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Previous issue date: 2012-07-19 === Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico === Squamous cell carcinoma of the lower lip is among the most common malignant tumors of the
oral and maxillofacial region, with good prognosis in more than 90% of patients with 5-year
survival. In these carcinomas, the development of lymph node metastasis decreases the
prognosis and it has been associated with the formation of new lymphatic vessels. It has been
suggested the important role of vascular endothelial growth factor-C (VEGF-C), the receptor
type 3 VEGF (VEGFR-3) and hypoxia-induced factor 1 (HIF-1) in this process. The aim of
this study was to evaluate the immunoexpression of VEGF-C, VEGFR-3 and HIF-1? and
correlate with intra and peritumoral lymphatic density in squamous cell carcinomas of the
lower lip metastatic and non-metastatic. The sample consisted of 50 cases of squamous cell
carcinoma of lower lip, of which 25 had regional lymph node metastasis and 25, absence of
metastasis. The percentages of cells immunostained for VEGF-C, VEGFR-3 and HIF-1? in
front of tumor invasion and in the center of tumor were evaluated. Microvessel density
lymphatic (MDL) was determined by the counting of lymph microvessels immunostained by
the anti-D2-40 in five fields (200?), in an area of evaluation with 0.7386 mm2. The invasion
of the lymph vessels by malignant cells was also evaluated. Immunostaining was correlated
with the presence and absence of metastasis, TNM clinical stage, local recurrence, disease
outcome (remission of injury or patient death) and histological grading. The analysis of intra
and peritumoral lymphatic density showed no significant association with clinicopathological
parameters and immunoexpressions of VEGF-C, VEGFR-3 and HIF-1? (p > 0,05). There was
a weak positive correlation, significant, between intra and peritumoral lymphatic density (r =
0,405; p = 0,004). VEGF-C showed no significant association with clinicopathological and
prognosis parameters (p > 0,05). For VEGFR-3, there was scarce membrane staining and
intense and homogenous cytoplasmic staining in neoplastic cells. Percentage of positive
cytoplasmic VEGFR-3 in center of tumor, exhibited a statistically significant association with
metastasis (p = 0,009), patient death (p = 0,008) and histological grades of malignancy
proposed by Bryne et al. (1992) (p = 0,002) and World Health Organization (p = 0,003). A
low positive correlation was statistically significant between the immunoreactivity of VEGFC
and VEGFR-3 cytoplasmic (r = 0,358; p = 0,011) and between the percentage of positive
cytoplasmic VEGFR-3 in front of tumor invasion and in the center of the tumor (r = 0,387; p
= 0,005) was also demonstrated. There was no association between HIF-1?,
clinicopathological and prognosis parameters, and VEGF-C and VEGFR-3. The percentage of
nuclear positivity for HIF-1? was significantly higher in cases without invasion of peritumoral
lymphatic (p = 0,040). Based on the results we can conclude that most cytoplasmic expression
of VEGFR-3 in center of tumor in metastatic cases, high degree of malignancy and poorly
differentiated, contributes to poor outcome of squamous cell carcinoma of the lower lip,
including patient death. Intra and peritumoral lymphatic density seems to be not associated
with lymph node metastasis in these carcinomas === O carcinoma epiderm?ide de l?bio inferior est? entre as les?es malignas mais comuns da
regi?o oral e maxilofacial, com progn?stico bom, em mais de 90% dos pacientes com
sobrevida de 5 anos. Nestas les?es, o desenvolvimento de met?stase linfonodal diminui
sobremaneira o progn?stico e tem sido associado ? forma??o de novos vasos linf?ticos. Tem
sido sugerido o importante papel do fator de crescimento endotelial vascular-C (VEGF-C), do
receptor tipo 3 do VEGF (VEGFR-3) e do fator 1 induzido por hip?xia (HIF-1) neste
processo. O objetivo desta pesquisa foi avaliar as imunoexpress?es de VEGF-C, VEGFR-3,
HIF-1? e a densidade linf?tica intra e peritumoral em carcinomas epiderm?ides de l?bio
inferior metast?ticos e n?o-metast?ticos, correlacionando-as com par?metros
clinicopatol?gicos e progn?sticos. A amostra foi constitu?da por 50 casos de carcinoma
epiderm?ide de l?bio inferior, 25 com met?stase linfonodal regional e 25 sem met?stase.
Foram avaliados os percentuais de c?lulas imunomarcadas para os anticorpos anti-VEGF-C,
anti-VEGFR-3 e anti-HIF-1?, no front de invas?o e no centro tumoral. A densidade
microvascular linf?tica (LMVD) foi estabelecida por meio da soma da contagem de
microvasos linf?ticos imunomarcados pelo anticorpo anti-D2-40, em cinco campos (200?),
em uma ?rea de avalia??o com 0,7386 mm2. A invas?o dos vasos linf?ticos por c?lulas
neopl?sicas tamb?m foi avaliada. A imunomarca??o foi relacionada com a presen?a e
aus?ncia de met?stase, estadiamento cl?nico TNM, recidiva local, desfecho da doen?a
(remiss?o da les?o ou ?bito dos pacientes) e grada??o histol?gica. A an?lise das densidades
linf?ticas intra e peritumorais n?o demonstrou associa??o significativa com os par?metros
clinicopatol?gicos, progn?sticos e imunoexpress?es de VEGF-C, VEGFR-3 e HIF-1? (p >
0,05). Houve fraca correla??o positiva, significativa, entre as densidades linf?ticas intra e
peritumorais (r = 0,405; p = 0,004). O VEGF-C n?o exibiu associa??o significativa entre os
par?metros clinicopatol?gicos e progn?sticos avaliados (p > 0,05). Para o VEGFR-3, houve
escassa marca??o membranar e intensa e homog?nea marca??o citoplasm?tica nas c?lulas
neopl?sicas. O percentual de positividade citoplasm?tica do VEGFR-3, no centro tumoral,
exibiu associa??o estatisticamente significativa com a presen?a de met?stase (p = 0,009),
?bito dos pacientes (p = 0,008) e grada??es histol?gicas de malignidade proposta por Bryne et
al. (1992) (p = 0,002) e pela Organiza??o Mundial de Sa?de (p = 0,003). Uma fraca
correla??o, estatisticamente significativa, entre a imunoexpress?o de VEGF-C e VEGFR-3
citoplasm?tica (r = 0,358; p = 0,011) e entre os percentuais de positividade citoplasm?tica de
VEGFR-3 no front de invas?o e no centro tumoral (r = 0,387; p = 0,005) tamb?m foi
demonstrada. N?o foi observada associa??o entre o HIF-1? os par?metros clinicopatol?gicos,
progn?sticos e o VEGF-C e VEGFR-3. O percentual de positividade nuclear para HIF-1? foi
significativamente maior nos casos sem invas?o dos linf?ticos peritumorais (p = 0,040). Com
base nos resultados pode-se concluir que a maior express?o citoplasm?tica de VEGFR-3, no
centro tumoral, nos casos metast?ticos, de alto grau de malignidade e pobremente
diferenciados, contribui para pior evolu??o dos carcinomas epiderm?ides de l?bio inferior,
incluindo o ?bito dos pacientes. As densidades linf?ticas intra e peritumorais parecem n?o
estar associadas ao densenvolvimento de met?stase linfonodal nestes carcinomas
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