INFECÇÃO Por Papilomavírus Humano e Expressão Das
proteínas P16 e Egfr Como Biomarcadores De
prognóstico em Carcinoma Epidermoide Oral E


Publication date: 30/03/2020

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Examining board:

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FLAVIA DE PAULA (M/D) Internal Examiner *

Summary: Oral and oropharyngeal squamous cell carcinoma has as main risk factors the
consumption of tobacco, alcohol and infection by Human Papillomavirus (HPV).
Studies indicate that HPV-positive patients have results more favorable in relation to
survival and response to radiochemical treatment. In the oropharynx, the worldwide
guidelines for the identification and treatment of cancer recommend that p16 protein
is an important prognostic indicator, an indirect way of assessing HPV infection. But
studies show that there is no absolute relationship between protein expression and
the presence of the virus. In addition, studies indicate a relationship between HPVnegative tumors and high expression of the Epidermal Growth Factor Receptor
(EGFR), highly expressed in oral and oropharyngeal squamous cell carcinoma and
already used as a target for immunotherapy. The aim of this study was to evaluate
the applicability of HR-HPV biomarkers EGFR and p16 as indicators of prognosis
and response to treatment in oral and oropharyngeal squamous cell carcinoma. The
presence of p16 and EGFR was performed by immuno-detection on tissue
microarray slides (TMA, from English Tissue Microarray) containing tumor samples
from epithelium adjacent to the tumor, dysplastic tissue and tumor tissue. The
detection of HPV DNA was performed using Polymerase Chain Reaction (PCR). The
detection of HPV E6 / E7 mRNA was performed by in situ hybridization using RNA
probes (ISH-RNA). Immunoexpression of p16, EGFR and HPV status were
associated with clinical-pathological variables and risk factors. Overall survival (OS)
and disease-free survival (DFS) curves were obtained using the Kaplan – Meier
method. Elevated EGFR expression was related to the larger tumor size in oral
squamous cell carcinoma. The frequency of HPV found in oral and oropharyngeal
squamous cell carcinoma using PCR was 2.25%. With the ISH-RNA technique, a
frequency of 8.08% was observed in oral squamous cell carcinoma and 10% in
oropharyngeal squamous cell carcinoma. A relationship was found between p16 and
the presence of E6 / E7 mRNA in oral squamous cell carcinoma (p = 0.046), but not
in oropharyngeal squamous cell carcinoma. There was an increasing and significant
correlation between p16 and HPV (p = 0.007), but a weak correlation was detected
between the two variables (rs = 0.239). Although the presence of HPV, detected by
ISH-RNA, did not directly impact on OS or DFS, it was observed that all HPV-positive
patients fell into the low-risk group, which had the highest OS rates (p = 0.028). In
conclusion, p16 and EGFR may not be good prognostic or progression biomarkers.
However, the expression of p16 can be used as an important tool for routine
screening. ISH-RNA seems to have greater sensitivity than conventional PCR and
the weak correlation between p16 expression and detection of E6 / E7 HPV RNA by
ISH leads to the conclusion that using p16 expression alone may not be the best
option to predict the HPV infection. The low frequency of HPV observed may indicate
that the oral cavity is an unusual anatomical site for HPV, not being a determinant for
oral carcinogenesis and that HPV is not yet a predominant causal factor for
oropharyngeal carcinogenesis, as it is in other countries, prevailing smoking and
drinking habits.

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