO2018 stage. Patients with LACC and persistent ctHPV DNA at end-of-treatment had significantly worse progression-free survival (PFS) than patients who had cleared the ctHPV DNA (p = 0.007). Patients with total ctDNA-levels above median in pre-treatment plasma had a worse PFS (p = 0.026), compared to patients with total ctDNA-levels below median. CONCLUSION: ctHPV DNA is a promising prognostic biomarker in locally advanced cervical cancer that should be studied further for clinical use.


Assuntos
Alphapapillomavirus , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias do Colo do Útero , Alphapapillomavirus/genética , Biomarcadores Tumorais/genética , Feminino , Papillomavirus Humano 16/genética , Humanos , Papillomaviridae/genética , Neoplasias do Colo do Útero/patologia
6.
Acta Otolaryngol ; 138(9): 855-858, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29764277

RESUMO

BACKGROUND: Distinguishing branchial cleft cysts (BCCs) from cystic metastases of a human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Fine needle aspirates (FNAs) from cystic metastasis may be non-representative, while reactive squamous cells from BCC can be atypic. Based on cytology and with the support of HPV DNA positivity many centers treat cystic metastasis oncological and thus patients are spared neck dissection. To do so safely, one must investigate whether HPV DNA and p16INK4a overexpression is found exclusively in cystic metastases and not in BCC. PATIENTS AND METHODS: DNA was extracted from formalin fixed paraffin embedded (FFPE) surgically resected BCCs from 112 patients diagnosed 2007-2015 at Karolinska University Hospital and amplified by PCR. A multiplex bead-based assay used to detect 27 HPV-types and p16INK4a expression was analyzed by immunohistochemistry (IHC). RESULTS: All 112 BCCs were HPV DNA negative, and of 105 BCCs possible to evaluate for p16INK4a, none overexpressed p16INK4a. CONCLUSIONS: HPV DNA and p16INK4a overexpression were absent in BCCs. Lack of HPV DNA and p16 protein overexpression in BCCs is helpful to discriminate benign BCCs from HPV+ OPSCC metastasis. HPV testing definitely has a role in the diagnostics of cystic masses of the neck.


Assuntos
Branquioma/diagnóstico , Carcinoma de Células Escamosas/secundário , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias Orofaríngeas/secundário , Papillomaviridae/isolamento & purificação , Adolescente , Adulto , Idoso , Branquioma/virologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/virologia , DNA Viral/análise , Diagnóstico Diferencial , Feminino , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pescoço/virologia , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/virologia , Papillomaviridae/genética , Adulto Jovem
7.
Oncotarget ; 8(21): 35339-35350, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28525363

RESUMO

BACKGROUND: Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+ TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes. PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants. RESULTS: 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed. CONCLUSIONS: In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.


Assuntos
Mutação , Neoplasias Primárias Desconhecidas/virologia , Infecções por Papillomavirus/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Língua/virologia , Neoplasias Tonsilares/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Desconhecidas/genética , Prognóstico , Análise de Sequência de DNA , Análise de Sobrevida , Neoplasias da Língua/genética , Neoplasias Tonsilares/genética , Proteína Supressora de Tumor p53/genética
8.
Oral Oncol ; 68: 53-59, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28438294

RESUMO

OBJECTIVE: Head-neck cancer therapy has become intensified. With radiotherapy alone, 3-year disease-free survival (DFS) is 80% for HPV-positive TSCC/BOTSCC and better for patients with favorable characteristics, suggesting therapy could be tapered for some, decreasing side-effects. Therefore, we built a model to predict progression-free survival for patients with HPV-positive TSCC and BOTSCC. MATERIAL AND METHODS: TSCC/BOTSCC patients treated curatively between 2000 and 2011, with HPV16 DNA/E7 mRNA positive tumors examined for CD8+ TILs, HPV16 mRNA and HLA class I expression were included. Patients were split randomly 65/35 into training and validation sets, and LASSO regression was used to select a model in the training set, the performance of which was evaluated in the validation set. RESULTS: 258 patients with HPV DNA/E7 mRNA positive tumors could be included, 168 and 90 patients in the respective sets. No treatment improved prognosis compared to radiotherapy alone. CD8+ TIL counts and young age were the strongest predictors of survival, followed by T-stage <3 and presence of HPV16 E2 mRNA. The model had an area under curve (AUC) of 76%. A model where the presence of three of four of these markers defined good prognosis captured 56% of non-relapsing patients with a positive predictive value of 98% in the validation set. Furthermore, the model identified 35% of our cohort that was overtreated and could safely have received de-escalated therapy. CONCLUSION: CD8+ TIL counts, age, T-stage and E2 expression could predict progression-free survival, identifying patients eligible for randomized trials with milder treatment, potentially reducing side effects without worsening prognosis.


Assuntos
Biomarcadores , Carcinoma de Células Escamosas/patologia , Neoplasias Orofaríngeas/patologia , Infecções por Papillomavirus/patologia , Infecções Tumorais por Vírus/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/virologia , Análise de Sobrevida , Resultado do Tratamento , Infecções Tumorais por Vírus/virologia
9.
Anticancer Res ; 37(2): 665-673, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179315

RESUMO

BACKGROUND: Human papillomavirus (HPV) is a favourable prognostic factor in oropharyngeal cancer. Moreover, we and others reported that HPV-positive cancer of unknown primary in the head and neck region (HNCUP) has better outcome than HPV-negative HNCUP. However, not all studies concord. Here, our previous finding was investigated in a new cohort and additional biomarkers were analyzed. MATERIALS AND METHODS: A total of 19 HNCUPs diagnosed 2008-2013 were analyzed for HPV DNA by polymerase chain reaction assay (PCR) and p16 by immunohistochemistry (IHC). Thereafter, 69 HNCUPs diagnosed between 2000-2013 were analyzed for HPV16 mRNA by PCR (if HPV16DNA-positive) and cluster of differentiation 8 positive (CD8+) tumour-infiltrating lymphocytes (TILs) and human leukocyte antigen (HLA) class I-expression using IHC. RESULTS: HPV DNA, alone and in combination with p16 overexpression, was validated as a favourable prognostic factor in HNCUP. HPV16 mRNA was present in most HPV16 DNA-positive cases, confirming HPV-driven carcinogenesis in HNCUP. High CD8+ TIL counts indicated favourable prognosis. CONCLUSION: HPV status is useful for the management of patients with HNCUP and the role of CD8+ TILs should be further explored.


Assuntos
Biomarcadores Tumorais/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Primárias Desconhecidas/imunologia , Infecções por Papillomavirus/imunologia , Idoso , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , DNA Viral/genética , DNA Viral/imunologia , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/virologia , Papillomaviridae/genética , Papillomaviridae/imunologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Prognóstico , Sensibilidade e Especificidade
10.
Head Neck ; 39(3): 419-426, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27898186

RESUMO

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has a better outcome than most head neck squamous cell carcinomas (HNSCCs) and an HPV-positive lymph node metastasis likely has an HPV-positive oropharyngeal SCC origin. Determining HPV-status in cervical lymph nodes by fine-needle aspiration cytology (FNAC) may be useful for diagnosis. METHODS: FNACs from 66 patients with neck masses were prospectively examined for HPV DNA and HPV16 mRNA by a polymerase chain reaction (PCR)-based assay, and the data correlated to diagnosis and HPV-status obtained from histopathological specimens. RESULTS: Aspirates from 17 of 66 patients, later diagnosed with HPV-positive oropharyngeal SCC, were HPV16 DNA-positive. HPV16 mRNA was detected in all cases with extractable RNA. All remaining FNACs, including 18 branchial cleft cysts, were HPV DNA-negative. HPV DNA status in the aspirates showed perfect concordance with corresponding biopsies. CONCLUSION: HPV16 DNA detection in fine-needle aspirations from neck masses is reliable and HPV16 DNA in a metastasis is a strong indicator of an HPV-positive oropharyngeal SCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: 419-426, 2017.


Assuntos
Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/genética , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/diagnóstico , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/terapia , Estudos de Coortes , Citodiagnóstico/métodos , DNA Viral/genética , Bases de Dados Factuais , Feminino , Papillomavirus Humano 16/isolamento & purificação , Humanos , Imuno-Histoquímica , Incidência , Linfonodos/patologia , Linfonodos/virologia , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/epidemiologia , Neoplasias Orofaríngeas/terapia , Infecções por Papillomavirus/epidemiologia , Reação em Cadeia da Polimerase/métodos , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , RNA Viral/genética , RNA Viral/isolamento & purificação , Medição de Risco , Distribuição por Sexo , Análise de Sobrevida , Suécia
11.
Anticancer Res ; 36(2): 487-93, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26851001

RESUMO

Human papillomavirus (HPV) is recognized as a risk factor for oropharyngeal squamous cell carcinomas (SCC), especially tonsillar and base of tongue cancer. Furthermore, HPV-positive tonsillar and base of tongue SCC have a significantly better prognosis than their HPV-negative counterparts and head and neck cancer (HNSCC) in general. HPV has recently also been implicated in cancer of unknown primary (CUP) in the head and neck region, where a primary tumour is not found despite extensive workup. Using fine-needle aspiration cytology to determine CUP HPV status in cervical lymph nodes could be of advantage, since it is minimally invasive and it is assumed that an HPV-positive lymph node metastasis likely has an HPV-positive otopharyngeal SCC origin. We review the current knowledge of HPV in HNSCC, with an emphasis on CUP of the head and neck region, its relation to oropharyngeal, tonsillar and base of tongue SCC and implications of HPV status for diagnosis, prognosis and treatment.


Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico , Testes de DNA para Papilomavírus Humano/métodos , Neoplasias Primárias Desconhecidas/diagnóstico , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Neoplasias Primárias Desconhecidas/epidemiologia , Neoplasias Primárias Desconhecidas/virologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia
12.
Mol Clin Oncol ; 5(6): 671-674, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28105346

RESUMO

Human papillomavirus (HPV), in addition to smoking and alcohol, is a cause of oropharyngeal squamous cell carcinoma (OPSCC), particularly of the tonsils and base of the tongue (TSCC and BOTSCC, respectively). Moreover, HPV-positive TSCC and BOTSCC are associated with a better outcome compared with their HPV-negative counterparts (80 vs. 40% 3-year disease-free survival rate, respectively) and their incidence has increased in several countries. Recently, accumulating evidence of HPV in a considerable proportion of cancers of unknown primary (CUP) in the head and neck region and in a small proportion of hypopharyngeal SCCs has been reported. Furthermore, HPV-positive tumours, particularly cases with HPV DNA positivity in combination with overexpression of p16, also tend to have a better clinical outcome compared with that of the corresponding HPV-negative tumours. This finding is particularly prominent in HPV-positive CUPs of the head and neck region, where the primary tumour likely originates from the oropharynx. Thus, the determination of HPV status and p16 expression may be of value for the diagnosis and treatment of CUP of the head and neck region and may also be of value for hypopharyngeal cancers in the future. However, for hypopharyngeal cancer as well as other non-OPSCCs, additional studies per subsite on the effect of HPV status on survival are required.

13.
Eur J Cancer ; 51(12): 1580-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26025766

RESUMO

AIM: To combine clinical and molecular markers into an algorithm for predicting outcome for individual patients with human papillomavirus (HPV) DNA/p16(INK4a) positive tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC). BACKGROUND: Head-neck cancer treatment has become more intensified, comprising not only surgery and radiotherapy, but also induction/concomitant chemotherapy and targeted therapy. With less treatment, 3-year disease free survival (DFS) is 80% for HPV-positive TSCC and BOTSCC. An 85-100% 3-year DFS is observed for HPV(+) TSCC and BOTSCC with absence of HLA class I, or CD44 expression, or high CD8(+) tumour-infiltrating lymphocyte (TIL) counts suggesting that therapy could be tapered for many if patients could be identified individually. PATIENTS AND METHODS: Patients treated curatively, with HPV DNA/p16(INK4a) positive tumours examined for HLA class I and II, CD44 and CD8(+)TILs, were included. An L1-regularised logistic regression was used to evaluate the effect of the biomarker data, age, stage, diagnosis, smoking and treatment on 3-year risk of death or relapse on a training cohort of 197 patients diagnosed 2000-2007 and validated on a cohort of 118 patients diagnosed 2008-2011. RESULTS: The variables finally included in the model were HLA class I, CD8(+) TILs, age, stage and diagnosis (TSCC or BOTSCC). The model showed acceptable discrimination and calibration. The discriminative ability of the model did not diminish after validation (AUC=0.77). CONCLUSION: To our knowledge, this is the first model to utilise information from several markers to predict an individual probability of clinical outcome for patients with HPV DNA/p16(INK4a) positive tumours.


Assuntos
Carcinoma de Células Escamosas , Neoplasias da Língua , Neoplasias Tonsilares , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , DNA Viral/análise , Feminino , Humanos , Receptores de Hialuronatos/imunologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Neoplasias da Língua/imunologia , Neoplasias da Língua/metabolismo , Neoplasias da Língua/patologia , Neoplasias da Língua/virologia , Neoplasias Tonsilares/imunologia , Neoplasias Tonsilares/metabolismo , Neoplasias Tonsilares/patologia , Neoplasias Tonsilares/virologia
14.
Cancer Med ; 3(2): 376-84, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24510528

RESUMO

Patients with cancer of unknown primary (CUP) in the head neck region are generally treated with neck dissection followed by radiotherapy at times combined with chemotherapy, a treatment associated with considerable side effects. Some of these tumors may originate as human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OSCC), with better clinical outcome than head neck squamous cell cancer (HNSCC) in general, and could potentially do well with less treatment. Here, we therefore investigated whether HPV status and p53-expression correlated to clinical outcome in patients with CUP in the head neck region. Fifty metastases were analyzed for presence of HPV DNA, and expression of p16(INK4A) and p53 and the data were correlated to clinical outcome. Patients with HPV DNA-positive (HPVDNA+) metastases had significantly better 5-year overall survival (OS) compared to those with HPVDNA- metastases (80.0% vs. 36.7%, respectively; P = 0.004), with a similar tendency for disease-free survival (DFS). These survival rates showed excellent concordance with those of HPVDNA+ and HPVDNA- OSCC in Sweden during the same time period, strengthening the hypothesis that HPVDNA+ head and neck CUP may originate from HPVDNA+ OSCC. In addition, having absent/intermediary-low as compared to high expression of p53 correlated to a better prognosis with a 69% as compared to 14% 5-year OS, respectively (P < 0.001), and for DFS the tendency was analogous. In conclusion, both HPV status and p53 expression are valuable prognostic factors in patients with CUP in the head and neck region and should be further explored for clinical use.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Neoplasias Primárias Desconhecidas/metabolismo , Neoplasias Primárias Desconhecidas/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Idoso , Carcinoma de Células Escamosas/genética , Inibidor p16 de Quinase Dependente de Ciclina , DNA Viral/análise , DNA Viral/genética , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Primárias Desconhecidas/genética , Papillomaviridae/genética , Inclusão em Parafina , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética
15.
Scand J Infect Dis ; 45(11): 878-81, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23957537

RESUMO

The rise in human papillomavirus (HPV) infection has been suggested to be responsible for the increased incidence of oropharyngeal cancer in the Western world. This has boosted interest in oral HPV prevalence and whether HPV vaccines can prevent oral HPV infection. In a previous study we showed oral HPV prevalence to be almost 10% in youth aged 15-23 y attending a youth clinic in Stockholm, Sweden. However, this may not be a generalizable sample within the Swedish population. Therefore, mouthwashes were used to investigate oral HPV prevalence in 335 Swedish high school students aged 17-21 y (median age 18 y), from 1 municipality with 140,000 inhabitants. The presence of HPV DNA in the oral samples, as examined by a Luminex-based assay, was significantly lower in this cohort, only 1.8% (3.1% in females and 0.6% in males), as compared to our previous study.


Assuntos
Boca/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Adolescente , DNA Viral/genética , DNA Viral/isolamento & purificação , Feminino , Humanos , Masculino , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Prevalência , Suécia/epidemiologia , Adulto Jovem
16.
Eur J Cancer ; 49(11): 2522-30, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23571147

RESUMO

Patients with human papillomavirus (HPV) positive tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) have a better clinical outcome than those with HPV negative tumours, irrespective of treatment. However, to better individualise treatment, additional biomarkers are needed together with HPV status. In a pilot study, we showed that high numbers of CD8(+) tumour infiltrating lymphocytes (TILs) in HPVDNA+ p16(INK4a+) TSCC indicated a better outcome. Here this study was extended. Totally 203 TSCC and 77 BOTSCC formalin fixed paraffin embedded tumour biopsies, earlier tested for HPV DNA (79% HPVDNA+) and p16(INK4a) from patients treated with curative intention, were analysed for CD8(+) and CD4(+) TILs by immunohistochemistry. Data obtained for 275 patients were correlated to HPVDNA and p16(INK4a) status, overall survival (OS) and disease free survival (DFS). In both HPVDNA+ and HPVDNA+ p16(INK4a+) tumours higher CD8(+) TIL counts correlated to a better 3-year OS (logrank test, both p<0.001) and 3-year DFS (logrank test, p = 0.003 and p = 0.004 respectively) as compared to the lowest quartile in the groups. A similar pattern was observed when analysing TSCC alone, while for BOTSCC significance was obtained only for 3-year OS. In HPVDNA- tumours the trend was similar, but significance was obtained again only for 3-year OS. The number of CD4(+) TILs did not generally correlate to survival. In conclusion, in HPVDNA+ and/or HPVDNA+ p16(INK4a+) tumours high CD8(+) TIL counts indicated a better 3-year OS. This suggests that high CD8(+) TIL counts together with HPVDNA+ or HPVDNA+ p16(INK4a+) could be used when selecting patients for more individualised treatment.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Linfócitos do Interstício Tumoral/imunologia , Infecções por Papillomavirus/imunologia , Neoplasias da Língua/imunologia , Neoplasias Tonsilares/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Papillomaviridae/imunologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Projetos Piloto , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias da Língua/patologia , Neoplasias da Língua/terapia , Neoplasias da Língua/virologia , Neoplasias Tonsilares/patologia , Neoplasias Tonsilares/terapia , Neoplasias Tonsilares/virologia , Resultado do Tratamento
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