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Radiotherapy is the standard treatment for head and neck squamous cell carcinoma (HNSCC), however, radioresistance remains a major clinical problem despite significant improvements in treatment protocols. Therapeutic outcome could potentially be improved if a patient's tumour response to irradiation could be predicted ex vivo before clinical application. The present study employed a bespoke microfluidic device to maintain HNSCC tissue whilst subjecting it to external beam irradiation and measured the responses using a panel of cell death and proliferation markers. HNSCC biopsies from five newly-presenting patients [2 lymph node (LN); 3 primary tumour (PT)] were divided into parallel microfluidic devices and replicates of each tumour were subjected to single-dose irradiation (0, 5, 10, 15 and 20 Gy). Lactate dehydrogenase (LDH) release was measured and tissue sections were stained for cytokeratin (CK), cleaved-CK18 (cCK18), phosphorylated-H2AX (γH2AX) and Ki67 by immunohistochemistry. In addition, fragmented DNA was detected using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Compared with nonirradiated controls, higher irradiation doses resulted in elevated CK18-labelling index in two lymph nodes [15 Gy; 34.8% on LN1 and 31.7% on LN2 (p=0.006)] and a single laryngeal primary tumour (20 Gy; 31.5%; p=0.014). Significantly higher levels of DNA fragmentation were also detected in both lymph node samples and one primary tumour but at varying doses of irradiation, i.e., LN1 (20 Gy; 27.6%; p=0.047), LN2 (15 Gy; 15.3%; p=0.038) and PT3 (10 Gy; 35.2%; p=0.01). The γH2AX expression was raised but not significantly in the majority of samples. The percentage of Ki67 positive nuclei reduced dose-dependently following irradiation. In contrast no significant difference in LDH release was observed between irradiated groups and controls. There is clear inter- and intra-patient variability in response to irradiation when measuring a variety of parameters, which offers the potential for the approach to provide clinically valuable information.
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Carcinoma de Células Escamosas/radioterapia , DNA de Neoplasias/efeitos da radiação , Neoplasias de Cabeça e Pescoço/radioterapia , Lactato Desidrogenases/metabolismo , Técnicas Analíticas Microfluídicas/instrumentação , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Fragmentação do DNA , Relação Dose-Resposta à Radiação , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
AIM: Head and neck squamous cell carcinomas (HNSCC) are solid tumors with low overall survival (40-60%). In a move toward personalized medicine, maintenance of tumor biopsies in microfluidic tissue culture devices is being developed. METHODOLOGY/RESULTS: HNSCC (n = 15) was dissected (5-10 mg) and either analyzed immediately or cultured in a microfluidic device (37°C) for 48 h. No difference was observed in morphology between pre- and postculture specimens. Dissociated samples were analyzed using trypan blue exclusion (viability), propidium iodide flow cytometry (death) and MTS assay (proliferation) with no significant difference observed highlighting tissue maintenance. Computational fluid dynamics showed laminar flow within the system. CONCLUSION: The microfluidic culture system successfully maintained HNSCC for 48 h, the culture system will allow testing of different treatment modalities with response monitoring.
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BACKGROUND: The neutrophil/lymphocyte ratio (NLR) has been found to be predictive of survival outcome in a range of tumors. The purpose of this study was to investigate the prognostic value of pretreatment (NLR) in patients with laryngeal squamous cell carcinoma (SCC). METHODS: A retrospective analysis of 140 patients with laryngeal SCC treated between 2005 and 2010 in the Hull and East Yorkshire Hospitals NHS Trust was carried out. Patient records were evaluated and both pretreatment neutrophil and lymphocyte counts were documented together with survival data, sex, smoking status, nodal classification, and disease staging. RESULTS: An elevated NLR was significantly associated with advanced disease stage (eg, node-positive and tumors stage III and IV). In addition, a high NLR was significantly associated with poor overall survival (OS) but not disease-free survival (DFS) on multivariate analysis, with the greatest significance seen in patients with the highest NLR. CONCLUSION: Pretreatment NLR may serve as a useful prognostic marker in laryngeal SCC; however, a large prospective study is required to determine an optimal NLR cutoff value. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1903-E1908, 2016.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Neoplasias Laríngeas/diagnóstico , Linfócitos/citologia , Neutrófilos/citologia , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: The tumour microenvironment is a highly complex region where multiple interactions occur between host and cancer cells. The host response is defined by the presence and function of different tumour infiltrating lymphocytes and cytokines. Head and neck squamous cell carcinomas comprise a subgroup of human cancers with significant morbidity and mortality. METHOD: A literature review was performed to identify studies, which have investigated the impact of immune factors within the tumour microenvironment of head and neck squamous cell carcinomas on clinical outcomes. RESULTS: Higher counts of intratumoral dendritic cells and CD8+ T-lymphocytes are associated with a favorable prognosis in head and neck cancers. However, contrasting results have been found with T-regulatory cells whereby higher intratumoral counts appear favorable particularly in tumours of oropharyngeal origin. A number of studies have found a link between various biomarkers, e.g. IL-10 in oral cancers, and clinical outcome. CONCLUSIONS: We have identified immune factors within the tumour microenvironment, which are critically related to prognosis and also those, which require further work to elucidate their full relevance. Furthermore it is clear that if immunotherapy is to be introduced as an adjunct in the treatment of head and neck cancers, different immunological parameters will need to be selected for each distinct subsite.
Assuntos
Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Microambiente Tumoral/imunologia , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: The aim of this study was to investigate how head and neck squamous cell carcinoma (HNSCC) tissue biopsies maintained in a pseudo in vivo environment within a bespoke microfluidic device respond to radiation treatment. STUDY DESIGN: Feasibility study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Thirty-five patients with HNSCC were recruited, and liver tissue from 5 Wistar rats was obtained. A microfluidic device was used to maintain the tissue biopsy samples in a viable state. Rat liver was used to optimize the methodology. HNSCC was obtained from patients with T1-T3 laryngeal or oropharyngeal SCC; N1-N2 metastatic cervical lymph nodes were also obtained. Irradiation consisted of single doses of between 2 Gy and 40 Gy and a fractionated course of 5×2 Gy. Cell death was assessed in the tissue effluent using the soluble markers lactate dehydrogenase (LDH) and cytochrome c and in the tissue by immunohistochemical detection of cleaved cytokeratin18 (M30 antibody). RESULTS: A significant surge in LDH release was demonstrated in the rat liver after a single dose of 20 Gy; in HNSCC, it was seen after 40 Gy compared with the control. There was no significant difference in cytochrome c release after 5 Gy or 10 Gy. M30 demonstrated a dose-dependent increase in apoptotic index for a given increase in single-dose radiotherapy. There was a significant increase in apoptotic index between 1×2 Gy and 5×2 Gy. CONCLUSION: M30 is a superior method compared with soluble markers in detecting low-dose radiation-induced cell death. This microfluidic technique can be used to assess radiation-induced cell death in HNSCC and therefore has the potential to be used to predict radiation response.
Assuntos
Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Morte Celular/efeitos da radiação , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Animais , Apoptose , Citocromos c/análise , Estudos de Viabilidade , Humanos , Imuno-Histoquímica , Queratina-18/análise , L-Lactato Desidrogenase/análise , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Fígado/patologia , Técnicas Analíticas Microfluídicas , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/radioterapia , Dosagem Radioterapêutica , Ratos , Ratos WistarRESUMO
The presence of regulatory T (Treg) cells is thought to be an important mechanism by which head and neck squamous cell carcinoma (HNSCC) successfully evades the immune system. Using multicolour flow cytometry, the frequency and functional capacity of two CD4(+) CD127(low/-) Treg cell populations, separated on the basis of different levels of CD25 expression (CD25(inter) and CD25(high) ), from the peripheral circulation of newly presenting HNSCC patients were assessed with regard to clinicopathological features and healthy controls. The frequency of circulating Treg cells was similar between HNSCC patients and healthy controls, and for patients with HNSCC developing from different subsites (laryngeal compared with oropharyngeal). However, patients with advanced stage tumours and those with nodal involvement had significantly elevated levels of CD4(+) CD25(high) CD127(low/-) Treg cells compared with patients who had early stage tumours (P = 0·03) and those without nodal involvement (P = 0·03), respectively. CD4(+) CD25(high) CD127(low/-) Treg cells from the entire HNSCC patient cohort and from patients whose tumours had metastasized to the lymph nodes were also shown to suppress the proliferation of effector T cells significantly more, compared with those from healthy controls (P = 0·04) or patients with no nodal involvement (P = 0·04). Additionally, CD4(+) CD25(inter) CD127(low/-) Treg cells consistently induced greater suppressive activity than CD4(+) CD25(high) CD127(low/-) Treg cells on the proliferation of the effector T-cell populations (CD4(+) CD25(-) CD127(-/+) and CD4(+) CD25(+) CD127(+) ). Peripheral Treg cells, identified by the CD127(low/-) phenotype, have been shown to be influenced by a patient's tumour stage and/or nodal status in HNSCC; suggesting a role in tumour progression that could be manipulated by future immunotherapy.
Assuntos
Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Circulação Sanguínea , Antígenos CD4/metabolismo , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Metástase Linfática , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Evasão TumoralRESUMO
BACKGROUND: The nature of the tumour microenvironment immune response in head and neck cancer patients has an important role in tumour development and metastasis, but it is unknown if this differs between cancer subsites or whether it is related to the peripheral immune response. METHODS: Immune cells (CD4, CD8, Foxp3) in head and neck squamous cell carcinoma tissue (HNSCC; n = 66), detected by immunohistochemistry, have been correlated with tumour subsite and immune cells in the peripheral circulation (CD4(+)CD25(High)Foxp3(+) Treg and CD4(+) T cells), identified using flow cytometry. RESULTS: Oropharyngeal tumours had a greater number of infiltrating immune cells in both tumour and stroma compared with other subsites, but no difference was observed in the circulating levels. Immune cells in the stroma were positively related to those in the tumour with consistently higher levels in stroma. A strong relationship was found between the number of CD4(+) and Foxp3(+) cells but not between the number of CD8(+) and Foxp3(+) cells in the tumour. The number of Foxp3(+) cells within the tumour was positively correlated with the percentage of circulating CD4(+)CD25(High) cells positive for Foxp3. Late stage laryngeal tumours showed a higher number of Foxp3(+) lymphocytes compared with early stage malignancies, and oropharyngeal tumours had more CD4(+) cells in node negative tumours compared with node positive ones. CONCLUSION: The level of immune cell infiltration in head and neck squamous cell carcinoma appears to be subsite dependent residing primarily in the stroma and is likely to be dependent on the peripheral immune response.
Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Linfócitos do Interstício Tumoral/citologia , Neoplasias Orofaríngeas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Orofaríngeas/imunologia , Resultado do TratamentoRESUMO
Over 2,200 cases of carcinoma of the larynx are diagnosed in the UK annually, with an overall 5-year survival rate of 67%. Angiogenesis is vital for the growth and metastasis of solid tumours and the expression of key angiogenesis-related proteins has been shown to be of prognostic significance. In this study we reported the expression of key angiogenesis-related factors, selected from a pilot array study, in a cohort of laryngeal tumours and associated metastatic lymph nodes. Forty patients diagnosed with squamous cell carcinoma of the larynx were recruited. Tissue specimens were obtained intra-operatively, prior to chemo- and/or radiotherapy, from the tumours and secondary lymph nodes. The patient group comprised 32 men and 8 women with a mean age of 68 years (range, 51-89 years). The relative expression of the angiogenesis-related proteins angiogenin, interleukin (IL)-8, tissue inhibitor of metalloproteinases-1 (TIMP-1), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-basic and insulin-like growth factor binding protein 3 (IGFBP3) was determined in the tissue lysates by ELISA. The expression of angiogenin was higher in early-stage compared with late-stage tumours (P=0.034) and the expression of IGFBP3 was higher in tumours compared with the metastatic lymph nodes (P=0.016). No statistically significant differences were recorded for VEGF, FGF, TIMP-1 or IL-8 between tumour stages or primary tumours and lymph nodes. To the best of our knowledge, this study was the first to investigate multiple angiogenic factors in the lysates of laryngeal carcinomas and metastatic nodes and identified angiogenin and IGFBP3 as factors possibly involved in tumour progression. A greater understanding of their function may offer novel prognostic and/or therapeutic options.
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Tumors are heterogeneous masses of cells characterized pathologically by their size and spread. Their chaotic biology makes treatment of malignancies hard to generalize. We present a robust and reproducible glass microfluidic system, for the maintenance and "interrogation" of head and neck squamous cell carcinoma (HNSCC) tumor biopsies, which enables continuous media perfusion and waste removal, recreating in vivo laminar flow and diffusion-driven conditions. Primary HNSCC or metastatic lymph samples were subsequently treated with 5-fluorouracil and cisplatin, alone and in combination, and were monitored for viability and apoptotic biomarker release 'off-chip' over 7 days. The concentration of lactate dehydrogenase was initially high but rapidly dropped to minimally detectable levels in all tumor samples; conversely, effluent concentration of WST-1 (cell proliferation) increased over 7 days: both factors demonstrating cell viability. Addition of cell lysis reagent resulted in increased cell death and reduction in cell proliferation. An apoptotic biomarker, cytochrome c, was analyzed and all the treated samples showed higher levels than the control, with the combination therapy showing the greatest effect. Hematoxylin- and Eosin-stained sections from the biopsy, before and after maintenance, demonstrated the preservation of tissue architecture. This device offers a novel method of studying the tumor environment, and offers a pre-clinical model for creating personalized treatment regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Técnicas Analíticas Microfluídicas , Apoptose/efeitos dos fármacos , Biópsia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Citocromos c/metabolismo , Feminino , Fluoruracila/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Hidroliases/metabolismo , Metástase Linfática , Masculino , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Proteínas de Neoplasias/metabolismo , Células Tumorais CultivadasRESUMO
IL10, but not IL12 or T regulatory cells in the circulation of newly presenting, pre-treatment head and neck squamous cell carcinoma (HNSCC) patients, has been shown previously to be related to survival over a mean follow-up period of 15 months. Here, we followed the same patients for a longer period to determine whether these associations change. Pre- and post-treatment serum IL10/IL12 and circulating T regs were measured using ELISA and flow cytometry respectively and were correlated with survival after a 33 month average follow-up in a cohort of newly presenting HNSCC patients (n=107), with cancers of the hypopharynx (n=16), larynx (n=36), oral cavity (n=21), oropharynx (n=25), sinonasal (n=4) or unknown origin (n=5). Although the mean survival time of patients with detectable levels of IL10 pre-treatment was lower (40.6 months) than that of those without detectable levels of IL10 (45.6 months), the difference was no longer significant, in contrast to earlier follow-up data. In conclusion, although serum levels of IL10 may be a prognostic indicator for HNSCC patients over the short-term, they become less significant as follow-up time increases.
Assuntos
Carcinoma de Células Escamosas/sangue , Neoplasias de Cabeça e Pescoço/sangue , Interleucina-10/sangue , Interleucina-12/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/imunologia , Estudos de Coortes , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Interleucina-10/imunologia , Interleucina-12/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
The expression of angiogenesis-related proteins was determined in laryngeal tumour tissue, associated tumour involved lymph nodes, apparently normal mucosa and control tissue and were related to tumour stage. Both laryngeal tumour tissue and associated metastatic nodes were obtained from seven patients undergoing surgical resection; in four cases apparently normal mucosa was also dissected from the tumour specimen margins. Control uvula mucosa was obtained from five healthy volunteers undergoing uvulopalatopharyngoplasty. The relative expression of 55 angiogenesis-related proteins was determined in tissue lysates using a Proteome Profiler human angiogenesis array kit. The level of 32/55 angiogenesis-related proteins was higher in tumour tissue compared with controls. Furthermore, in these tumour biopsies higher levels of proteins were associated with increasing tumour stage. A similar trend was seen for 29/32 of these proteins in the nodal tissue. In T4 stage tumour tissue samples, 29/55 angiogenensis-related proteins were more highly expressed compared with the adjacent normal mucosa from the same patient, and this decreased to 8 proteins in tumour tissue from the T1 stage patients. In contrast, the expression of 23 angiogenesis-related proteins in metastatic lymph node tissue from T4 stage patients was lower compared with that found in the normal mucosa adjacent to the tumour. In conclusion, this study has identified a number of factors involved in angiogenesis that are likely to contribute to the growth and metastasis of laryngeal tumours. Furthermore, a number of factors were also substantially altered in metastatic deposits compared with the primary tumour mass or adjacent normal tissue. This study requires confirmatory analysis of the selected key factors in a larger cohort of patients.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Laríngeas/irrigação sanguínea , Neoplasias Laríngeas/metabolismo , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mucosa Laríngea/metabolismo , Mucosa Laríngea/patologia , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Metástase Linfática , Masculino , Estadiamento de Neoplasias/métodos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismoRESUMO
The aim of this study was to determine the effect of HNSCC tumour treatment on systemic Th1 and Th2 cytokine levels and investigate correlations with clinicopathological parameters. IL2, IL4, IL5, IL6, IL8, IL10, IL13, GMCSF, IFNγ and TNFα were measured in the serum of 101 newly-presenting HNSCC patients (9 oral cavity, 27 oropharynx, 57 laryngopharynx, 1 sinonasal, 1 parotid and 6 unknown), prior to and following treatment, using a Quantibody(®) array based multiplex sandwich ELISA (Raybiotech). Data were analysed with respect to T stage, nodal status, age and sex of the patient as well as time between collection of pre- and post-treatment serum. A significant decrease in the levels of the Th2 cytokines IL4, IL5, IL6 and IL10 and the Th1 cytokines IL2 and IL8 was observed between the pre- and post-treatment serum samples. IL13 and TNFα were significantly higher in early stage (T1/T2) tumours compared with late stage (T3/T4) and this trend was maintained for nodal involvement. IL4 was higher in node positive patients compared with node negative, whereas the converse was true for IL2; IL4 was also higher in younger patients compared with the older age group. These results suggest that removal of HNSCC tumours from patients results in reduced circulating Th2 cytokines without a concurrent increase in Th1 cytokines, indicative of a partial rebalance of the Th1/Th2 system following treatment. Furthermore the cytokine profile may be influenced by the size and nodal involvement of the tumour.
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Advances in the treatment modalities for head and neck squamous cell carcinoma (HNSCC) over the last 20 years involving surgery, radiotherapy, chemotherapy, and immunotherapy are not fully reflected in increases in the 5-year survival rates, mainly due to locoregional recurrences and to a lesser extent, distant metastasis. This can, in part, be attributed to the fact that HNSCC induces severe depression of a patient's immune system. Recent advances in understanding the complex host-tumor interactions have led to the identification of a distinct suppressor cell population known as regulatory T cells that play a crucial role in maintaining T-cell tolerance to self-antigens. Here, we present a critical review of our understanding of the involvement of regulatory T cells in controlling the T-cell immune response in tumor occurrence and progression in HNSCC with an emphasis on current and future immunotherapeutic approaches involving regulatory T cells.
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Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Linfócitos T Reguladores/fisiologia , Animais , Autoimunidade/imunologia , Células Dendríticas/imunologia , Progressão da Doença , Humanos , Tolerância Imunológica/fisiologia , Linfonodos/imunologia , Transporte Proteico/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Conventional chemotherapy has no role to play in the curative treatment of laryngeal carcinoma, yet the mortality rate from advanced disease has improved little over the last 20 years. Somatostatin is a naturally occurring peptide, which exerts anti-proliferative and anti-angiogenic effects via 5 membrane-bound receptor subtypes (SSTRs 1-5). We have previously studied the expression of SSTRs 1 and 2 and demonstrated loss of SSTR2 in laryngeal carcinoma. This study was therefore undertaken to study the expression of the remaining SSTR subtypes in laryngeal pathology. The expression of SSTRs 3, 4 and 5 was studied in benign (Reinke's oedema), pre-malignant and malignant laryngeal specimens using immunohistochemistry. There was very little expression of SSTR3, with low to moderate levels detected in just 1/6 (17%) benign and pre-malignant specimens and 3/12 (25%) malignant laryngeal tumours. A variable degree of SSTR4 expression was detected across the three groups, with low to moderate levels in 3/6 (50%) benign specimens, compared to only 1/6 (17%) pre-malignant specimens but 8/12 (67%) malignant laryngeal tumours. The majority of all specimens, however, demonstrated moderate to high levels of expression of SSTR5. This receptor was detected in 4/6 (67%) benign, all pre-malignant (100%) and 10/12 (83%) malignant cases. All the laryngeal carcinomas studied expressed either SSTR4 or SSTR5, with 60% expressing both, but very few expressing SSTR3. Somatostatin receptors warrant further investigation to determine whether they have a therapeutic role in carcinoma of the larynx.
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Neoplasias Laríngeas/metabolismo , Laringe/metabolismo , Lesões Pré-Cancerosas/metabolismo , Receptores de Somatostatina/metabolismo , Adulto , Idoso , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-IdadeRESUMO
Head and neck squamous cell carcinoma (HNSCC) demonstrates significant differences in the biological and clinical behaviour of tumours found at different sub-sites. We investigated the genetic profiles of 68 carcinomas (larynx n=35, hypopharynx n=19, oropharynx n=14) using chromosomal comparative genomic hybridisation in order to identify sub-site specific differences. Multiple genetic aberrations were found throughout the tumour genomes, including +3q (82%), -3p (75%), +8q (66%), +5p (49%), +7q (49%), +1q (47%), -4p (46%), -11q (46%), -13q (46%), -5q (44%), +11q (43%) and +12p (43%). The mean number of chromosomal arms with at least one aberration was 15. Laryngeal carcinomas (LSCC) were found to have significantly more aberrations on chromosomal arms than oropharyngeal carcinomas (OpSCC); (mean of 17 vs. 11, respectively (p=0.011). It was noted that -4p, +8q, +12q, and -18q were significantly associated with LSCC when compared with both hypopharyngeal SCC (HpSCC) and OpSCC. HpSCC was significantly associated with -2q whereas no aberrations were found to be significantly associated with OpSCC. In conclusion a large number of common chromosomal aberrations are associated with HNSCC however in addition further aberrations are significantly associated with individual sub-sites of head and neck cancer. These aberrations may be responsible for the diverse biological behaviour of these different tumour types. Further research is required to identify the specific genes associated with these chromosomal regions and evaluate their individual impact on disease progression.
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Carcinoma de Células Escamosas/genética , Aberrações Cromossômicas/estatística & dados numéricos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Laríngeas/genética , Hibridização de Ácido Nucleico , Oncogenes/genética , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Dosagem de Genes , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Laríngeas/patologia , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Neoplasias Faríngeas/genética , Neoplasias Faríngeas/patologiaRESUMO
Information from the genetic analysis of head and neck cancer has grown enormously in the last 20 years. The advent of high-resolution genetic analysis techniques such as microarray technology will further expand this field in the future. Here we review the data on chromosomal aberrations of head and neck squamous cell carcinoma, focusing on the data generated by comparative genomic hybridization analysis, and suggest how such findings will be taken forward over the next decade. With the search engine PUBMED, the key words "comparative genomic hybridisation," "head and neck," "oral," "hypopharyngeal," "laryngeal," and "squamous cell carcinoma" were used. Publications unavailable in English were excluded.
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Carcinoma de Células Escamosas/genética , Aberrações Cromossômicas , Neoplasias de Cabeça e Pescoço/genética , Predisposição Genética para Doença , Humanos , Hibridização de Ácido NucleicoRESUMO
BACKGROUND: Angiogenesis is essential for tumor growth and invasion. Vascular endothelial growth factor A (VEGF-A) is a prime mediator of tumor angiogenesis; VEGF-C, another member of the closely related VEGF family of proteins, has major effects on lymphatic endothelial cells and may be important in the process of lymphatic metastasis. OBJECTIVES: To evaluate the expression of these cytokines in hypopharyngeal squamous cell carcinoma and to ascertain the effects of these proteins on lymphatic metastasis and vascular angiogenesis. DESIGN: Retrospective analysis of microvessel density and the expression of VEGF-A and VEGF-C. SETTING: An academic referral center. Subjects Thirty-four patients with stage T2 to T4 squamous cell carcinoma of the piriform fossa. INTERVENTIONS: Expression of VEGF-A and VEGF-C was determined by immunohistochemistry on formalin-fixed, paraffin-embedded biopsy specimens. Angiogenesis was measured as microvessel density by staining endothelial cells for platelet-endothelial cell adhesion molecule 1/CD31. RESULTS: Of the 34 tumors, 21 had clinicoradiologic evidence of lymphatic metastasis. Expression of VEGF-C was associated with lymphatic metastasis (P<.001), but not with microvessel density. The VEGF-A expression correlated with microvessel density (P<.001), but neither VEGF-A expression nor microvessel density was associated with lymphatic metastasis. CONCLUSIONS: The expression of VEGF-C is associated with lymphatic metastasis in squamous cell carcinoma of the piriform fossa. This is not secondary to effects on vascular angiogenesis and is hypothesized to be due to effects on lymphatic endothelial cells.
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Carcinoma de Células Escamosas/patologia , Neoplasias Hipofaríngeas/patologia , Hipofaringe/irrigação sanguínea , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/análise , Fator B de Crescimento do Endotélio Vascular/análise , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipofaringe/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Posterior laryngeal cleft (PLC) is a rare developmental abnormality, which requires early diagnostic laryngoscopy and management if considerable morbidity and mortality are to be avoided. We report the case of a 25-year-old man with a life-long history of a weak, breathy voice, in whom the diagnosis of PLC was made by CT scanning. This is the first reported case of a PLC being diagnosed by CT scanning. Whilst direct laryngoscopy should remain the investigation of choice in congenital stridor, CT scanning may occasionally be useful.
Assuntos
Fissura Palatina/diagnóstico por imagem , Laringe/anormalidades , Tomografia Computadorizada por Raios X , Adulto , Fissura Palatina/complicações , Fissura Palatina/terapia , Humanos , Laringoscopia , Laringe/diagnóstico por imagem , Masculino , Tomografia Computadorizada por Raios X/métodos , Distúrbios da Voz/etiologiaRESUMO
OBJECTIVES/HYPOTHESIS: The objectives are to determine the frequency of chromosomal aberrations in 22 patients in the United Kingdom with head and neck squamous cell carcinoma and to compare our results with studies reported from western Europe and North America and highlight changes common to all groups, thus enabling focused study of important gene loci. STUDY DESIGN: Prospective experimental, then comparative observational study. METHODS: Comparative genomic hybridization was used to detect regions of chromosomal gain or loss across the entire genome. The aberration frequency was contrasted with other published series, and similarities and differences were highlighted. RESULTS: The most common chromosomal gain in all studies was 3q (50% to 87%). Other common chromosomal gains varied considerably between centers. The most common loss was 3p in three of the studies; one group in the United States reported 19p loss most frequently. The frequency of other losses varied considerably. CONCLUSIONS: Comparative genomic hybridization has highlighted a number of common genetic events in head and neck squamous cell carcinoma. The prevalence of individual aberrations differed between centers. Further cooperative multicenter studies of this technique are warranted.