Louredo BrendoViniciusRodrigues M

UNIVERSIDADE ESTADUAL DE CAMPINAS
FACULDADE DE ODONTOLOGIA DE PIRACICABA
BRENDO VINICIUS RODRIGUES LOURÊDO
EPIDEMIOLOGIA E SOBREVIDA DE PACIENTES COM

CARCINOMA ESPINOCELULAR DE LÁBIO, CAVIDADE ORAL E
OROFARINGE EM UMA POPULAÇÃO DO SUDESTE BRASILEIRO
EPIDEMIOLOGY AND SURVIVAL OF PATIENTS WITH LIP, ORAL

CAVITY, AND OROPHARYNGEAL SQUAMOUS CELL CARCINOMA
IN A SOUTHEAST BRAZILIAN POPULATION
Piracicaba
2021
BRENDO VINICIUS RODRIGUES LOURÊDO
EPIDEMIOLOGIA E SOBREVIDA DE PACIENTES COM

CARCINOMA ESPINOCELULAR DE LÁBIO, CAVIDADE ORAL E
OROFARINGE EM UMA POPULAÇÃO DO SUDESTE BRASILEIRO
EPIDEMIOLOGY AND SURVIVAL OF PATIENTS WITH LIP, ORAL

CAVITY, AND OROPHARYNGEAL SQUAMOUS CELL CARCINOMA
IN A SOUTHEAST BRAZILIAN POPULATION
Dissertação apresentada à Faculdade de

Odontologia de Piracicaba da Universidade
Estadual de Campinas como parte dos
requisitos exigidos para a obtenção do título
de Mestre em Estomatopatologia, na área de
Patologia.
Dissertation presented to the Piracicaba
Dental School of the University of Campinas
in partial fulfillment of the requirements for
the degree of Master in Oral Medicine and
Oral Pathology, in the Pathology area.
Orientador: Prof. Dr. Pablo Agustin Vargas
Coorientadora: Dra. Maria Paula Curado

Este trabalho corresponde à versão final da
dissertação defendida pelo aluno Brendo
Vinicius Rodrigues Lourêdo, e orientada pelo
Prof. Dr. Pablo Agustin Vargas.
Piracicaba
2021
Agência de fomento e nº de processo: CAPES, 88887.482426/2020-00
Ficha catalográfica
Universidade Estadual de Campinas
Biblioteca da Faculdade de Odontologia de Piracicaba
Marilene Girello - CRB 8/6159
Lourêdo, Brendo Vinicius Rodrigues, 1993-

L934e Epidemiologia e sobrevida de pacientes com carcinoma espinocelular de
lábio, cavidade oral e orofaringe em uma população do sudeste brasileiro /
Brendo Vinicius Rodrigues Lourêdo. – Piracicaba, SP : [s.n.], 2021.
Orientador: Pablo Agustin Vargas.

Coorientador: Maria Paula Curado.
Dissertação (mestrado) – Universidade Estadual de Campinas, Faculdade
de Odontologia de Piracicaba.
1. Carcinoma de células escamosas. 2. Lábios. 3. Boca. 4. Orofaringe. 5.

Sobrevida. I. Vargas, Pablo Agustin, 1973-. II. Curado, Maria Paula. III.
Universidade Estadual de Campinas. Faculdade de Odontologia de Piracicaba.
IV. Título.
Informações para Biblioteca Digital
Título em outro idioma: Epidemiology and survival of patients with lip, oral cavity, and
oropharyngeal squamous cell carcinoma in a southeast brazilian population
Palavras-chave em inglês:
Carcinoma, squamous cell
Lips
Mouth
Oropharynx
Survivorship (Public health)
Área de concentração: Patologia
Titulação: Mestre em Estomatopatologia
Banca examinadora:
Maria Paula Curado [Coorientador]
Célia Maria País Viegas
Vivian Petersen Wagner
Data de defesa: 30-07-2021
Programa de Pós-Graduação: Estomatopatologia
Identificação e informações acadêmicas do(a) aluno(a)

- ORCID do autor: https://orcid.org/0000-0002-5057-4008
- Currículo Lattes do autor: http://lattes.cnpq.br/8012766409830044
UNIVERSIDADE ESTADUAL DE CAMPINAS
Faculdade de Odontologia de Piracicaba
A Comissão Julgadora dos trabalhos de Defesa de Dissertação de Mestrado, em sessão

pública realizada em 30 de julho de 2021, considerou o candidato BRENDO VINICIUS
RODRIGUES LOURÊDO aprovado.
PROFª. DRª. MARIA PAULA CURADO
PROFª. DRª. CÉLIA MARIA PAÍS VIEGAS
PROFª. DRª. VIVIAN PETERSEN WAGNER
A Ata da defesa, assinada pelos membros da Comissão Examinadora, consta no

SIGA/Sistema de Fluxo de Dissertação/Tese e na Secretaria do Programa da Unidade.
“Não adianta se entregar aos sonhos se
você se esquece de viver”
J. K. Rowling
DEDICATÓRIA
Dedico este trabalho à minha pequena e amada irmã
Isadora Helena Rodrigues Louredo,
por compreender minha ausência nos últimos anos.

AGRADECIMENTOS
O presente trabalho foi realizado com apoio da Coordenação de Aperfeiçoamento de Pessoal

de Nível Superior – Brasil (CAPES) – Código de Financiamento 001.
À Faculdade de Odontologia de Piracicaba da Universidade Estadual de Campinas, na pessoa

do seu Diretor, Prof. Dr. Francisco Haiter Neto.
Ao Prof. Dr. Pablo Agustin Vargas, coordenador do Programa de Pós-Graduação em

Estomatopatologia da Faculdade de Odontologia de Piracicaba – UNICAMP, que me concedeu
a honra de ser seu orientado durante o mestrado e pela parceria que se seguirá no doutorado.
Sou grato por seus ensinamentos e pelas inúmeras oportunidades que o senhor me concedeu
mesmo em meio a uma pandemia tão desafiadora. Agradeço ainda por me permitir trabalhar
com pessoas tão competentes e prestigiadas no meio acadêmico e da patologia oral. Tenho
muito orgulho em dizer que sou seu aluno.
À Dra. Maria Paula Curado que aceitou ser minha coorientadora durante o mestrado.
Humildade, disponibilidade, competência e paciência são apenas algumas das várias qualidades
que a senhora possui. Obrigado por compartilhar conhecimentos tão importantes da
epidemiologia. Obrigado por me conceder a honra de aprender com a sua experiência. E
obrigado por todas as portas que se abriram com o seu auxílio.
Ao Prof. Dr. Alan Roger dos Santos Silva por me conceder a oportunidade de integrar o grupo
de revisões sistemáticas da estomatopatologia. Sou muito grato por todas os ensinamentos e
trabalhos realizados nos últimos meses, além da oportunidade de conhecer e interagir com
colegas de profissão e pesquisadores renomados do cenário nacional e mundial.
Aos Profs. Drs. Edgar Graner, Jacks Jorge Junior, Márcio Ajudarte Lopes e Oslei Paes
de Almeida que ministraram créditos importantes durante o mestrado. Seus compromissos
éticos e seus ensinamentos foram fundamentais para o meu desenvolvimento profissional e
pessoal.
À minha colega de pós-graduação e amiga Maria Eduarda Pérez de Oliveira que desde o
início estendeu a mão e não mediu esforços para me ajudar tanto no grupo de revisões
sistemáticas quanto na confecção desta dissertação. À minha também colega e amiga Anna
Luiza Damaceno Araújo que desde antes de eu ingressar no mestrado se dispôs de forma tão
humilde a passar ensinamentos importantes. Sua amizade é muito especial.
Aos meus amados pais, Doraci e Henrique. A vocês eu não tenho palavras para descrever o
quão fundamentais são na trajetória que estou construindo. Só posso dizer que eu sou resultado
de toda a persistência, luta, humildade e honestidade que vocês possuem. Obrigado pelo apoio
incondicional em todas as minhas escolhas de vida. À minha pequena irmã Isadora, meu amor
maior, minha alegria de vida, meu tudo. Um dia você irá entender o porquê da minha ausência.
Ao Leandro da Silva Lyra, pela parceria de vida e pelo apoio fundamental para que meu
caminho fosse trilhado da melhor forma possível. Obrigado por mudar sua vida por mim. Sou
muito grato por tudo que fez e ainda faz por mim. Por fim, vocês são o que tenho de mais
precioso e, por isso, é uma honra amar vocês.
À Deus, a minha eterna gratidão por todas as vitórias e bênçãos a mim concedidas. Sem Ele,
nada seria.
RESUMO
O câncer de cabeça e pescoço é um problema crescente de saúde pública, afetando homens e

mulheres ao redor do planeta. Os carcinomas espinocelular (CECs) de lábio, cavidade oral e
orofaringe são os principais e mais prevalentes representantes desse grupo. Apesar de
compartilharem semelhanças entre si, a exposição crônica à radiação solar é o principal
carcinógeno do CEC de lábio, tabaco e álcool do CEC de cavidade oral e o papilomavirus
humano do CEC de orofaringe. O objetivo deste estudo foi descrever o perfil epidemiológico e
a sobrevida dos pacientes com CEC de lábio, cavidade oral e orofaringe no estado de São Paulo.
Os dados clinicopatológicos de todos os pacientes com CEC de lábio (ICD-O-3: C00), cavidade
oral (C02-06) e orofaringe (C01 e C08-10) foram obtidos dos registros hospitalares de câncer
da Fundação Oncocentro do Estado de São Paulo entre os anos de 2010 e 2015. Taxas de
sobrevida e outras análises foram realizadas através do programa SPSS. Dos 368.116 casos de
câncer, 12.099 pacientes foram diagnosticados com CEC de lábio, cavidade oral e orofaringe.
Houve uma maior prevalência de pacientes do sexo masculino, especialmente nos casos de
orofaringe (82,3%). A média de idade foi maior para os casos de lábio (65±13,5 anos)
comparado aos outros sítios (cavidade oral: 60,3±12,1 anos; orofaringe: 58,6±10 anos). O nível
de escolaridade foi baixo para a maioria dos pacientes em todos os três sítios estudados (≤ 8
anos de estudo), com a maior taxa observada para as lesões de lábio (87,9%). Cerca de 90,6%
de todos os pacientes obtiveram o diagnóstico através do sistema único de saúde (SUS). A
maioria dos pacientes com CEC de cavidade oral (71,8%) e de orofaringe (86,3%) apresentaram
doença em estágio avançado, enquanto 83,3% dos pacientes com CEC de lábio foram
diagnosticados com tumor em estágios iniciais (I-II). Excisão cirúrgica foi o principal
tratamento para CEC de lábio (72%) e cavidade oral (23.5%) e a combinação de radioterapia e
quimioterapia para CEC de orofaringe (40.2%). A sobrevida global em 5 anos para CEC de
lábio, cavidade oral e orofaringe foi de 66,3%, 30,9% e 22,6%, respectivamente. A análise
multivariada revelou que o período de diagnóstico e o diagnóstico através do SUS foram
preditores independentes de sobrevida apenas para os pacientes com CEC de orofaringe, a idade
acima de 60 anos para CEC de lábio e cavidade oral e o sexo masculino e tempo entre
diagnóstico e tratamento superior a 60 dias para os casos de cavidade oral e orofaringe. O
estágio clínico foi preditor independente para as três localizações e os diferentes tipos de
tratamento variaram entre as topografias. Portanto, concluiu-se que esses tumores ocorrem mais
em homens acima dos 60 anos de idade, com baixa instrução e doença em estágio avançado nos
casos de cavidade oral e orofaringe. Os preditores de sobrevida variaram de acordo com a
topografia analisada e as taxas de sobrevida foram melhores para os pacientes com CEC de
lábio.
Palavras-chave: Carcinoma de Células Escamosas; Lábio; Cavidade oral; Orofaringe;

Análise de Sobrevida.
ABSTRACT
Head and neck cancer is a growing public health problem affecting men and women around the
world. Lip, oral cavity, and oropharyngeal squamous cell carcinoma (SCC) are the main and
most prevalent types of this group. Despite sharing similarities, chronic exposure to solar
radiation is the main carcinogen for lip SCC, tobacco and alcohol consumption for oral cavity
SCC, and human papillomavirus for oropharyngeal SCC. This study aimed to describe the
epidemiological profile and survival of patients with lip, oral cavity, and oropharyngeal SCC
in the state of São Paulo. The clinicopathological data of all patients with lip (ICD-O-3: C00),
oral cavity (C02-06), and oropharyngeal (C01 and C08-10) SCC were obtained from the
hospital cancer registries of the Fundação Oncocentro do Estado de São Paulo between 2010
and 2015. Survival rates and other analyzes were performed through the SPSS software. Of the
368,116 cancer cases, 12,099 patients were diagnosed with lip, oral cavity, and oropharyngeal
SCC. There was a higher prevalence of male patients, especially in oropharyngeal cases
(82.3%). The mean age was higher for lip cases (65±13.5 years) compared to other sites (oral
cavity: 60.3±12.1 years; oropharynx: 58.6±10 years). Schooling level was low for most patients
of all three sites studied (≤ 8 years of study), with the highest rate observed for lip lesions
(87.9%). About 90.6% of all patients were diagnosed through the Sistema Único de Saúde
(SUS). Most patients with the oral cavity (71.8%) and oropharyngeal (86.3%) SCC had the
advanced-stage disease, while 83.3% of patients with lip SCC were diagnosed with early-stage
(I -II) tumor. Surgical excision was the main treatment for lip (72%) and oral cavity (23.5%)
SCC, and the combination of radiotherapy and chemotherapy for oropharyngeal (40.2%) SCC.
The 5-year overall survival rates for lip, oral cavity, and oropharyngeal SCC were 66.3%,
30.9%, and 22.6%, respectively. The multivariate analysis revealed that the period of diagnosis
and diagnosis by SUS were independent predictors of survival only for patients with
oropharyngeal SCC, age over 60 years for lip and oral cavity SCC, and male sex and time
between diagnosis and treatment more than 60 days for cases of oral cavity and oropharynx.
The clinical stage was an independent predictor for the three sites and the different types of
treatment varied between the sites. Therefore, it was concluded that these tumors occur more
often in men over 60 years of age, with low education and advanced-stage disease in cases of
oral cavity and oropharynx. Survival predictors varied according to the topography analyzed,
and survival rates presented better results for patients with lip SCC.
Keywords: squamous cell carcinoma; lip; oral cavity; oropharynx; survival analysis.
LISTA DE ILUSTRAÇÕES
Figura 1 Paciente apresentando lesão nodular com superfície crostosa e 18

endurecida à palpação em lábio inferior esquerdo com 2 meses de
evolução (A). Paciente com nódulo exofítico, acastanhado, com bordas
irregulares e limites mal definidos, endurecido à palpação, com área
ulcerada em mucosa labial esquerda com evolução de 24 meses (B).
Figura 2 Paciente apresentando placa eritroleucoplásica em borda lateral direita 18

de língua com cerca de 12 meses de evolução (A). Paciente com lesão
ulcerada infiltrativa, de bordas irregulares, consistência firme à palpação
e sintomatologia dolorosa em borda lateral de língua com evolução de 8
meses (B).
Figura 3 Paciente apresentando lesão ulcerada com bordas elevadas em pilar 18

amigdaliano esquerdo com 1 mês de evolução (A). Paciente com lesão
nodular extensa, de consistência firme e infiltrativa em base de língua
com evolução de 6 meses. Os dois terços anteriores da língua estavam
endurecidos e sem movimentos (B).
Figura 4 Fotomicrografias do carcinoma espinocelular de cavidade oral. Ninhos 19

e cordões de células neoplásicas proliferando a partir do epitélio de
superfície displásico (A). Imagem em maior aumento evidenciando a
proliferação das células tumorais se destacando do epitélio de superfície
em direção ao tecido conjuntivo subjacente inflamado (B). Ninhos de
células tumorais bem diferenciadas com formação abundante de pérolas
de ceratina (C). Em menor aumento, observa-se intenso pleomorfismo
celular com nucléolos evidentes e figuras de mitoses atípicas, permeados
por um estroma escasso e celularizado (D).
Figura 5 Fluxograma da seleção da amostra do estudo. 45

Figura 6 Distribuição dos carcinomas espinocelulares de lábio, cavidade oral e 46
orofaringe diagnosticados entre 2010 e 2015 segundo os 17
Departamentos Regionais de Saúde do Estado de São Paulo.
Figura 7 Sobrevida global em cinco anos de 10.659 pacientes com carcinoma 47

espinocelular de lábio, cavidade oral e orofaringe diagnosticados no
Estado de São Paulo, 2010-2015, por localização do tumor.
Figura Curvas de sobrevida de Kaplan-Meier de pacientes diagnosticados com 50

suplementar 1 carcinoma espinocelular de lábio no Estado de São Paulo, 2010-2015,
por período de diagnóstico (A), sexo (B), faixa etária (C) e nível de
escolaridade (D).

suplementar 2 carcinoma espinocelular de lábio no Estado de São Paulo, 2010-2015,
por tipo de diagnóstico (A), estágio clínico (B), tempo entre o
diagnóstico e o tratamento (C) e o tratamento (D).

suplementar 3 carcinoma espinocelular de cavidade oral no Estado de São Paulo, 2010-
2015, por período de diagnóstico (A), sexo (B), faixa etária (C) e nível
de escolaridade (D).

suplementar 4 carcinoma espinocelular de cavidade oral no Estado de São Paulo, 2010-
2015, por tipo de diagnóstico (A), estágio clínico (B), tempo entre o

suplementar 5 carcinoma espinocelular de orofaringe no Estado de São Paulo, 2010-
2015, por período de diagnóstico (A), sexo (B), faixa etária (C) e nível
de escolaridade (D).
suplementar 6 carcinoma espinocelular de orofaringe no Estado de São Paulo, 2010-
2015, por tipo de diagnóstico (A), estágio clínico (B), tempo entre o
LISTA DE TABELAS
Tabela 1 Características clinicopatológicas e demográficas de 12.099 pacientes 39

com carcinoma espinocelular de lábio, cavidade oral e orofaringe
diagnosticados no Estado de São Paulo, 2010-2015.
Tabela 2 Probabilidades de sobrevivência em 5 anos em pacientes com carcinoma 41

espinocelular de lábio, cavidade oral e orofaringe diagnosticados no
Estado de São Paulo, 2010-2015.
Tabela 3 Relação das variáveis clinicopatológicas e demográficas com o risco de 43

morte em pacientes com carcinoma espinocelular de lábio, cavidade oral
e orofaringe diagnosticados no Estado de São Paulo, 2010-2015 -
regressão de Cox univariada.
Tabela 4 Relação de variáveis clinicopatológicas e demográficas com o risco de 44

morte em pacientes com carcinoma espinocelular de lábio, cavidade oral
e orofaríngeo diagnosticados no Estado de São Paulo, 2010-2015 -
modelo de regressão multivariada de Cox criado usando todas as
variáveis que alcançaram um valor p < 0,20 na análise de regressão de
Cox univariada.
Tabela Distribuição dos 12.099 pacientes com diagnóstico de carcinoma 49

suplementar 1 espinocelular de lábio, cavidade oral e orofaringe de acordo com a
localização do tumor.
SUMÁRIO
1 INTRODUÇÃO 16
1.1 Epidemiologia do carcinoma espinocelular de lábio, cavidade oral e orofaringe 16

1.2 Características clínicas e demográficas do CEC de lábio, cavidade oral e orofaringe 17
1.3 Tratamento e sobrevida do CEC de lábio, cavidade oral e orofaringe 22
2 ARTIGO: Epidemiology and survival outcomes of the lip, oral cavity, and
oropharyngeal squamous cell carcinoma in a southeast Brazilian population 23
3 CONCLUSÃO 59
REFERÊNCIAS* 60
ANEXOS 64
ANEXO 1 – Dispensa de aprovação no Comitê de Ética em Pesquisa 64

ANEXO 2 – Relatório de verificação e prevenção de plágio 65
ANEXO 3 – Comprovante de submissão do artigo 66
16
1 INTRODUÇÃO
1.1 Epidemiologia do carcinoma espinocelular de lábio, cavidade oral e orofaringe
O projeto GLOBOCAN da Agência Internacional para Pesquisa do Câncer (IARC) é

um banco de dados que reúne informações sobre a incidência e mortalidade de 36 tipos de
cânceres em 185 países (Ferlay et al. 2020). De acordo com a última edição publicada em 2021,
estimou-se cerca de 19,3 milhões de novos casos e 10 milhões de mortes no mundo em 2020
(Sung et al. 2021). Além disso, no ano de 2019, a Organização Mundial da Saúde estimou que
o câncer foi a primeira ou segunda principal causa de morte antes dos 70 anos em mais da
metade dos países analisados (World Health Organization 2020).
Desse total, estima-se que cerca de 377,713 novos casos ocorram em lábio e cavidade
oral, sendo apontado como um dos tipos de câncer mais prevalentes, estando entre os dez
principais em vários países do mundo e sendo responsável por 177,757 mortes anualmente
(Sung et al. 2021). Quanto ao câncer de orofaringe, estima-se a ocorrência de 98,412 novos
casos e 48,143 mortes e quando analisados em conjunto com o câncer de lábio e cavidade oral,
essas duas localizações compreendem a oitava posição no top 10 dos mais prevalentes,
correspondendo a 2.5% de todos os casos (Warnakulasuriya and Greenspan 2020).
Variações regionais consideráveis são observadas na incidência desses cânceres. O

câncer de lábio, por exemplo, ocorre com maior frequência em países desenvolvidos como
Austrália, Espanha, Grécia, Ucrânia e partes do Canadá (Diz et al. 2017; Warnakulasuriya and
Greenspan 2020). Por outro lado, estima-se que aproximadamente dois terços dos casos de
câncer de cavidade oral ocorram em países de baixa renda e em desenvolvimento,
principalmente nos países do sul da Ásia (Índia, Sri Lanka e Paquistão) que compreendem cerca
de metade dos casos no mundo. Partes da Europa Ocidental (por exemplo, Portugal e França),
Leste europeu (por exemplo, Hungria, Eslováquia e Eslovênia) e partes das Américas Central
(Porto Rico) e do Sul (por exemplo, Brasil e Uruguai) são outras regiões que apresentam altas
taxas de incidência para o câncer de cavidade oral (Han et al. 2016; Warnakulasuriya and
Greenspan 2020).
O câncer de orofaringe tem sido alvo de maior interesse nas últimas décadas devido à
tendência de aumento de novos casos, principalmente de tumores relacionados ao
papilomavírus humano (HPV) (Chaturvedi et al. 2013). Essa tendência é observada
principalmente em países desenvolvidos da Europa (França, por exemplo), América do Norte
17
e Austrália (Diz et al. 2017; Warnakulasuriya and Greenspan 2020). A revisão sistemática mais
recente sobre o assunto (Mariz et al. 2020) descreve que Nova Zelândia, Suécia e Dinamarca
apresentam as maiores proporções de CEC de orofaringe HPV+ do mundo (61.7-74.5%),
enquanto que as menores foram encontradas no Brasil (11.1%).
O carcinoma espinocelular (CEC) corresponde por até 90% dos tumores malignos
diagnosticados em cavidade oral e orofaringe e de acordo com Curado et al. (2016) a incidência
desses tumores na América do Sul entre os anos de 1998 e 2007 mostrou que as maiores taxas
foram encontradas no Brasil, até três vezes maior quando comparadas aos países vizinhos. O
Instituto Nacional do Câncer (INCA) estimou que cerca de 15,190 novos casos de cânceres de
lábio, cavidade oral e orofaringe tenham ocorrido no Brasil no ano de 2020, ocupando a quinta
e décima terceira posições entre todos os cânceres em homens e mulheres, respectivamente
(INCA 2019).
1.2 Características clínicas e demográficas do CEC de lábio, cavidade oral e orofaringe
Classicamente, os CECs de lábio, cavidade oral e orofaringe sempre mostraram uma alta
incidência em homens comparado a mulheres. Essa proporção já esteve em 7:1, mas, atualmente
essa relação já se mostra de 2:1 na maioria dos países. Isso se deve, em grande parte à adoção
de hábitos historicamente associados ao comportamento masculino, por parte das mulheres,
principalmente tabagismo e consumo de álcool (Warnakulasuriya and Greenspan 2020).
Contudo, os CECs de lábio e orofaringe continuam mostrando alta prevalência em homens com
proporção masculino-feminino de 4.6:1 e 6:1, respectivamente (Han et al. 2016; Schnelle et al.
2017; Kowalski et al. 2020). E curiosamente, essas duas localizações estão associadas a fatores
de risco distintos (radiação ultravioleta para o lábio e HPV para a orofaringe) do CEC de
cavidade oral (Moore et al. 1999; Gillison et al. 2019).
A incidência do CEC de lábio e cavidade oral aumenta com a idade e a maioria dos casos
acomete pacientes acima dos 50 anos (Warnakulasuriya and Greenspan 2020). Em diversos
países, incluindo o Canadá (Lubpairee et al. 2019), Uruguai (Oliveira et al. 2015), Estados
Unidos (Han et al. 2016), Japão (Fukumoto et al. 2020), México (Hernández-Guerrero et al.
2013), entre outros, a média de idade ao diagnóstico está acima dos 60 anos. Por outro lado, a
incidência de CEC de orofaringe aumentou muito em indivíduos mais jovens (inferior a 60
anos), afetados principalmente pelos tumores HPV+ (Chaturvedi et al. 2013; Mariz et al. 2020).
Estudos da Austrália (Elwood et al. 2014) e Estados Unidos da América (Dahlstrom et al. 2015),
18
por exemplo, mostraram média de idade em torno de 55 anos para pacientes afetados por CEC
de orofaringe.
A definição dos limites da cavidade oral varia entre os estudos. Alguns autores incluem
lábios nas análises, enquanto outros não (Oliveira et al. 2015). A prevalência do CEC de lábio
apresenta substanciais diferenças regionais. No Brasil, essa malignidade representou 10% de
todos os carcinomas orais (Souza et al. 2011). Nos Estados Unidos, a prevalência relatada foi
de aproximadamente 30% (Han et al. 2016), enquanto na Austrália, foi de 49% de todos os
cânceres orais (Abreu et al. 2009).
Quanto a localização, a literatura reconhece o lábio inferior como o principal sítio

acometido em pacientes diagnosticados com CEC de lábio (Abreu et al. 2009; Casal et al. 2010;
Maruccia et al. 2012; Han et al. 2016), pois o lábio superior é naturalmente mais protegido da
exposição prolongada à radiação solar (Luna-Ortiz et al. 2004). Dos tumores intraorais, a grande
maioria dos estudos de diferentes países como Brasil (Moro et al. 2018), Canadá (Lubpairee et
al. 2019), África (Asio et al. 2018), Uruguai (Oliveira et al. 2015), China (Bai et al. 2020) e
França (Jéhannin-Ligier et al. 2017) descrevem a parte móvel da língua como o sitio mais
afetado pelo CEC intraoral. Contudo, em países do sul e sudeste asiáticos como Índia (Tandon
et al. 2017; Abdulla et al. 2018), Siri Lanka (Jayasooriya et al. 2016) e outros dessas regiões
(Shrestha et al. 2020), a mucosa bucal/jugal é o sítio mais comumente afetado por esses
tumores, tradicionalmente associados ao hábito cultural dessas populações de mastigar tabaco
e seus derivados como o reconhecido sachê de Betel. Na orofaringe, o CEC HPV+ apresenta
forte predileção pela base de língua e tonsilas (Fakhry et al. 2014; Dahlstrom et al. 2015),
enquanto que o CEC HPV-, envolve mais comumente o palato mole (El-Naggar et al. 2017).
Por ser uma região de fácil acesso e visibilidade, a grande maioria dos CECs de lábio
são detectados e diagnosticados ainda nos estágios iniciais da doença (estágios I e II do
estadiamento TNM da American Joint Committee on Cancer - AJCC) (American Joint
Committee on Cancer 2017; Moro et al. 2018). No estudo de Han et al, 78.5% e 12% dos casos
foram diagnosticados ainda em estágios clínicos I e II, respectivamente (Han et al. 2016). No
Brasil, esses valores são menores – 67.3% no estágio I e 16.6% no estágio II (Biasoli et al.
2016). Contudo, o mesmo nem sempre se reproduz para os tumores da cavidade oral e
orofaringe. Pra os casos intraorais, tanto em países considerados desenvolvidos como França
(Jéhannin-Ligier et al. 2017), Alemanha (Listl et al. 2013) e Japão (Fukumoto et al. 2020)
quanto em países em desenvolvimento da África (Asio et al. 2018) e América Latina, como
19
Brasil (Curado et al. 2016) e Uruguai (Oliveira et al. 2015), a maioria dos casos são
diagnosticados em estágios avançados (estágios III e IV). Mas alguns países como Canadá
(Lubpairee et al. 2019) e China (Bai et al. 2020), esses tumores são diagnosticados mais
precocemente. Independente do país de origem, cerca de 80% dos CECs de orofaringe são
diagnosticados em estágios avançados da doença (Dahlstrom et al. 2015; Curado et al. 2016;
Kowalski et al. 2020; Schroeder et al. 2020).
Os sinais e sintomas iniciais comuns do CEC de lábio são ulceração, formação de crosta
e dor. Nos estágios avançados apresentam-se como extensas lesões ulcerativas e/ou infiltrativas
(figura 1) (Moore et al. 1999). O CEC de cavidade oral possui múltiplas formas de
apresentação. A manifestação clínica mais comum em estágios iniciais da doença é a presença
de uma lesão eritroleucoplásica (figuras 2A). Por outro lado, lesão nodular, ulceração, e fixação
dos tecidos adjacentes associada a dor são apresentações clássicas da doença em estágio
avançado (figura 2B) (Warnakulasuriya and Greenspan 2020).
O CEC de orofaringe frequentemente se apresenta em um estágio mais avançado que o

CEC de lábio e cavidade oral devido à sua capacidade de crescer sem ser detectado e sua
propensão para metástases. Devido a isso, as queixas principais mais comuns são a presença de
uma massa cervical (doença metastática) para os tumores HPV-positivos e dor de garganta e
disfagia para os tumores HPV-negativos (Chi et al. 2015). Clinicamente, o CEC de orofaringe
se desenvolve com mais frequência nas tonsilas e na base da língua, frequentemente
apresentando-se como um nódulo ulcerado, irregular, com alteração eritematosa da mucosa
(figura 3).
A classificação mais recente da AJCC publicada em 2016 – oitava edição, apresentou

mudanças significantes para o estadiamento do CEC de cavidade oral e orofaringe. A
atualização mais significativa foi a criação de um algoritmo de estadiamento separado para
câncer de orofaringe associado ao HPV de alto risco, distinguindo-o do câncer de orofaringe
associado à tabaco e etilismo crônico. Isso aconteceu, pois já é reconhecido que os tumores
HPV positivos são altamente responsivos ao tratamento e apresentam um melhor prognóstico.
A superexpressão da proteína p-16 (≥75%) é considerada um indicador robusto para a
carcinogênese mediada pelo HPV, sendo, portanto, uma fator prognóstico independente de
sobrevida para o câncer de orofaringe associado ao HPV e indicado para todos os tumores dessa
localização (Lydiatt et al. 2017). Outras alterações importantes foram realizadas nas categorias
do tamanho do tumor e envolvimento noral.
20
Figura 1. Paciente apresentando lesão nodular com superfície crostosa e endurecida à palpação
em lábio inferior esquerdo com 2 meses de evolução (A). Paciente com nódulo exofítico,
acastanhado, com bordas irregulares e limites mal definidos, endurecido à palpação, com área
ulcerada em mucosa labial esquerda com evolução de 24 meses (B).
A B
Fonte: Orocentro FOP/UNICAMP.
Figura 2. Paciente apresentando placa eritroleucoplásica em borda lateral direita de língua com
cerca de 12 meses de evolução (A). Paciente com lesão ulcerada infiltrativa, de bordas
irregulares, consistência firme à palpação e sintomatologia dolorosa em borda lateral de língua
com evolução de 8 meses (B).
A B
Figura 3. Paciente apresentando lesão ulcerada com bordas elevadas em pilar amigdaliano
esquerdo com 1 mês de evolução (A). Paciente com lesão nodular extensa, de consistência firme
e infiltrativa em base de língua com evolução de 6 meses. Os dois terços anteriores da língua
estavam endurecidos e sem movimentos.
A B

21
Figura 4. Fotomicrografias do carcinoma espinocelular de cavidade oral. Ninhos e cordões de

células neoplásicas proliferando a partir do epitélio de superfície displásico (A). Imagem em
maior aumento evidenciando a proliferação das células tumorais se destacando do epitélio de
superfície em direção ao tecido conjuntivo subjacente inflamado (B). Ninhos de células
tumorais bem diferenciadas com formação abundante de pérolas de ceratina (C). Em maior
aumento, observa-se intenso pleomorfismo celular com nucléolos evidentes e figuras de
mitoses atípicas, permeados por um estroma escasso e celularizado (D).
A B
C D
Fonte: Laboratório de Patologia Oral da FOP/UNICAMP.

22
1.3 Tratamento e sobrevida do CEC de lábio, cavidade oral e orofaringe
Os carcinomas de lábio, por serem detectados geralmente em uma fase mais precoce, são
tratados apenas por excisão cirúrgica com bom prognóstico. A sobrevida global em 5 anos para
pacientes com CEC de lábio gira em torno de 85% (Warnakulasuriya and Greenspan 2020).
Contudo, diferenças regionais e socioeconômicas também interferem nas taxas de sobrevida
dessa doença, até mesmo entre países economicamente desenvolvidos como Alemanha (Listl
et al. 2013) e Estados Unidos (Han et al. 2016), onde a sobrevida relatada foi de 86.5% e 69%,
respectivamente. No CEC de cavidade oral, os determinantes prognósticos adversos e doença
em estágio avançado, geralmente estabelece a necessidade de radioterapia e/ou quimioterapia
adjuvante ao tratamento cirúrgico (Warnakulasuriya and Greenspan 2020).
Apesar dos avanços tecnológicos nas modalidades de tratamento e diagnóstico nas

últimas décadas, as taxas de sobrevida continuam baixas para o CEC de cavidade oral (Rao et
al. 2013). Alguns países como Japão (85.8%) (Fukumoto et al. 2020) e Itália (76.8%) (Arduino
et al. 2008) apresentam resultados bem acima da média encontrada na maior parte dos outros
países. Contudo, a grande maioria reporta taxas de sobrevida em 5 anos em torno dos 50%,
como é o caso do Uruguai (58.5%) (Oliveira et al. 2015), China (54.5%) (Wang et al. 2013),
Brasil (51%) (Kowalski et al. 2020), Estados Unidos da América (49%) (Farhood et al. 2019)
e África (20.7%) (Asio et al. 2018).
A maioria dos carcinomas de orofaringe são tratados por terapia combinada de cirurgia,
radioterapia e/ou quimioterapia, pois muitos desses casos são diagnosticados em estágios
avançados da doença, necessitando, portanto, de tratamentos mais complexos quando possível
(Kowalski et al. 2020). Isso resulta, claro, em taxas de sobrevida ainda mais baixas que o CEC
de cavidade oral. Contudo, a literatura já reconhece que os pacientes com CEC de orofaringe
positivos para HPV apresentam melhor prognóstico e melhores taxas de sobrevida em 5 anos
em comparação aos casos HPV- nos Estados Unidos (72.7% vs 50.1%) (Schroeder et al. 2020),
na França (80% vs 40%) (Mirghani et al. 2019) e na América do Sul (75.6% vs 44.6%)
(Abrahão et al. 2020). O estudo de Fakhry e colaboradores descreve o status do HPV como um
preditor forte e independente de sobrevida, pois estimou que a positividade do HPV nesses
tumores reduziu em 52% as chances de óbito (Fakhry et al. 2014).
A seguir apresentaremos os resultados da nossa Dissertação na forma de artigo

científico.
23
2 ARTIGO: Epidemiology and survival outcomes of the lip, oral cavity, and
oropharyngeal squamous cell carcinoma in a southeast Brazilian population
Artigo submetido ao periódico internacional Oral Oncology (Anexo 3)
Brendo Vinícius Rodrigues Lourêdoa, DDS, Maria Paula Curadob, MD, PhD, Maria Eduarda
Pérez-de-Oliveiraa, DDS, MSc, Márcio Ajudarte Lopesa, DDS, PhD, Luiz Paulo Kowalskia,c,d,
MD, PhD, Pablo Agustin Vargasa, DDS, PhD, FRCPath
a
Oral Pathology Area, Department of Oral Diagnosis, Piracicaba Dental School, State
University of Campinas, 13414-903, Piracicaba, SP, Brazil.

b
Group of Epidemiology and Statistics on Cancer, International Research Center, A. C.
Camargo Cancer Center, 01525-001, São Paulo, SP, Brazil.

c
Department of Head and Neck Surgery and Otorhinolaryngology, A. C. Camargo Cancer
Center, 01525-001, São Paulo, SP, Brazil.

d
Department of Head and Neck Surgery, São Paulo State Cancer Institute, School of Medicine,
University of São Paulo, 01246-000, São Paulo, SP, Brazil.
Corresponding author:
Pablo Agustin Vargas, DDS, PhD, FRCPath
Department of Oral Diagnosis, Oral Pathology Area
Piracicaba Dental School, State University of Campinas (UNICAMP)
Av. Limeira, 901, Areão, 13.414-903, Piracicaba, São Paulo, Brazil
Telephone number: +55 19 21065319
Electronic address: [email protected]
Word count: 3,495 words

24
ABSTRACT
Objectives: The epidemiological and clinical profile and survival outcomes of lip, oral cavity,
and oropharyngeal squamous cell carcinoma (SCC) was studied in São Paulo State, Brazil.
Patients and methods: The clinicopathological data of patients with lip, oral cavity, and
oropharyngeal SCC were obtained from hospital cancer registries of the Fundação Oncocentro
de São Paulo, Brazil (2010–2015). Survival rates and other analyses were performed using
SPSS software. Results: The data from 12,099 patients were obtained. A clear male
predominance was observed, particularly for patients with oropharyngeal SCC (88.3%). The
average age of patients was higher for lip cases (65 ± 13.5 years) compared to other sites. The
schooling level was low for most patients, especially in lip cases (87.9%). Most of the patients
with oral cavity (71.8%) and oropharyngeal SCC (86.3%) had advanced-stage (III–IV) disease.
However, the majority of lip cases (83.3%) were at an early stage (I–II). Surgical excision was
the main treatment for lip (72%) and oral cavity SCC (23.5%), and chemoradiotherapy was the
main treatment for oropharyngeal SCC (40.2%). The 5-year overall survival (OS) for patients
with lip, oral cavity, and oropharyngeal SCC were 66.3, 30.9, and 22.6%, respectively.
Multivariate analysis revealed that the determinants of OS were different for lip, oral cavity,
and oropharyngeal SCC, except for those at the clinical stage, which was an independent
predictor for all sites. Conclusion: OS-independent determinants varied according to the
affected site. Oral cavity and oropharyngeal SCC presented worse survival rates than those for
lip SCC.
Keywords: squamous cell carcinoma of head and neck; lip neoplasms; mouth neoplasms;
oropharyngeal neoplasms; survival analysis.

25
INTRODUCTION
Oral cancer, including lip cancer, is one of the most common cancers around the world,
falling within the top ten cancers in several countries, with an estimated 377,713 new cases in
2020. When analysed together with the oropharynx, these two locations comprise
approximately 476,125 new cases, accounting for 2.5% of all cancer cases and 225,900 deaths
(177,757 deaths for oral cancer and 48,143 deaths for oropharyngeal cancer) [1,2].
In 2020, the estimated age-standardised rates of lip and oral cavity cancers were 6.0 and
2.3 per 100,000 in men and women, respectively, whereas for oropharyngeal cancer, they were
1.8 and 0.4 per 100,000 in men and women, respectively [1]. Most patients diagnosed with oral
cavity and oropharyngeal cancers report a previous history of smoking and alcohol
consumption, which are well recognised risk factors [3]. Additionally, human papillomavirus
(HPV) infection has been associated with the development of a distinct subset of head and neck
squamous cell carcinomas (SCC), particularly in the oropharynx [4], and ultraviolet radiation
from sunlight exposure for lip SCC [1].
The incidence of oral cavity and oropharyngeal SCC in South America is not
homogenous, and the highest rates are seen in Brazil, particularly for males, and are up to three-
times higher than in other South American countries [5]. The Fundação Oncocentro de São
Paulo (FOSP) is a Brazilian public database that collects data from all hospitals that perform
cancer treatment in São Paulo State, and it is updated every three months. The epidemiological
and clinical profile and survival outcomes of the lip, oral cavity, and oropharyngeal SCC were
assessed in the São Paulo State, Brazil, from a FOSP database (2010–2015).
26
PATIENTS AND METHODS
Sample
This is a retrospective cross-sectional study using secondary data. Data of patients with
histopathological diagnosis of primary lip (International Classification of Diseases for
Oncology [ICD-O-03]: C00), oral cavity (ICD-O-3: C02, C03, C04, C05 [except C05.1 and
C05.2] and C06), and oropharyngeal (ICD-O-3: C01, C05.1, C05.2, C09, and C10) cancers in
São Paulo State were obtained from hospital cancer registries (HCRs) in the FOSP database
from January 2010 to December 2015 (available at:
http://www.fosp.saude.sp.gov.br/publicacoes/downloadarquivos, accessed 15 January 2021).
The morphological codes (8051/3, 8052/3, 8070/3, 8071/3, 8072/3, 8073/3, 8074/3, 8075/3,
8076/3, 8078/3, 8082/3, 8083/3, and 8084/3) [6] used for lip, oral cavity, and oropharyngeal
SCC were considered for analysis.
Data collect
São Paulo State has 17 Heath Regional Departments (HRDs): São Paulo, Araçatuba,
Araraquara, Baixada Santista, Barretos, Bauru, Campinas, Franca, Marília, Piracicaba,
Presidente Prudente, Registro, Ribeirão Preto, São João da Boa Vista, São José do Rio Preto,
Sorocaba, and Taubaté. The following variables were collected: HRD, period of diagnosis,
gender, age group, schooling level, primary tumour site, previous diagnosis and treatment, type
of diagnosis, clinical stage (TNM: I-II and III-IV) [7,8], time between diagnosis and treatment,
cancer treatment, and patients’ status (alive or died).
Statistical analysis
The qualitative and quantitative data were presented descriptively, and missing values
were excluded from the analysis, with only valid percentages being considered. An association
analysis between demographic and clinicopathological variables with tumour site was
performed using the Chi-square test. All lip, oral cavity, and oropharyngeal SCC cases that
27
reported the patients’ follow-up and status were included for survival analysis. The Kaplan-
Meier method was used to estimate survival rates, and the difference between survival curves
was investigated by using the Log-Rank univariate test. The univariate Cox proportional hazard
regression model was employed to identify potential prognostic factors. A multivariate Cox
regression model was created using all variables that achieved a p-value ≤ 0.20. Data analyses
were performed with SPSS software version 22.0 (IBM Corporation, Armonk, NY, USA), and
a p-value ≤ 0.05 was considered statistically significant.
The present study assessed information from a Brazilian public database (FOSP), with
no risk of patient data disclosure; thus, ethical approval was not required (Resolution 510/16 of
the Brazilian National Health Council).
RESULTS
The data collected from 76 HCRs of the São Paulo State found a total of 368,116 cancer
cases in the period between 2010 and 2015. Of these, 12,099 patients were diagnosed with lip,
oral cavity, and oropharyngeal SCC (Figure 5). Figure 6 shows the distribution of all cases
according to the 17 HRDs in São Paulo State. The demographic and clinicopathological features
of the 12,099 cases of lip, oral cavity, and oropharyngeal SCC are summarised in Table 1.
Lip SCC
About 73.3% (n = 732) of 998 patients with lip SCC were male, with a male-to-female
ratio of 2.8:1. Regarding schooling level, most individuals (87.9%; n = 717) had less than or
equal to 8 years of formal education. The patients' ages ranged from 22 to 104 years old, with
a mean age at diagnosis of 65.0 ± 13.5 years, mainly affecting patients over 60 years (61.8%; n
= 616).
28
The most common site-affected subsite was the lower lip (79.4%; n = 793), followed by
lip, not otherwise specified (NOS; 9.5%; n = 95) and upper lip (7.5%; n = 75; Supplemental
Table 1). Most patients presented early-stage tumours (I–II) at diagnosis (83.3%; n = 810).
For most patients, the treatment was performed 60 days after diagnosis (69.5%; n =
423), with surgery being the main treatment modality (72.0%; n = 718), followed by
radiotherapy (RT) alone (7.1%; n = 71), and a combination of surgery and RT (7%; n = 69).
Approximately 5.1% (n = 51) of cases did not receive any active treatment, and the main reason
was not specified (2.8%; n = 29).
Data from 789 (78.8%) individuals with lip SCC with a median follow-up time of 52
months were available (range: 1–122 months). Survival analysis from the Kaplan-Meier
method estimated that the 5-year overall survival (OS) for lip SCC was 66.3% (Figure 7).
Based on the log-rank test (Table 2), there was a significant increase in the OS for patients
diagnosed in more recent years (58.7% in 2010–2012 to 72.7% in 2013–2015; p < 0.0001).
Oral cavity SCC
Among 5,398 individuals with oral cavity SCC (OSCC), 77.4% (n = 4,179) were male,
with a male-to-female ratio of 3.4:1. The patients’ ages ranged from 11 to 100 years old, with
a mean age of 60.3 ± 12.1 years. The most affected age group were patients over 60 years old
(46.2%; n = 2,496). For schooling level, 81.0% (n = 3,195) of patients had less than or equal to
8 years of formal education.
The mobile tongue comprised 42.5% (n = 2,298) of cases, followed by the floor of the
mouth (22.2%; n = 1,200), mouth NOS (10.9%; n = 590), retromolar trigone (7.9%; n = 429),
and hard palate (7.1%; n = 383; Supplemental Table 1). At diagnosis, 71.8% (n = 3,743) of
patients were diagnosed with stages III/IV.

29
Approximately 60.9% (n = 2,605) of patients received treatment in the period of more
than 60 days after diagnosis. Proportionally, surgery alone was the main treatment employed,
being used in 23.5% (n = 1,270) of cases, followed by chemoradiotherapy (CT; 19.3%; n =
1,040), and a combination of surgery, RT, and CT (15.4%; n = 833). About 7.9% (n = 423) of
individuals did not receive any treatment, and the main described reasons were that the patient
died of disease before commencing treatment (3.1%; n = 172) or had advanced untreatable
disease (1.8%; n = 98).
Of those evaluated, 4,759 (88.2%%) had a median follow-up time of 19 months (range:
1–122 months). The OS rate for OSCC was 30.9% in the 5 years after diagnosis (Figure 7).
However, an improvement was observed in the overall survival for patients diagnosed in the
more recent years of study (25.1% in 2010–2012 to 35.8% in 2013–2015; p < 0.0001; Table 2).
Oropharyngeal SCC
Of the 5,703 patients with oropharyngeal SCC (OPSCC), 88.3% (n = 5,035) were male,
with a male-to-female ratio of 7.5:1. The patients' ages ranged from 20 to 99 years old, with a
mean age of 58.6 ± 10 years at diagnosis, with the most cases occurring in the sixth decade of
life (40.6%; n = 2,317). Based on schooling level, 81.5% (n = 3,349) of patients had less than
or equal to 8 years of formal education.
Most cases did not report the exact location of the tumour (oropharynx, NOS; 30.5%; n
= 1,741; Supplemental Table 1). The base of the tongue (30%; n = 1,711), tonsils (18.7%; n =
1,067), soft palate (11.4%; n = 650), and lateral oropharyngeal wall (3.2%; n = 180) were the
most affected sites of the oropharynx. Most of the tumours (86.3%) were at an advanced clinical
stage (III–IV).
In most cases, the treatment was performed 60 days after diagnosis (54%; n = 2,506),
and chemoradiotherapy was the main treatment (40.2%; n = 2,290), followed by a combination
30
of surgery, RT, and CT (11.4%; n = 649), and RT alone (10.2%; n = 579). Approximately 10%
(n = 572) of individuals did not receive any active treatment, and the main reasons reported
were that the patient died of disease before commencing treatment 4.4% (n = 258) or had an
advanced untreatable tumour 2.6% (n = 149).
For survival analysis, 5,114 (89.7%) patients with a median follow-up time of 15 months
were considered (range: 1–120 months). Five-year OS for OPSCC was 22.6% (Figure 7), with
a slight increase observed from 2013 to 2015, compared with the period of 2010 to 2012 (27.7%
vs 20.2%, respectively; p < 0.0001; Table 2).
The results showed a significant association between all demographical and
clinicopathological variables, except period of diagnosis and tumour site (Table 1). The
proportion of patients lost to follow-up was 21.2, 11.8, and 10.3% for lip SCC, OSCC, and
OPSCC, respectively.
For lip SCC, the multivariate analysis model (Table 4) revealed that patients aged over
60 years (hazard ratio (HR): 2.45; 95% CI, 1.33–4.52), advanced-stage disease (HR: 1.97; 95%
CI, 1.32–2.95), patients treated by chemoradiation (HR: 4.56; 95% CI, 2.15–9.67), and other
treatments such as RT alone, CT alone, and other combinations (HR: 2.90; 95% CI, 2.06–4.08)
were associated with a higher mortality hazard. For patients with OSCC, mortality hazards were
significantly higher among male patients (HR: 1.20; 95% CI, 1.05–1.38), in those over 60 years
old (1.25; 95% CI, 1.09–1.45), with time between diagnosis and treatment over 60 days (HR:
1.27; 95% CI, 1.14–1.41), in those with advanced-stage tumours (HR: 2.19; 95% CI, 1.88–
2.55), and in patients treated by chemoradiation (HR: 1.62; 95% CI, 1.37–1.91) and other
treatments (HR: 2.21; 95% CI, 1.88–2.61).
In OPSCC (Table 4), an increase in mortality hazard was observed for patients
diagnosed between 2010–2012 (HR: 1.13; 95% CI, 1.01–1.26), in male individuals (HR: 1.45;
31
95% CI, 1.23–1.71), those with diagnosis from SUS (HR: 2.45; 95% CI, 1.66–3.62), those with
time between diagnosis and treatment over 60 days (HR: 1.19; 95% CI, 1.08–1.31), those with
advanced stage cancer (HR: 2.51; 95% CI, 2.09–3.00), and patients treated by other treatments
(HR: 1.42; 95% CI, 1.15–1.75).
DISCUSSION
Lip, oral cavity, and oropharyngeal cancers represent a major health problem in the
global scenario, and together, comprise the eighth most common malignancy worldwide [2].
Brazil has the highest incidence of oral cavity and oropharyngeal cancer in South America, and
over 90% of cases are represented by the SCC [5].
Data retrieved from the FOSP showed that lip SCC, OSCC, and OPSCC accounted for
8.3 (n = 998), 44.6 (n = 5,398), and 47.1% (n = 5,705) of the cases evaluated, respectively, in
2010–2015. Among them, there was marked male predominance at the three sites, especially in
the oropharynx, in accordance with the available literature [3,9–14].
Lip SCC and OSCC mainly occurred in older people. The average age at the time of
diagnosis was approximately 65 ± 13.5 years and 60.3 ± 12.1 years in the present study,
respectively, which corroborates previous studies performed in Italy [14], Mexico [15], and the
United States (US) [16] for lip SCC and Brazil [11], Japan [17], and Australia [18] for OSCC.
In contrast, the mean age at diagnosis was lowest for OPSCC (58.6 ± 10 years), with the
prevalence peaking in the sixth decade of life. Similar findings were reported by other studies
[10,19], in which the average age was lower compared to lip SCC and OSCC, mainly in the
cases of HPV-driven OPSCC, where the mean age was usually less than 60 years [20,21].
However, the FOSP database did not report the HPV status in the recorded OPSCC cases.
Oral cancer is related to socioeconomic status and deprivation, with the highest
incidence rates occurring in the most disadvantaged population groups [2]. Moro et al. [3],
32
Oliveira et al. [22], and Asio et al. [23] reported a marked association between lip
SCC/OSCC/OPSCC and the low schooling level of patients. Similarly, 81.9% of all patients in
the present study had up to 8 years of formal education. Nevertheless, studies from developed
countries, such as the US [20] and Australia [12], reported higher educational levels in these
patients.
The definition of the limits of the oral cavity varies between studies. Some authors
include lips [3,15,23], whereas others do not [11,22]. Due to this controversy, the lip and oral
cavity were classified as different sites in this study. Lip SCC accounted for approximately one-
third of OSCC cases [16]. When lip SCC was exclusively analysed, previous studies reported
that the lower lip was the most commonly affected site [14,16,24], similar to our findings. In
the oral cavity, according to previous reports [3,9,15,23] and our results, the tongue (excluding
the base of the tongue) was the most commonly affected subsite. However, in India and
surrounding countries, the most frequent subsite of OSCC was the buccal mucosa, as a
repercussion of the habit of chewing tobacco [25]. However, Elwood et al. [19] and Dahlstrom
et al. [20] reported that the most common subsite for OPSCC were tonsils, which is in contrast
with the present study, where the base of the tongue was the most common subsite.
In general, the lip region is more accessible, facilitating early cancer detection and
diagnosis [3]. Previous studies performed in the US [16] and Serbia [24] reported that most lip
SCC cases were in the early stage (I–II) at diagnosis, with few patients presenting regional and
distant metastasis. In contrast, Fukumoto et al. [17], Oliveira et al. [22], and Listl et al. [26]
described that the diagnosis of OSCC was usually delayed, allowing for local extension and
regional metastasis; consequently, most cases were advanced-stage disease (III–IV). Schroeder
et al. [21] and Kowalski et al. [11] observed that more than 70% of OPSCC patients were at
stages III–IV. In agreement, these observations were consistent with our findings for the three
sites.
33
Due to the early stages at the time of diagnosis, surgical resection with wide local
excision was the main choice of treatment for lip SCC [16,24]. Likewise, in our sample, 72%
of lip SCC cases were treated with surgery alone. Although most cases were in the advanced
stage, surgery alone was the most frequently employed treatment for OSCC cases in our sample,
which corroborates previous reports [11,17,27]. Nevertheless, in the studies performed by Asio
et al. [23] and Oliveira et al. [22], RT alone was the most used treatment in OSCC cases. The
oropharynx is not easy to access, and OPSCC usually presents as an advanced disease.
Chemoradiotherapy was the main choice of treatment, being employed in approximately 40.2%
of our cases, and confirming previous reports from Brazil [11] and another from the United
Kingdom [21].
It is important to emphasise that lip SCC exhibited a better survival curve in our study,
with a 5-year OS rate of 66.3%, which agreed with reports in the US [16] and Germany [26]
that showed 5-year OS rates of 69.9 and 86.5%, respectively. Although advances in cancer
treatments have occurred in recent decades, OSCC and OPSCC are still considered cancers with
poor prognosis, presenting lower survival rates when compared to lip SCC. The SEER database
analysis by Farhood et al. [28] demonstrated an OS rate of 49% at 5 years after the initial
diagnosis for OSCC. A study conducted in Northeast China [29] found that the 5-year OS rate
was slightly better than the report from the US, at 54.5%. The worst outcomes were reported in
southern Taiwan [30] and Uganda [23], in which the 5-year OS rates were 36.1 and 20.7%,
respectively. Similarly, a 5-year OS rate of 30.9% for OSCC was observed in the current study.
Tumours located in the oropharynx present worse survival rates, especially in HPV-
negative cases [3]. OPSCC showed a lower 5-year OS (22.6%) between the three sites analysed
in the sample. Similarly, Kowalski et al. [11] and Miller et al. [31] reported 5-year OS of 45
and 29.6%, respectively. A study conducted by Fakhry et al. [32] concluded that when
compared to p16-negative OPSCC patients, p16-positive OPSCC patients had an estimated

34
52% reduction in risk of death being associated with better OS rates [21]. Similarly, Abrahão
et al. [33] found that 3-year OS rates were 44.6% and 75.6% for p16-negative OPSCC and p16-
positive OPSCC, respectively, and concluded that HPV status was an important prognosis
predictor of OS (HR: 3.35; 95% CI, 1.33–8.45).
Male sex was an independent predictor of OS in the multivariate analysis for OSCC
(HR: 1.20; 95% CI, 1.05–1.38) and OPSCC (HR: 1.45; 95% CI, 1.23–1.71). These findings
were consistent with a study that collected data from four countries in South America, in which
male patients with OPSCC (HR: 1.84; 95% CI, 1.08–3.14) [33] presented higher mortality rates
than females. Nevertheless, Farhood et al. [28] (HR: 0.98; 95% CI, 0.93–1.04) and Kowalski et
al. [11] (HR: 1.14; 95% CI, 0.86–1.51) did not observe an increase in mortality hazard for male
patients with OSCC. In contrast, this study showed that the increasing age for patients with lip
SCC (> 60 years—HR: 2.45; 95% CI, 1.33–4.52) and OSCC (> 60 years—HR: 1.25; 95% CI,
1.09–1.45) was associated with low OS rates, which corroborates the findings by Han et al. [16]
(HR, 1.07; 95% CI, 1.07–1.08) for lip SCC and Abrahão et al. [33] (HR: 1.82; 95% CI, 1.18–
2.78) for OSCC. Individuals diagnosed with lip SCC (HR: 1.97; 95% CI, 1.32–2.95), OSCC
(HR: 2.19; 95% CI, 1.88–2.55), and OPSCC (HR: 2.51; 95% CI, 2.09–3.00) with advanced-
stage (stages III–IV) tumours were more likely to die than patients with early-stage disease,
which was an important independent determinant of OS, corroborating the findings reported in
earlier studies [9,11,16,23,28]. The meta-analysis performed by Seoane et al. [34] reported that
diagnostic delay was moderately related to mortality hazard for patients with head and neck
cancer.
Pathology laboratories provide cancer diagnostic services and key prognostic factors
that guide patient treatment decisions [35]. In Brazil, the university oral pathology laboratories
performed an important role in oral cancer diagnosis and the national public health system
(SUS) [36]. In our study, patients with OPSCC diagnosed by public laboratories/hospitals
35
(SUS) presented higher mortality rates (HR: 2.45; 95% CI, 1.66–3.62). Furthermore, the delay
between diagnosis and the start of treatment at over 60 days was associated with a low mortality
hazard for OSCC (HR: 1.27; 95% CI, 1.14–1.41) and OPSCC (HD: 1.19; 95% CI, 1.08–1.31)
patients. In Australia [18], the median time between diagnosis and treatment was 30 days for
OSCC, and in Brazil, the median time was up to 3-times higher [37], which was similar to our
findings (75 days). Finally, according to Felippu et al. [37], this delay was associated with
factors such as the low intellectual and social status of most patients, as well as the shortcomings
of the public health care system.
Patients treated with surgery alone presented higher survival rates compared to patients
treated with combinations of RT and CT. Fukumoto et al. [17], Bai et al. [9], and Farhood et al.
[28] found similar results. However, the treatment must be done carefully, as advanced-stage
disease usually requires more complex treatments with the use of RT and/or CT. Furthermore,
the protocols used and the patient's collaboration can also influence the choice of treatment.
CONCLUSION
Based on this robust analysis of 12,099 cases of lip SCC, OSCC, and OPSCC derived
from the FOSP database, this report highlights a marked male predominance, mainly affecting
patients over 60 years old and with less than or equal to 8 years of education, presenting as an
advanced-stage (stages III–IV) disease. The independent prognostic factors varied according to
tumour site in multivariate analysis, except for tumour stage, which was a significant
determinant of survival for all three sites. In addition, OSCC and OPSCC presented worse 5-
year OS rates, whereas lip SCC had a high OS rate. However, an improvement in OS was
observed for patients diagnosed in the more recent years of study (2013–2015).
36
REFERENCES
[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global
cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36
cancers in 185 countries. CA Cancer J Clin 2021;71:209–49.
https://doi.org/10.3322/caac.21660.
[2] Warnakulasuriya S, Greenspan JS. Textbook of Oral Cancer: Prevention, Diagnosis and
Management. 2020.
[3] Moro J da S, Maroneze MC, Ardenghi TM, Barin LM, Danesi CC. Oral and
oropharyngeal cancer: epidemiology and survival analysis. Einstein (Sao Paulo) 2018;16:1–5.
https://doi.org/10.1590/S1679-45082018AO4248.
[4] Gillison ML, Akagi K, Xiao W, Jiang B, Pickard RKL, Li J, et al. Human papillomavirus
and the landscape of secondary genetic alterations in oral cancers. Genome Res 2019;29:1–17.
https://doi.org/10.1101/gr.241141.118.
[5] Curado MP, Johnson NW, Kerr AR, Silva DRM e, Lanfranchi H, Pereira DL, et al. Oral
and oropharynx cancer in South America. Transl Res Oral Oncol 2016;1:1–7.
https://doi.org/10.1177/2057178x16653761.
[6] WHO Library Cataloguing-in-Publication Data. International Classification of Diseases
for Oncology (ICD-O). 3rd ed. Geneva: World Health Organization; 2013.
https://doi.org/10.32388/5xg1qe.
[7] INTERNATIONAL UNION AGAINST CANCER. TNM classification of malignant
tumours. 7th ed. Chichester: Wiley-Blackwell; 2010.
[8] Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Instituto Câncer de Cãncer.
TNM: Classificação de Tumores Malignos. 6th ed. Rio de Janeiro: INCA; 2004.
37
[9] Bai X, Zhang J, Wei L. Analysis of primary oral and oropharyngeal squamous cell
carcinoma in inhabitants of Beijing , China — a 10-year continuous single-center study. BMC
Oral Health 2020;20:1–7. https://doi.org/10.1186/s12903-020-01192-6.
[10] Ghazawi FM, Lu J, Savin E, Zubarev A, Chauvin P, Sasseville D, et al. Epidemiology
and Patient Distribution of Oral Cavity and Oropharyngeal SCC in Canada. J Cutan Med Surg
2020;24:340–9. https://doi.org/10.1177/1203475420915448.
[11] Kowalski LP, de Oliveira MM, Lopez RVM, E Silva DRM, Ikeda MK, Curado MP.
Survival trends of patients with oral and oropha-ryngeal cancer treated at a cancer center in são
paulo, Brazil. Clinics 2020;75:1–8. https://doi.org/10.6061/clinics/2020/e1507.
[12] Schnelle C, Whiteman DC, Porceddu S V, Panizza BJ, Antonsson A. Past sexual
behaviors and risks of oropharyngeal squamous cell carcinoma: a case–case comparison. Int J
Cancer 2017;140:1027–34. https://doi.org/10.1002/ijc.30519.
[13] Osazuwa-Peters N, Simpson MC, Massa ST, Adjei Boakye E, Antisdel JL, Varvares
MA. 40-year incidence trends for oropharyngeal squamous cell carcinoma in the United States.
Oral Oncol 2017;74:90–7. https://doi.org/10.1016/j.oraloncology.2017.09.015.
[14] Maruccia M, Onesti MG, Parisi P, Cigna E, Troccola A, Scuderi N. Lip cancer: A 10-
year retrospective epidemiological study. Anticancer Res 2012;32:1543–6.
[15] Hernández-Guerrero J, Jacinto-Alemán L, Jiménez-Farfán M, Macario-Hernández, A
Hernández-Flores F, Alcántara-Vázquez A. Prevalence trends of oral squamous cell carcinoma.
Mexico City’s General Hospital experience 2013;18:306–11.
https://doi.org/10.4317/medoral.18043.
[16] Han AY, Kuan EC, Clair JMS, Alonso JE, Arshi A, St John MA. Epidemiology of
squamous cell carcinoma of the lip in the United States a population-based cohort analysis.
38
JAMA Otolaryngol - Head Neck Surg 2016;142:1216–23.
https://doi.org/10.1001/jamaoto.2016.3455.
[17] Fukumoto C, Ogisawa S, Tani M, Hyodo T, Kamimura R, Sawatani Y, et al. Clinical
characteristics, treatment methods and prognoses of patients with oral squamous cell carcinoma
in Japanese population: a single institution retrospective cohort study. BMC Geriatr 2020;20:1–
10. https://doi.org/10.1186/s12877-020-01902-3.
[18] Kaing L, Manchella S, Love C, Nastri A, Wiesenfeld D. Referral patterns for oral
squamous cell carcinoma in Australia : 20 years progress. Aust Dent J 2016;61:29–34.
https://doi.org/10.1111/adj.12314.
[19] Elwood JM, Youlden DR, Chelimo C, Ioannides SJ, Baade PD. Comparison of
oropharyngeal and oral cavity squamous cell cancer incidence and trends in New Zealand and
Queensland, Australia. Cancer Epidemiol 2014;38:16–21.
https://doi.org/10.1016/j.canep.2013.12.004.
[20] Dahlstrom KR, Bell D, Hanby D, Li G, Wang LE, Wei Q, et al. Socioeconomic
characteristics of patients with oropharyngeal carcinoma according to tumor HPV status,
patient smoking status, and sexual behavior. Oral Oncol 2015;51:832–8.
https://doi.org/10.1016/j.oraloncology.2015.06.005.
[21] Schroeder L, Pring M, Ingar K, Pawlita M, Leary SD, Thomas SJ, et al. HPV driven
squamous cell head and neck cancer of unknown primary is likely to be HPV driven squamous
cell oropharyngeal cancer. Oral Oncol 2020;107:1–7.
https://doi.org/10.1016/j.oraloncology.2020.104721.
39
[22] Oliveira ML, Petersen V, Carrard V, Filho M, Hugo F, Martins M. A 10-year analysis
of the oral squamous cell carcinoma profile in patients from public health centers in Uruguay
2015;29:1–8. https://doi.org/10.1590/1807-3107BOR-2015.vol29.0075.
[23] Asio J, Kamulegeya A, Banura C. Survival and associated factors among patients with
oral squamous cell carcinoma (OSCC) in Mulago hospital, Kampala, Uganda. Cancers Head
Neck 2018;3:1–10. https://doi.org/10.1186/s41199-018-0036-6.
[24] Vukadinovic M, Jezdic Z, Petrovic M, Medenica LM, Lens M. Surgical Management
of Squamous Cell Carcinoma of the Lip: Analysis of a 10-Year Experience in 223 Patients. J
Oral Maxillofac Surg 2007;65:675–9. https://doi.org/10.1016/j.joms.2006.03.054.
[25] Abdulla R, Adyanthaya S, Kini P, Mohanty V, D’Souza N, Subbannayya Y.
Clinicopathological analysis of oral squamous cell carcinoma among the younger age group in
coastal Karnataka, India: A retrospective study. J Oral Maxillofac Pathol 2018;22:180–7.
https://doi.org/10.4103/jomfp.JOMFP.
[26] Listl S, Jansen L, Stenzinger A, Freier K, Emrich K, Holleczek B, et al. Survival of
Patients with Oral Cavity Cancer in Germany. PLoS One 2013;8:1–6.
https://doi.org/10.1371/journal.pone.0053415.
[27] Lubpairee T, Poh CF, Laronde DM, Rosin MP, Zhang L, Sciences M, et al. Oral
Squamous Cell Carcinomas are Associated with Poorer Outcome with Increasing Ages. J Oncol
Res Ther 2019;3:1–19.
[28] Farhood Z, Simpson M, Ward GM, Walker RJ, Osazuwa-Peters N. Does anatomic
subsite influence oral cavity cancer mortality? A SEER database analysis. Laryngoscope
2019;129:1400–6. https://doi.org/10.1002/lary.27490.
40
[29] Wang B, Zhang S, Yue K, Wang XD. The recurrence and survival of oral squamous cell
carcinoma: A report of 275 cases. Chin J Cancer 2013;32:614–8.
https://doi.org/10.5732/cjc.012.10219.
[30] Chen YK, Huang HC, Lin LM, Lin CC. Primary oral squamous cell carcinoma: An
analysis of 703 cases in southern Taiwan. Oral Oncol 1999;35:173–9.
https://doi.org/10.1016/S1368-8375(98)00101-8.
[31] Miller CS, Henry RG, Rayens MK. Disparities in risk of and survival from
oropharyngeal squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2003;95:570–5. https://doi.org/10.1067/moe.2003.108.
[32] Fakhry C, Zhang Q, Nguyen-tan PF, Rosenthal D, El-naggar A, Garden AS, et al.
Human Papillomavirus and Overall Survival After Progression of Oropharyngeal Squamous
Cell Carcinoma 2014;32:3365–73. https://doi.org/10.1200/JCO.2014.55.1937.
[33] Abrahão R, Perdomo S, Pinto LFR, de Carvalho FN, Dias FL, de Podestá JR V., et al.
Predictors of survival after head and neck squamous cell carcinoma in South America: The
interchange study. J Glob Oncol 2020;6:486–99. https://doi.org/10.1200/GO.20.00014.
[34] Seoane J, Takkouche B, Varela-Centelles P, Tomás I, Seoane-Romero JM. Impact of
delay in diagnosis on survival to head and neck carcinomas: A systematic review with meta-
analysis. Clin Otolaryngol 2012;37:99–106. https://doi.org/10.1111/j.1749-
4486.2012.02464.x.
[35] Anglade F, Milner DA, Brock JE. Can pathology diagnostic services for cancer be
stratified and serve global health? Cancer 2020;126:2431–8.
https://doi.org/10.1002/cncr.32872.
41
[36] Abrantes TC, Bezerra KT, Silva CN, Costa LC, Cabral MG, Agostini M, et al. Oral
cancer diagnosis during the COVID-19 pandemic in an oral pathology laboratory in Rio de
Janeiro, Brazil. Oral Dis 2020:1–2. https://doi.org/10.1111/odi.13669.
[37] Felippu AWD, Freire EC, de Arruda Silva R, Guimarães AV, Dedivitis RA. Impact of
delay in the diagnosis and treatment of head and neck cancer. Braz J Otorhinolaryngol
2016;82:140–3. https://doi.org/10.1016/j.bjorl.2015.10.009.
42
Table 1. Demographical and clinicopathological features of 12,099 patients with lip, oral
cavity, and oropharyngeal squamous cell carcinoma diagnosed in São Paulo State, 2010–2015.
Lip Oral cavity Oropharynx All sites

Characteristics pa
No. (%) No. (%) No. (%) No. (%)
Total 998 (8.3) 5,398 (44.6) 5,703 (47.1) 12,099 (100.0)
Period of diagnosis 0.887
2010-2012 480 (48.1) 2,591 (48.0) 2,763 (48.4) 5,834 (48.2)
2013-2015 518 (51.9) 2,807 (52.0) 2,940 (51.6) 6,265 (51.8)
Gender <0.0001
Male 732 (73.3) 4,179 (77.4) 5,035 (88.3) 9,946 (82.2)
Female 266 (26.7) 1,219 (22.6) 668 (11.7) 2,153 (17.8)
Schooling level <0.0001
≤ 8 years 717 (87.9) 3,195 (81.0) 3,349 (81.5) 7,261 (81.9)
> 8 years 99 (12.1) 749 (19.0) 758 (18.5) 1,606 (18.1)
Age group (years) <0.0001
Mean (±SD) 65.0 (±13.5) 60.3 (±12.1) 58.6 (±10) 59.9 (±11.4)
≤ 50 141 (14.1) 1,080 (20.0) 1,158 (20.4) 2,379 (19.7)
51-60 241 (24.1) 1,822 (33.8) 2,317 (40.6) 4,380 (36.2)
> 60 616 (61.8) 2,496 (46.2) 2,228 (39.0) 5,340 (44.1)
Previous diagnosis and
<0.0001
treatment
No diagnosis and without
601 (60.2) 2,453 (45.4) 2,855 (50.1) 5,909 (48.8)
treatment
With diagnosis and without
397 (39.8) 2,945 (54.6) 2,848 (49.1) 6,190 (51.2)
treatment
Type of diagnosis <0.0001
Health insurance 38 (5.0) 359 (8.7) 274 (6.4) 671 (7.3)
Public (SUS) 716 (93.2) 3,685 (89.1) 3,893 (91.6) 8,294 (90.6)
Private 14 (1.8) 94 (2.2) 82 (2.0) 190 (2.1)
Clinical stage <0.0001
I-II 810 (83.3) 1,468 (28.2) 760 (13.7) 3,038 (25.9)
III-IV 162 (16.7) 3,743 (71.8) 4,781 (86.3) 8,686 (74.1)
Time between diagnosis and
<0.0001
treatment
Median (days) 90 75 65 70
≤ 60 days 186 (30.5) 1,673 (39.1) 2,134 (46.0) 3,993 (41.9)
> 60 days 423 (69.5) 2,605 (60.9) 2,506 (54.0) 5,534 (58.1)
Cancer treatment <0.0001
Surgery alone 718 (72.0) 1,270 (23.5) 393 (6.9) 2,381 (19.7)
Surgery + RT 69 (7.0) 769 (14.2) 260 (4.5) 1,098 (9.1)
Surgery + RT + CT 25 (2.5) 833 (15.4) 649 (11.4) 1,507 (12.5)
RT + CT 17 (1.6) 1,040 (19.3) 2,290 (40.2) 3,347 (27.7)
Othersb 118 (11.8) 1,063 (19.7) 1,539 (27.0) 2,720 (22.5)
No treatment 51 (5.1) 423 (7.9) 572 (10.0) 1,046 (8.5)
Patient’s status at last follow-up <0.0001
Alive with disease 22 (2.8) 211 (4.5) 209 (4.2) 442 (4.2)
Alive, NOS 454 (57.8) 1,119 (23.5) 806 (15.7) 2,379 (22.3)
Died of Disease 107 (13.6) 2,705 (56.8) 3,363 (65.7) 6,175 (57.9)
Died of the other causes, NOS 203 (25.8) 724 (15.2) 736 (14.4) 1,663 (15.6)
Abbreviations CT: chemotherapy; NOS: not otherwise specified; RT: radiotherapy; SD: standard
deviation; SUS: Brazilian national health system.
43
Missing data schooling level: 3,232 cases (26.7%); type of diagnosis: 2,944 cases (24.3%); clinical
stage: 375 cases (3.1%); time between diagnosis and treatment: 2,572 cases (21.3%); patient’s status at
last follow-up: 1,440 cases (11.9%).
a
Comparison between the three topographies (lip, oral cavity, and oropharynx) and the
clinicopathological variables.
b
Radiotherapy alone: 1,067 cases (39.2%); Chemotherapy alone: 726 cases (26.7%); Surgery +
Chemotherapy: 235 cases (8.7%); other combinations, not specified: 692 cases (25.4%).
44
Table 2. Survival probabilities after 5 years in patients with lip, oral cavity, and oropharyngeal squamous cell carcinoma diagnosed in São Paulo
State, 2010–2015.
Lip Oral cavity Oropharynx

(n=786) (n=4,759) (n=5,114)
Variables Deaths/Total 5-year Estimative Deaths/Total 5-year Estimative Deaths/Total 5-year Estimative p-value
survival (95% CI) survival (95% CI) survival (95% CI)
(%) (%) (%)
Overall 310/786 66.3 80.2 (76.5-83.8) 3,429/4,759 30.9 43.1 (41.7-44.4) 4,099/5,114 22.6 33.4 (32.2-34.6) <0.0001
Period <0.0001
2010-2012 188/361 58.7 75.6 (70.8-80.5) 1,761/2,197 25.1 40.0 (38.2-41.9) 2,029/2,418 20.2 30.2 (28.7-31.7)
2013-2015 122/425 72.7 65.5 (62.5-68.4) 1,668/2,562 35.8 37.9 (36.5-39.3) 1,976/2,696 27.7 30.9 (29.7-32.1)
Gender <0.0001
Male 222/575 66.8 81.6 (77.4-85.7) 2,773/3,725 28.7 41.0 (39.5-42.5) 3,696/4,529 21.2 31.9 (30.8-33.1)
Female 88/211 64.9 78.1 (71.6-84.5) 656/1,034 38.7 50.8 (47.6-54.0) 403/585 32.8 44.2 (40.2-48.3)
Age group
≤ 50 years 18/103 84.5 98.4 (91.5-105.4) 643/926 33.4 46.6 (43.5-49.8) 795/1019 23.7 35.6 (33.0-38.2) <0.0001
51-60 years 49/182 78.6 89.9 (83.7-96.0) 1,144/1,626 32.7 45.4 (43.1-47.8) 1,650/2,096 24.1 35.4 (33.5-37.2)
> 60 years 243/501 58.1 71.2 (66.8-75.6) 1,642/2,207 28.5 39.5 (37.5-41.4) 1,654/1,999 20.3 29.8 (28.1-31.4)
Schooling level <0.0001
≤ 8 years 229/579 67.0 81.1 (77.0-485.1) 2,151/2,898 29.0 42.3 (40.6-44.0) 2,538/3,078 20.8 32.2 (30.8-33.6)
> 8years 23/75 73.3 86.1 (76.4-95.9) 393/623 39.6 51.5 (47.6-55.5) 432/613 31.8 42.4 (38.8-46.0)
Diagnosis type <0.0001
Health insurance 5/23 78.3 82.7 (62.3-103.1) 132/259 51.7 49.7 (43.8-55.6) 96/201 54.7 55.3 (47.4-63.1)
Public (SUS) 200/583 69.3 83.4 (79.2-87.5) 2,343/3,343 32.2 44.8 (43.1-46.5) 2,801/3,583 24.1 35.0 (33.6-36.4)
Private 4/10 60.0 69.7 (49.6-89.8) 17/57 73.7 75.6 (62.3-88.8) 16/34 52.9 41.6 (28.6-54.7)
Time between <0.0001
diagnosis and
treatment
≤ 60 days 57/137 56.9 70.7 (62.6-78.7) 1,100/1,461 28.1 39.5 (37.2-41.9) 1,544/1,908 21.9 32.8 (31.0-34.6)
> 60 days 121/336 68.8 83.4 (78.0-88.8) 1,624/2,355 34.0 47.4 (45.5-49.4) 1,775/2,292 25.4 37.2 (35.5-38.9)
Clinical stage <0.0001
0-II 209/635 72.4 87.1 (83.2-90.9) 580/1,186 56.0 69.5 (66.5-72.4) 386/637 45.7 56.1 (52.4-59.8)
III-IV 90/136 40.4 50.8 (43.1-58.5) 2,731/3,417 22.3 34.4 (32.9-35.8) 3,594/4,339 19.4 30.3 (29.1-31.4)
45
Treatment <0.0001
Surgery 176/573 75.2 89.3 (85.3-93.3) 534/1,032 51.8 64.6 (61.3-67.9) 209/333 42.6 48.2 (43.1-53.4)
Surgery+RT 25/56 60.7 76.4 (64.8-88-0) 370/663 49.2 63.0 (59.1-66.8) 139/228 43.9 55.9 (49.9-61.9)
Surgery+RT+CT 13/24 42.3 58.0 (42.9-73.1) 527/750 33.9 48.6 (45.3-51.9) 412/582 33.3 47.2 (43.8-50.7)
RT+CT 11/14 28.6 31.5 (15.8-47.2) 807/969 18.2 30.6 (28.4-32.9) 1,630/2,062 23.5 36.2 (34.5-38.0)
Othersa 60/85 36.5 48.7 (40.1-57.3) 835/966 15.9 26.0 (23.9-28.2) 1,223/1,414 15.8 25.1 (23.2-26.9)
No treatment 25/34 29.4 31.3 (21.2-41.4) 356/379 6.6 10.6 (8.2-13.0) 486/495 2.0 6.2 (5.1-7.2)
Abbreviations CI: confidence interval; CT: chemotherapy; RT: radiotherapy; SUS: Brazilian national health system.
a
Radiotherapy alone: 976 cases (9.1%); chemotherapy alone: 682 cases (6.4%); surgery + chemotherapy: 213 cases (1.9%); other combinations: 594 cases
(5.6%).
46
Table 3. Relationship of demographics and clinicopathological variables to the hazard of death

for patients with lip, oral cavity, and oropharyngeal squamous cell carcinoma diagnosed in São
Paulo State, 2010–2015—univariate Cox regression.
(n=786) (n=4,759) (n=5,114)
Variables HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value
Period
2010-2012 1.39 (1.10-1.77) 0.006 1.16 (1.08-1.24) <0.0001 1.19 (1.12-1.26) <.0001
2013-2015 Reference Reference Reference
Gender
Male 1.07 (0.83-1.37) 0.607 1.26 (1.15-1.37) <0.0001 1.33 (1.20-1.48) <0.0001
Female Reference Reference Reference
Age group
≤ 50 years Reference Reference Reference
51-60 years 1.59 (0.93-2.73) 0.0092 0.99 (0.91-1.10) 0.992 1.00 (0.92-1.09) 0.925
> 60 years 3.42 (2.12-5.51) <0.0001 1.18 (1.08-1.29) <0.0001 1.16 (1.06-1.26) 0.001
Schooling level
≤ 8 years 1.34 (0.87-2.06) 0.179 1.28 (1.15-1.43) <0.0001 1.33 (1.20-1.47) <0.0001
> 8 years Reference Reference Reference
Diagnosis type
Health insurance Reference Reference Reference
Public (SUS) 1.34 (0.55-3.26) 0.518 1.42 (1.19-1.70) <0.0001 2.07 (1.69-2.54) <0.0001
Private 1.29 (0.35-4.81) 0.704 0.52 (0.31-0.86) 0.010 1.23 (0.72-2.08) 0.449
Time between
diagnosis and
treatment
≤ 60 days 1.45 (1.08-1.96) 0.014 1.23 (1.14-1.33) <0.0001 1.18 (1.10-1.26) <0.0001
> 60 days Reference Reference Reference
Clinical stage
0-II Reference Reference Reference
III-IV 3.01 (2.35-3.85) <0.0001 2.56 (2.34-2.81) <0.0001 2.07 (1.86-2.30) <0.0001
Treatment
Surgery Reference Reference Reference
Surgery + RT 1.54 (1.02-2.35) 0.042 1.02 (0.89-1.16) 0.801 0.79 (0.64-0.98) 0.031
Surgery + RT + CT 2.27 (1.29-4.00) 0.004 1.42 (1.26-1.61) <0.0001 0.96 (0.83-1.15) 0.765
RT + CT 5.65 (3.06-10.43) <0.0001 2.31 (2.07-2.58) <0.0001 1.35 (1.17-1.56) <0.0001
a
Others 3.28 (2.45-4.41) <0.0001 2.84 (2.54-3.16) <0.0001 1.79 (1.86-2.51) <0.0001
No treatment 5.32 (3.49-8.12) <0.0001 7.73 (6.75-8.86) <0.0001 7.46 (6.32-8.79) <0.0001
Abbreviations CI: confidence interval; CT: chemotherapy; HR: hazard ratio; RT: radiotherapy; SUS:
Brazilian national health system.
a
Radiotherapy alone: 976 cases (9.1%); chemotherapy alone: 682 cases (6.4%); surgery +
chemotherapy: 213 cases (1.9%); other combinations: 594 cases (5.6%).
47
Table 4. Relationship of demographics and clinicopathological variables to the hazard of death

for patients with lip, oral cavity, and oropharyngeal squamous cell carcinoma diagnosed in São
Paulo State, 2010–2015—multivariate Cox regression model created using all variables that
achieved a p-value < 0.20 in univariate Cox regression analysis.
(n=786) (n=4,759) (n=5,114)
Variables HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value
Period
2010-2012 1.04 (1.20-2.67) 0.822 1.09 (0.97-1.22) 0.148 1.13 (1.01-1.26) 0.034
2013-2015 Reference Reference Reference
Gender
Male - - 1.20 (1.05-1.38) 0.010 1.45 (1.23-1.71) <0.0001
Female - - Reference Reference
Age group
≤ 50 years Reference Reference Reference
51-60 years 1.02 (0.50-2.08) 0.958 0.99 (0.86-1.15) 0.925 0.85 (0.75-0.97) 0.019
> 60 years 2.45 (1.33-4.52) 0.004 1.25 (1.09-1.45) 0.002 1.04 (0.90-1.19) 0.617
Schooling level
≤ 8 years 1.06 (0.63-1.80) 0.823 1.04 (0.90-1.21) 0.596 1.07 (0.94-1.23) 0.304
> 8 years Reference Reference Reference
Diagnosis type
Health insurance - - Reference Reference
Public (SUS) - - 1.02 (0.76-1.37) 0.893 2.45 (1.66-3.62) <0.0001
Private - - 0.85 (0.36-1.99) 0.703 1.39 (0.53-3.61) 0.502
Time between
diagnosis and
treatment
≤ 60 days 1.37 (0.98-1.91) 0.069 Reference Reference
> 60 days Reference 1.27 (1.14-1.41) <0.0001 1.19 (1.08-1.31) 0.001
Clinical stage
0-II Reference Reference Reference
III-IV 1.97 (1.32-2.95) 0.001 2.19 (1.88-2.55) <0.0001 2.51 (2.09-3.00) <0.0001
Treatment
Surgery Reference Reference Reference
Surgery+ RT 1.00 (0.60-1.65) 0.996 0.83 (0.69-1.00) .053 0.59 (0.44-0.80) 0.001
Surgery + RT + CT 1.93 (0.98-3.79) 0.057 1.05 (0.88-1.26) .572 0.65 (0.51-0.83) <0.0001
RT + CT 4.56 (2.15-9.67) <0.0001 1.62 (1.37-1.91) <0.0001 0.86 (0.70-1.06) 0.168
a
Others 2.90 (2.06-4.08) <0.0001 2.21 (1.88-2.61) <0.0001 1.42 (1.15-1.75) 0.001
No treatment 4.28 (2.49-7.35) <0.0001 6.18 (5.01-7.64) <0.0001 6.21 (4.87-7.94) <0.0001
Abbreviations CI: confidence interval; CT: chemotherapy; HR: hazard ratio; RT: radiotherapy; SUS:
Brazilian national health system.
a
Radiotherapy alone: 976 cases (9.1%); chemotherapy alone: 682 cases (6.4%); surgery +
chemotherapy: 213 cases (1.9%); other combinations: 594 cases (5.6%).
48
Figure 5. Flow diagram of selection of study sample.
a
Salivary gland cancer (480 cases); Lymphomas (230 cases); Sarcoma (47 cases); Neuroendocrine
tumour (15 cases); Malignant tumour, not otherwise specified (33 cases); other malignant tumours (28
cases).
Abbreviations ICD: International classification of diseases; OC: Oral cavity; SCC: Squamous cell
carcinoma.
49
Figure 6. Distribution of lip, oral cavity, and oropharyngeal squamous cell carcinoma diagnosed between 2010 and 2015 according to 17 Heath
Regional Departments of São Paulo State.
Missing data n=660 cases (5.5%)

50
Figure 7. Five-year overall survival of 10,659 patients with lip, oral cavity, and oropharyngeal
squamous cell carcinoma diagnosed in São Paulo State, 2010–2015, by tumour site.
51
Material Suplementar do artigo

52
Supplemental table 1. Distribution of 12,099 patients diagnosed with lip, oral cavity, and
oropharyngeal squamous cell carcinoma according to subsite tumor.
Lips Oral Cavity Oropharynx
Site N (%) Site N (%) Site N (%)
Upper lip 75 (7.5) Oral tongue 2,298 (42.5) Base of tongue 1,711 (30.0)
Lower lip 793 (79.4) Floor of the mouth 1,200 (22.2) Tonsil 1,067 (18.7)
Commissure 35 (3.6) Retromolar trigone 429 (7.9) Soft palate 650 (11.4)
Lip, NOS 95 (9.5) Hard palate 383 (7.1) Lateral wall 180 (3.2)
Gum 300 (5.6) Vallecula 116 (2.0)
Buccal mucosa 198 (3.8) Uvula 99 (1.7)
Mouth, NOS 590 (10.9) Posterior wall 76 (1.3)
Anterior face of epiglottis 63 (1.2)
Oropharynx, NOS 1,741 (30.5)
Total 998 (100) Total 5,398 (100) Total 5,703 (100)
Abbreviations NOS: not otherwise specified.
53
Supplemental figure 1. Kaplan-Meier survival curves of patients with LIP SQUAMOUS

CELL CARCINOMA diagnosed at São Paulo State, 2010-2015, by period of diagnosis (A),
gender (B), age group (C), and schooling level (D).
54
Supplemental figure 2. Kaplan-Meier survival curves of patients with LIP SQUAMOUS

CELL CARCINOMA diagnosed at São Paulo State, 2010-2015, by diagnosis type (A),
clinical stage (B), time between diagnosis and treatment (C), and treatment (D).
55
Supplemental figure 3. Kaplan-Meier survival curves of patients with ORAL CAVITY

SQUAMOUS CELL CARCINOMA diagnosed at São Paulo State, 2010-2015, by period of
diagnosis (A), gender (B), age group (C), and schooling level (D).
56
Supplemental figure 4. Kaplan-Meier survival curves of patients with ORAL CAVITY

SQUAMOUS CELL CARCINOMA diagnosed at São Paulo State, 2010-2015, by diagnosis
type (A), clinical stage (B), time between diagnosis and treatment (C), and treatment (D).
57
Supplemental figure 5. Kaplan-Meier survival curves of patients with OROPHARYNGEAL

SQUAMOUS CELL CARCINOMA diagnosed at São Paulo State, 2010-2015, by period of
diagnosis (A), gender (B), age group (C), and schooling level (D).
58
Supplemental figure 6. Kaplan-Meier survival curves of patients with OROPHARYNGEAL

SQUAMOUS CELL CARCINOMA diagnosed at São Paulo State, 2010-2015, by diagnosis
type (A), clinical stage (B), time between diagnosis and treatment (C), and treatment (D).
59
3 CONCLUSÃO
• Os CECs de lábio, cavidade oral e orofaringe tratados no estado de São Paulo entre os
anos de 2010 e 2015 acometeram preferencialmente pacientes do sexo masculino acima
dos 60 anos de idade e com baixa escolaridade;
• Mais de 90% dos pacientes obtiveram o diagnóstico de câncer através do sistema único
de saúde (SUS);
• A maioria dos pacientes com CEC de lábio apresentaram tumor em estágio inicial
(estágios I e II). Por outro lado, a maioria dos pacientes com CEC de cavidade oral e
orofaringe apresentaram doença em estágio avançado (estágios III e IV) no momento
do diagnóstico;
• A excisão cirúrgica foi o principal tratamento para os casos de CEC de lábio e cavidade
oral, e a combinação de radioterapia e quimioterapia para os casos de orofaringe;
• As maiores taxas de sobrevida foram observadas nos pacientes com CEC de lábio e as
menores nos pacientes com CEC de orofaringe. Contudo, notou-se uma melhora na
sobrevida global dos pacientes diagnosticados nos anos mais recentes do estudo (2013-
2015);
• O período do diagnóstico e o diagnóstico através do SUS foram preditores
independentes de sobrevida apenas para os pacientes com CEC de orofaringe, a idade
acima de 60 anos para CEC de lábio e cavidade oral e o sexo masculino e o tempo entre
diagnóstico e tratamento superior a 60 dias para os casos de cavidade oral e orofaringe.
O estágio clínico foi preditor independente para as três localizações e os diferentes tipos
de tratamento variaram entre as topografias;
60
REFERÊNCIAS
Abdulla R, Adyanthaya S, Kini P, Mohanty V, D’Souza N, Subbannayya Y.

Clinicopathological analysis of oral squamous cell carcinoma among the younger age
group in coastal Karnataka, India: A retrospective study. J oral Maxillofac Pathol.
2018;22(3):180–7.
Abrahão R, Perdomo S, Pinto LFR, de Carvalho FN, Dias FL, de Podestá JR V., et al.
Predictors of survival after head and neck squamous cell carcinoma in South America:
The interchange study. J Glob Oncol. 2020;6:486–99.
Abreu LPS, Kruger E, Tennant M. Lip cancer in Western Australia, 1982-2006: A 25-year
retrospective epidemiological study. Aust Dent J. 2009;54(2):130–5.
American Joint Committee on Cancer. The American Joint Committee on Cancer (AJCC)
AJCC Cancer Staging Manual. 8th ed. Springer; 2017.
Arduino PG, Carrozzo M, Chiecchio A, Broccoletti R, Tirone F, Borra E, et al. Clinical and
Histopathologic Independent Prognostic Factors in Oral Squamous Cell Carcinoma: A
Retrospective Study of 334 Cases. J Oral Maxillofac Surg. 2008;66(8):1570–9.
Asio J, Kamulegeya A, Banura C. Survival and associated factors among patients with oral
squamous cell carcinoma (OSCC) in Mulago hospital, Kampala, Uganda. Cancers Head
Neck. 2018;3(1):1–10.
Bai X, Zhang J, Wei L. Analysis of primary oral and oropharyngeal squamous cell carcinoma
in inhabitants of Beijing , China — a 10-year continuous single-center study. BMC Oral
Health. 2020;20(208):1–7.
Biasoli ÉR, Valente VB, Mantovan B, Collado FU, Neto SC, Sundefeld MLMM, et al. Lip
Cancer: A Clinicopathological Study and Treatment Outcomes in a 25-Year Experience.
J Oral Maxillofac Surg. 2016;74(7):1360–7.
Casal D, Carmo L, Melancia T, Zagalo C, Cid O, Rosa-Santos J. Lip cancer: A 5-year review
in a tertiary referral centre. J Plast Reconstr Aesthetic Surg [Internet]. 2010;63(12):2040–
5. Available from: http://dx.doi.org/10.1016/j.bjps.2009.12.022
Chaturvedi AK, Anderson WF, Lortet-tieulent J, Curado MP, Ferlay J, Franceschi S, et al.
Worldwide Trends in Incidence Rates for Oral Cavity and Oropharyngeal Cancers. J Clin
Oncol. 2013;31(36):4550–9.
Chi AC, Day TA, Neville BW. Oral cavity and oropharyngeal squamous cell carcinoma-an
update. CA Cancer J Clin. 2015;65(5):401–21.
Curado MP, Johnson NW, Kerr AR, Silva DRM e, Lanfranchi H, Pereira DL, et al. Oral and
oropharynx cancer in South America. Transl Res Oral Oncol. 2016;1(901):1–7.
Dahlstrom KR, Bell D, Hanby D, Li G, Wang LE, Wei Q, et al. Socioeconomic
characteristics of patients with oropharyngeal carcinoma according to tumor HPV status,
patient smoking status, and sexual behavior. Oral Oncol [Internet]. 2015;51(9):832–8.
Available from: http://dx.doi.org/10.1016/j.oraloncology.2015.06.005
Diz P, Meleti M, Diniz-Freitas M, Vescovi P, Warnakulasuriya S, Johnson NW, et al. Oral
and pharyngeal cancer in Europe : Incidence , mortality and trends as presented to the
Global Oral Cancer Forum. Transl Res Oral Oncol. 2017;2:1–13.
61
El-Naggar A, Takashi T, Slootweg P, Chan J, Grandis J. WHO Classification of Head and

Neck Tumours. 4th ed. Lyon: IARC; 2017.
Elwood JM, Youlden DR, Chelimo C, Ioannides SJ, Baade PD. Comparison of oropharyngeal
and oral cavity squamous cell cancer incidence and trends in New Zealand and
Queensland , Australia. Cancer Epidemiol [Internet]. 2014;38(1):16–21. Available from:
http://dx.doi.org/10.1016/j.canep.2013.12.004
Fakhry C, Zhang Q, Nguyen-tan PF, Rosenthal D, El-naggar A, Garden AS, et al. Human
Papillomavirus and Overall Survival After Progression of Oropharyngeal Squamous Cell
Carcinoma. 2014;32(30):3365–73.
Farhood Z, Simpson M, Ward GM, Walker RJ, Osazuwa-Peters N. Does anatomic subsite
influence oral cavity cancer mortality? A SEER database analysis. Laryngoscope.
2019;129(6):1400–6.
Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. Global Cancer
Observatory: Cancer Today [Internet]. International Agency for Research on Cancer.
2020 [cited 2021 Jun 18]. Available from: https://gco.iarc.fr/today
Fukumoto C, Ogisawa S, Tani M, Hyodo T, Kamimura R, Sawatani Y, et al. Clinical
characteristics, treatment methods and prognoses of patients with oral squamous cell
carcinoma in Japanese population: a single institution retrospective cohort study. BMC
Geriatr. 2020;20(1):1–10.
Gillison ML, Akagi K, Xiao W, Jiang B, Pickard RKL, Li J, et al. Human papillomavirus and
the landscape of secondary genetic alterations in oral cancers. Genome Res.
2019;29(1):1–17.
Han AY, Kuan EC, Clair JMS, Alonso JE, Arshi A, St John MA. Epidemiology of squamous
cell carcinoma of the lip in the United States a population-based cohort analysis. JAMA
Otolaryngol - Head Neck Surg. 2016;142(12):1216–23.
Hernández-Guerrero J, Jacinto-Alemán L, Jiménez-Farfán M, Macario-Hernández, A
Hernández-Flores F, Alcántara-Vázquez A. Prevalence trends of oral squamous cell
carcinoma . Mexico City ’ s General Hospital experience. 2013;18(2):306–11.
INCA. Estimativa 2020 : incidência de câncer no Brasil / Instituto Nacional de Câncer José
Alencar Gomes da Silva. Rio de Janeiro: INCA; 2019.
Jayasooriya PR, Pitakotuwage TN, Ranjit B, Nihal R. Descriptive study of 896 Oral
squamous cell carcinomas from the only University based Oral Pathology Diagnostic
Service in Sri Lanka. BMC Oral Health [Internet]. 2016;1–6. Available from:
http://dx.doi.org/10.1186/s12903-015-0139-y
Jéhannin-Ligier K, Dejardin O, Lapôtre-Ledoux B, Bara S, Coureau G, Grosclaude P, et al.
Oral cancer characteristics in France: Descriptive epidemiology for early detection. J
Stomatol Oral Maxillofac Surg. 2017;118(2):84–9.
Kowalski LP, de Oliveira MM, Lopez RVM, E Silva DRM, Ikeda MK, Curado MP. Survival
trends of patients with oral and oropha-ryngeal cancer treated at a cancer center in são
paulo, Brazil. Clinics. 2020;75(4):1–8.
Listl S, Jansen L, Stenzinger A, Freier K, Emrich K, Holleczek B, et al. Survival of Patients
with Oral Cavity Cancer in Germany. PLoS One. 2013;8(1):1–6.
62
Lubpairee T, Poh CF, Laronde DM, Rosin MP, Zhang L, Sciences M, et al. Oral Squamous
Cell Carcinomas are Associated with Poorer Outcome with Increasing Ages. J Oncol Res
Ther. 2019;3(4):1–19.
Luna-Ortiz K, Güemes-Meza A, Villavicencio-Valencia V, Mosqueda-Taylor A. Lip cancer
experience in Mexico. An 11-year retrospective study. Oral Oncol. 2004;40(10):992–9.
Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. Head and
neck cancers-major changes in the American Joint Committee on cancer eighth edition
cancer staging manual. CA Cancer J Clin. 2017;67(2):122–37.
Mariz BALA, Kowalski LP, William WN, de Castro G, Chaves ALF, Santos M, et al. Global
prevalence of human papillomavirus-driven oropharyngeal squamous cell carcinoma
following the ASCO guidelines: A systematic review and meta-analysis. Crit Rev Oncol
Hematol. 2020;156(February):103–16.
Maruccia M, Onesti MG, Parisi P, Cigna E, Troccola A, Scuderi N. Lip cancer: A 10-year
retrospective epidemiological study. Anticancer Res. 2012;32(4):1543–6.
Mirghani H, Bellera C, Delaye J, Dolivet G, Fakhry N, Bozec A, et al. Prevalence and
characteristics of HPV-driven oropharyngeal cancer in France. Cancer Epidemiol
[Internet]. 2019;61(January):89–94. Available from:
https://doi.org/10.1016/j.canep.2019.05.007
Moore SR, Johnson NW, Pierce AM, Wilson DF. The epidemiology of lip cancer: A review
of global incidence and aetiology. Oral Dis. 1999;5:185–95.
Moro J da S, Maroneze MC, Ardenghi TM, Barin LM, Danesi CC. Oral and oropharyngeal
cancer: epidemiology and survival analysis. Einstein (Sao Paulo). 2018;16(2):1–5.
Oliveira ML, Petersen V, Carrard V, Filho M, Hugo F, Martins M. A 10-year analysis of the
oral squamous cell carcinoma profile in patients from public health centers in Uruguay.
2015;29(1):1–8.
Rao K, Mejia G, Roberts-thomson K. Epidemiology of Oral Cancer in Asia in the Past
Decade- An Update ( 2000-2012 ). Asian Pacific J Cancer Prev. 2013;14(10):5567–77.
Schnelle C, Whiteman DC, Porceddu S V, Panizza BJ, Antonsson A. Past sexual behaviors
and risks of oropharyngeal squamous cell carcinoma: a case–case comparison. Int J
cancer. 2017;140:1027–34.
Schroeder L, Pring M, Ingar K, Pawlita M, Leary SD, Thomas SJ, et al. HPV driven
squamous cell head and neck cancer of unknown primary is likely to be HPV driven
squamous cell oropharyngeal cancer. Oral Oncol. 2020;107:1–7.
Shrestha AD, Vedsted P, Kallestrup P, Neupane D. Prevalence and incidence of oral cancer in
low- and middle-income countries: A scoping review. Eur J Cancer Care (Engl).
2020;29(2):1–7.
Souza LR, Fonseca-Fonseca T, Oliveira-Santos CC, Corrêa GTB tista, Santos FBG, Cardoso
CM, et al. Lip squamous cell carcinoma in a Brazilian population: Epidemiological study
and clinicopathological associations. Med Oral Patol Oral Cir Bucal. 2011;16(6):757–62.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer
statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36
cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
63
Tandon A, Bordoloi B, Rohit J, Srivastava A, Singh RB, Shafique U. Demographic and

clinicopathological profile of oral squamous cell carcinoma patients of North India: A
retrospective institutional study. J Res Dent Sci. 2017;8(1):1–4.
Wang B, Zhang S, Yue K, Wang XD. The recurrence and survival of oral squamous cell
carcinoma: A report of 275 cases. Chin J Cancer. 2013;32(11):614–8.
Warnakulasuriya S, Greenspan JS. Textbook of Oral Cancer: Prevention, Diagnosis and
Management. 2020.
World Health Organization. Global Health Estimates 2020: Deaths by Cause, Age, Sex, by
Country and by Region, 2000-2019 [Internet]. WHO. 2020 [cited 2021 Jun 18].
Available from: https://www.who.int/data/gho/data/themes/mortality-and-global-health-
estimates/ghe-leading-causes-of-death
64
ANEXOS
ANEXO 1 – Dispensa de aprovação no Comitê de Ética em Pesquisa

65
ANEXO 2 – Relatório de verificação e prevenção de plágio

66
ANEXO 3 – Comprovante de submissão do artigo

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UNIVERSIDADE ESTADUAL DE CAMPINAS

FACULDADE DE ODONTOLOGIA DE PIRACICABA

BRENDO VINICIUS RODRIGUES LOURÊDO

EPIDEMIOLOGIA E SOBREVIDA DE PACIENTES COM

EPIDEMIOLOGY AND SURVIVAL OF PATIENTS WITH LIP, ORAL

EPIDEMIOLOGIA E SOBREVIDA DE PACIENTES COM

EPIDEMIOLOGY AND SURVIVAL OF PATIENTS WITH LIP, ORAL

Dissertação apresentada à Faculdade de

Orientador: Prof. Dr. Pablo Agustin Vargas

Coorientadora: Dra. Maria Paula Curado

Lourêdo, Brendo Vinicius Rodrigues, 1993-

Orientador: Pablo Agustin Vargas.

1. Carcinoma de células escamosas. 2. Lábios. 3. Boca. 4. Orofaringe. 5.

Informações para Biblioteca Digital

Identificação e informações acadêmicas do(a) aluno(a)

A Comissão Julgadora dos trabalhos de Defesa de Dissertação de Mestrado, em sessão

PROFª. DRª. MARIA PAULA CURADO

PROFª. DRª. CÉLIA MARIA PAÍS VIEGAS

PROFª. DRª. VIVIAN PETERSEN WAGNER

A Ata da defesa, assinada pelos membros da Comissão Examinadora, consta no

Dedico este trabalho à minha pequena e amada irmã

Isadora Helena Rodrigues Louredo,

por compreender minha ausência nos últimos anos.

O presente trabalho foi realizado com apoio da Coordenação de Aperfeiçoamento de Pessoal

À Faculdade de Odontologia de Piracicaba da Universidade Estadual de Campinas, na pessoa

Ao Prof. Dr. Pablo Agustin Vargas, coordenador do Programa de Pós-Graduação em

O câncer de cabeça e pescoço é um problema crescente de saúde pública, afetando homens e

Palavras-chave: Carcinoma de Células Escamosas; Lábio; Cavidade oral; Orofaringe;

Figura 1 Paciente apresentando lesão nodular com superfície crostosa e 18

Figura 2 Paciente apresentando placa eritroleucoplásica em borda lateral direita 18

Figura 3 Paciente apresentando lesão ulcerada com bordas elevadas em pilar 18

Figura 4 Fotomicrografias do carcinoma espinocelular de cavidade oral. Ninhos 19

Figura 5 Fluxograma da seleção da amostra do estudo. 45

Figura 7 Sobrevida global em cinco anos de 10.659 pacientes com carcinoma 47

Figura Curvas de sobrevida de Kaplan-Meier de pacientes diagnosticados com 50

Figura Curvas de sobrevida de Kaplan-Meier de pacientes diagnosticados com 51

Figura Curvas de sobrevida de Kaplan-Meier de pacientes diagnosticados com 52

Figura Curvas de sobrevida de Kaplan-Meier de pacientes diagnosticados com 53

Figura Curvas de sobrevida de Kaplan-Meier de pacientes diagnosticados com 54

Tabela 1 Características clinicopatológicas e demográficas de 12.099 pacientes 39

Tabela 2 Probabilidades de sobrevivência em 5 anos em pacientes com carcinoma 41

Tabela 3 Relação das variáveis clinicopatológicas e demográficas com o risco de 43

Tabela 4 Relação de variáveis clinicopatológicas e demográficas com o risco de 44

Tabela Distribuição dos 12.099 pacientes com diagnóstico de carcinoma 49

1.1 Epidemiologia do carcinoma espinocelular de lábio, cavidade oral e orofaringe 16

oropharyngeal squamous cell carcinoma in a southeast Brazilian population 23

ANEXO 1 – Dispensa de aprovação no Comitê de Ética em Pesquisa 64

1.1 Epidemiologia do carcinoma espinocelular de lábio, cavidade oral e orofaringe

O projeto GLOBOCAN da Agência Internacional para Pesquisa do Câncer (IARC) é

Variações regionais consideráveis são observadas na incidência desses cânceres. O

1.2 Características clínicas e demográficas do CEC de lábio, cavidade oral e orofaringe

Quanto a localização, a literatura reconhece o lábio inferior como o principal sítio

O CEC de orofaringe frequentemente se apresenta em um estágio mais avançado que o

A classificação mais recente da AJCC publicada em 2016 – oitava edição, apresentou

Fonte: Orocentro FOP/UNICAMP.

Fonte: Orocentro FOP/UNICAMP.

Fonte: Orocentro FOP/UNICAMP.

Figura 4. Fotomicrografias do carcinoma espinocelular de cavidade oral. Ninhos e cordões de

Fonte: Laboratório de Patologia Oral da FOP/UNICAMP.

1.3 Tratamento e sobrevida do CEC de lábio, cavidade oral e orofaringe