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Doctoral Thesis
DOI
https://doi.org/10.11606/T.17.2021.tde-10052021-131638
Document
Author
Full name
Carla Bento Nelem Colturato
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2021
Supervisor
Committee
León, Jorge Esquiche (President)
Brunaldi, Mariângela Ottoboni
Freitas, Luiz Carlos Conti de
Tango, Estela Kaminagakura
Title in Portuguese
Caracterização imunoistoquímica das diferenciações neuroendócrina e escamosa em carcinomas espinocelulares da região de cabeça e pescoço
Keywords in Portuguese
Cabeça e pescoço
Carcinoma espinocelular
Carcinoma neuroendócrino
Diferenciação escamosa
Diferenciação neuroendócrina
EBV
Hibridização in situ
HPV
Imunoistoquímica
Microarranjo de tecido
Abstract in Portuguese
O carcinoma espinocelular (CEC) é a neoplasia maligna mais comum (>90%) na região de cabeça e pescoço (CECCP). Apesar dos avanços científicos nos seus mecanismos moleculares e protocolos terapêuticos, a taxa de sobrevida global em 5 anos permanece em <50%. Além dos fatores prognósticos clássicos, existem variantes histopatológicas do CECCP mostrando diferenças no seu comportamento biológico e prognóstico. Notavelmente, alguns estudos mostram que o CECCP pode mostrar diferenciação neuroendócrina (dNE); no entanto, o significado deste achado e seu impacto prognóstico devem ser detalhadamente descritos em uma ampla série de casos. Segundo a Organização Mundial da Saúde (OMS, 2017), o carcinoma neuroendócrino (CNE) pobremente diferenciado da região de cabeça e pescoço é uma neoplasia altamente agressiva, a qual pode mostrar associação com o papilomavírus humano (HPV) ou vírus Epstein-Barr (EBV). Sendo assim, o CNE deve ser diferenciado do CECdNE, visando critérios diagnósticos, terapêuticos e prognósticos. Assim, no presente estudo foram avaliados 386 CECCPs, através da técnica de microarranjo de tecido (TMA), por meio da análise imunoistoquímica (IQ), usando os anticorpos cromogranina-A, sinaptofisina, CD56, CD57, CD99, Fli-1, p16INK4a, p40, CD10, vimentina, ciclina D1 e Ki-67; e por hibridização in situ (HIS) visando à detecção do HPV de alto risco (HPV-AR) e EBV (EBER1/2). Nossos resultados mostraram predomínio de homens (70%), leucodermas (74%), fumantes (83%) e etilistas (76%). A média de idade foi 59,4 ±11,64 anos, sem diferenças no gênero. Os locais mais afetados foram orofaringe (n=125), laringe (n=121) e cavidade oral (n=103), seguido por seios paranasais (n=15), nasofaringe (n=12) e outros (n=10). dNE (cromogranina-A e/ou sinaptofisina positivo) foi detectada em 27/386 (7%) casos (laringe, n=12; orofaringe, n=8; cavidade oral, n=4; seios paranasais, n=2; outros, n=1). Considerando agentes virais, 54 casos (orofaringe, n=23; laringe, n=21; cavidade oral, n=8; nasofaringe, n=1; outros, n=1) para HPV-AR e 3 casos (todos de nasofaringe) mostraram positividade EBER1/2, respectivamente. p16INK4a foi uniformemente positivo nos casos HPV-AR positivos. Sete casos apresentaram simultaneamente dNE/HPV-AR (orofaringe, n=4; laringe, n=2; boca, n=1). Todos os casos CD99 positivos foram Fli-1 negativos. CD10 e vimentina mostraram variável expressão nos casos com (53,9% e 12,5%) ou sem (31,8% e 9,6%) dNE, ou com (33,9% e 5,6%) ou sem (32,8% e 10,2%) associação com HPV-AR, respectivamente. Similarmente, Ki-67 e ciclina D1 mostraram variável expressão nos casos com (39,1% e 9,6%) ou sem (38,6% e 5,9%) dNE, ou com (42,1% e 7,2%) ou sem (38,8% e 5%) associação com HPV-AR, respectivamente. A sobrevida livre de doença (SLD) em 2 anos e sobrevida global (SG) em 5 anos, foram estatisticamente significantes para estadiamento III/IV em cavidade oral (ambos, p=0,02) e laringe (ambos, p=0,03); para tratamento cirúrgico em cavidade oral (ambos, p=0,03), orofaringe (ambos, p<0,01) e laringe (ambos, p<0,01); para radioterapia (ambos, p<0,01) e quimioterapia (ambos, p=0,02) em laringe. Não houve diferenças estatisticamente significantes na SLD e SG considerando dNE ou associação com HPV-AR em orofaringe, laringe e cavidade oral. Na regressão de Cox, somente em orofaringe houve diferença estatisticamente significante, observando-se que a positividade para cromogranina-A, CD56, e ausência do HPV-AR, se associava com maior risco de mortalidade (11, 6 e 3 vezes, respectivamente). Nossos resultados mostram que dNE pode ser detectada no CECCP, alguns deles associados com HPV-AR, expandindo o seu espectro clinicopatológico. No entanto, estes achados parecem não influenciar a SLD e SG em nossa população de estudo. Futuros estudos no contexto deste trabalho focando interações moleculares entre dNE e HPV-AR no CECCP, bem como análises comparativas com CNEs, são recomendados.
Title in English
Immunohistochemical characterization of neuroendocrine and squamous differentiations in squamous cell carcinomas of the head and neck region
Keywords in English
EBV
Head and neck
HPV
Immunohistochemistry
In situ hybridization
Neuroendocrine carcinoma
Neuroendocrine differentiation
Squamous cell carcinoma
Squamous differentiation
Tissue microarray
Abstract in English
Squamous cell carcinoma (SCC) is the most common malignant neoplasm (> 90%) in the head and neck region (HNSCC). Despite scientific advances in its molecular mechanisms and therapeutic protocols, the overall 5-year survival rate remains at <50%. In addition to the classic prognostic factors, there are histopathological variants of the HNSCC showing differences in its biological behavior and prognosis. Notably, some studies show that HNSCC can show neuroendocrine differentiation (NEd); however, the significance of this finding and its prognostic impact must be described in detail in a wide range of cases. According to the World Health Organization (WHO, 2017), neuroendocrine carcinoma (NEC) poorly differentiated from the head and neck region is an aggressive neoplasm, which may show association with human papillomavirus (HPV) or Epstein-Barr virus (EBV). Therefore, the NEC must be differentiated from the SCC NEd, aiming at diagnostic, therapeutic and prognostic criteria. Thus, in the present study 386 CECCPs were evaluated using the tissue microarray technique (TMA), using immunohistochemical analysis (IHQ), using the antibodies chromogranin-A, synaptophysin, CD56, CD57, CD99, Fli-1, p16INK4a, p40, CD10, vimentin, cyclin D1 and Ki-67; and by in situ hybridization (HIS) aiming at the detection of high-risk HPV (HRHPV) and EBV (EBER1 / 2). Our results showed a predominance of men (70%), white blood cells (74%), smokers (83%) and alcoholics (76%). The mean age was 59.4 ± 11.64 years, with no gender differences. The most affected sites were the oropharynx (n = 125), larynx (n = 121) and oral cavity (n = 103), followed by paranasal sinuses (n = 15), nasopharynx (n = 12) and others (n = 10). dNE (A-chromogranin and / or synaptophysin positive) was detected in 27/386 (7%) cases (larynx, n = 12; oropharynx, n = 8; oral cavity, n = 4; paranasal sinuses, n = 2; others, n = 1). Considering viral agents, 54 cases (oropharynx, n = 23; larynx, n = 21; oral cavity, n = 8; nasopharynx, n = 1; others, n = 1) and 3 cases (all of nasopharynx) were positive for HPV -AR and EBER1 / 2, respectively. p16INK4a was uniformly positive in HPV-AR positive cases. Seven cases simultaneously presented dNE / HPV-AR (oropharynx, n = 4; larynx, n = 2; mouth, n = 1). All CD99 positive cases were Fli-1 negative. CD10 and vimentin showed variable expression in cases with (53.9% and 12.5%) or without (31.8% and 9.6%) NEd, or with (33.9% and 5.6%) or without (32.8% and 10.2%) association with HPV-AR, respectively. Similarly, Ki-67 and cyclin D1 showed variable expression in cases with (39.1% and 9.6%) or without (38.6% and 5.9%) dNE, or with (42.1% and 7, 2%) or without (38.8% and 5%) association with HR-HPV, respectively. The 5-year overall survival (OS) for CgA (p = 0.79), SNF (p = 0.44) and HR-HPV (p = 0.93) in the oral cavity; CgA (p = 0.96), SNF (p = 0.13) and HR-HPV (p = 0.06) in the oropharynx; CgA (p = 0.83), SNF (p = 0.57) and HR-HPV (p = 0.46) in the larynx; no statistically significant differences over 5-years in OS considering dNE or association with HR-HPV. The OS at 5-years was statistically significant for staging III / IV in the oral cavity (p = 0.02) and larynx (p = 0.03); for surgical treatment in oral cavity (p = 0.03), oropharynx (p <0.01) and larynx (p <0.01); for radiotherapy (p <0.01) and chemotherapy (p = 0.02) in the larynx. In Cox regression, only in the oropharynx there was a statistically significant difference, noting that positivity for chromogranin-A, CD56, and absence of HR-HPV, was associated with a higher risk of mortality (11, 6 and 3 times, respectively). Our results show that NEd can be detected at HNSCC, some of which are associated with HR-HPV, expanding its clinicopathological spectrum. However, these findings do not appear to influence Disease-free survival in our study population. Future studies in the context of this work focusing on molecular interactions between NEd and HRHPV at HNSCC, as well as comparative analyzes with NECs, are recommended.
 
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Publishing Date
2021-05-21
 
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