Carlos Eduardo Xavier dos Santos Ribeiro da Silva *
Artur Cerri **
Francisco Octávio Teixeira Pacca ***
Ricardo Jahn ****

* Department of ENT/Head and Neck Surgery, UNIFESP, Sao Paulo, Brazil
   Department of Oral Medicine, UNISA, Santo Amaro University, Sao Paulo, Brazil
** Department of Oral Medicine, Santo Amaro University, UNISA, Sao Paulo, Brazil
*** Department of Oral Medicine, Santo Amaro University, UNISA, Sao Paulo, Brazil
**** Department of Periodontology, Santo Amaro University, UNISA, Sao Paulo, Brazil

Send all correspondence to Dr. Carlos Eduardo X. S. Ribeiro da Silva, Rua Pelotas, 358 – Vila Mariana, 04012-001, Sao Paulo,SP, Brazil Voice /Fax : 55 11 5571-1736
Email adress: dreduardosilva@terra.com.br

Case Report: Keratosis palmoplantaris associated to periodontal disease (Papillon-Lefévre Syndrome)

ABSTRACT

This report describes a rare case of a 16 years old girl with keratosis palmoplantaris associated to periodontopathy or Papillon-Lefèvre syndrome. The patient went to Santo Amaro University – Dental College for dental treatment. This report presents the medical and stomatological progression, and suggest how to treat this condition. This syndrome requires a multidisciplinary team for treatment and control and the prognosis is still poor.

KEYWORDS

Papillon-Lefèvre Disease – Hyperkeratosis palmoplantaris – periodontal disease

INTRODUCTION AND LITERATURE REVIEW

The Papillon-Lefèvre syndrome or keratosis palmoplantaris associated to periodontopathy was first described by Papillon-Lefèvre, in 1924. It is an autosomal recessive genetic disease, with alteration in the gene CTSC, located in chromosome 11q14.1-q14.4, more precisely in the protein called cathepsin C (Hart et al., 2000; Shafer et al., 1987; Neville et al., 2001; Tommasi, 2002; Allende & Moreno, 2003; Hewitt et al., 2004; Selvaraju et al., 2003 )

It affects children and young adults of both sexes with no distinction. It is a very rare disease, with a prevalence of one in one million individuals. Its main oral clinical characteristics include periodontopathies, premature loss of deciduous teeth, at the age of 4-5 years and of the permanent teeth at approximately 14 years (Allegra & Gennari, 2000; Regezi & Sciubba, 2000; Tommasi, 2002; Siragusa et al., 2000). According to Shafer et al. (1987), only the permanent dentition is affected in some cases.

Patients also present halitosis, intense destruction of alveolar bone, and, in some cases, calcification of cortical bone, pathological tooth mobility and migration, reddish gingiva, with deep periodontal pockets (Tommasi, 2002; Fermin & Carranza, 1986; Allegra & Gennari, 2000; Neville et al., 2001).

Other signs of this syndrome are fragile nails, hypotrichosis, thin and scarce hair, generalized hypohydrosis, hyperkeratosis palmoplantaris, skin scaling, dry skin with a “dirty” appearance, painful deep fissures that worsen during winter, frontal bossing and occasional intracranial calcifications (Fermin & Carranza, 1986; Neville et al., 2001; Shafer et al., 1987; Tommasi, 2002).

Some authors also reported other findings, such as microphtalmus, intracranial calcification, arachnodactyly, osteoporosis, abnormal hepatic function, renal abnormalities and mental retardation (Shafer et al., 1987; Mahajan et al., 2003)

In some countries of the world the diagnosis is practically based on clinical aspects because there are no genetic tests available to confirm the presumptive diagnosis.

The most important oral manifestation is reabsorption of alveolar bone with consequent tooth loss, with no calculus and/or periodontal inflammatory processes to justify this. The possible immunological alterations involved are impaired chemotaxis of neutrophils and, possibly an induced immunological defect caused by an interaction of periodontal pathogens and pocket epithelium (Regezi & Sciuba, 2000; Neville et al., 2001; Ghaffer et al.,1999).

Microscopically, there are alterations characterized by marked chronic inflammation of the lateral wall of the pocket, with intense osteoclastic activity and apparent absence of osteoblastic activity (Fermin & Carranza,1986). Bacterial studies of plaque in a case of Papillon-Lefèvre syndrome showed a flora similar to that of periodontitis and not of periodontosis, and was composed basically of Porphyromonas gingivalis, Prevotella intermedia and Actinomyces actinomycetemcomitans (Fermin & Carranza 1986; Neville et al., 2001; Robertson, 2001).

Treatment is based on preventive and therapeutical periodontal procedures comprising intense oral hygiene, followed by appropriate orientation, periodontal treatment and referral to dermatologists to treat skin lesions (Tommasi, 2002; Allegra & Gennari, 2000;). According to Tommasi, 2002 and Shafer et al., 1987, it is clear that adequate nutrition and elimination of any eventual systemic factor are essential for disease prognosis. (Mahajan et al., 2993 )

Dental splinting may contribute to longer maintenance. Regezi & Sciubba, 2000, explained that submersion of healthy roots, could stabilize height and alveolar bone conformation and improve prognosis. Other authors presented different protocols, such as extraction of deciduous teeth, followed by antibiotic therapy during and after permanent tooth eruption. Another management would include continuous and combined use of mechanic control of plaque and systemic therapy (specific antibiotic), which could change the course of disease (Neville et al., 2001; Pratchyapruit & Kullavanjaya, 2002).

However, all authors mentioned that treatment is problematic, there are many failures and dental prognosis is very poor (Allegra & Gennari, 2000; Neville et al., 2001; Shafer et al., 1987; ).

CASE REPORT

The authors report the case of a 16 years old black girl, came to Santo Amaro University – Oral Medicine Service complaining of “tooth softening”, and no report of pain at all.

The patient reported good general conditions and no use of systemic medicines, and her mother confirmed this status. On regional extra-oral clinical examination, a prominent frontal bossing was observed, as well as scarce and thin hair in the frontal region. Her face was symmetrical with dolichocephalic shape.

On intra-oral examination, teeth presented large root exposures, moderate to intense mobility, migration but there was no salivary calculus or intense gingival inflammation that could justify such bone losses and mobility (Figure 1). Investigating the family history, including a younger brother, nothing important was reported.

The panoramic and periapical radiographic examinations enabled visualizing great vertical and horizontal bone reabsorption in the maxilla and mandible, predominantly in the molar region (Figures 2 and 3). Other complementary tests were ordered including alkaline phosphatase, complete blood count, glycemia, calcium, phosphorus, skull X-ray (posteroanterior and lateral), femur X-ray, GOT, GPT, urea and creatinine, looking for signs of bone, inflammatory, fibrous or hormone diseases. All results were within normal standards for age and sex of patient.

Therefore, we decided to perform an incisional biopsy of gingival attachment, in the region of the lower left molars and lower incisors. The pathologist report was unspecific chronic recurrent inflammatory process. Therefore, no etiologic or neoplastic agent was demonstrated. The histological analysis was inconclusive but helped ruling out many common diseases in the oral cavity.

On the general physical examination, the patient presented frontal bossing, hypotrichosis, dry skin with fissures and hyperkeratosis palmoplantaris (Figure 4). Based on clinical and laboratory characteristics made a presumptive diagnosis of Papillon-Lefèvre syndrome.

The oral treatment proposed was scaling and root and crown planing of both dental arches, splint fixation of some teeth, encouragement for and orientation about oral hygiene, and referral to a dermatologist to evaluate skin abnormalities. There was a significant improvement in tooth mobility and gingival inflammation. The patient has been constantly followed-up considering the poor oral health prognosis in this syndrome.

Discussion

The diagnosis of Papillon-Lefèvre syndrome was made primarily based on the clinical aspects of the patient, that is, major alveolar bone destruction with fast progression and little dental calculus, besides skin involvement and analysis of laboratory tests. The molecular test specific for Papillon–Lefèvre syndrome is not available in Brazil.

The differential diagnosis of Papillon-Lefèvre syndrome includes other bone diseases and, particularly, hypophosphatemia. This is based on reports by Tommasi (2002), who stated both conditions are carried by a dominant autosomal gene, and their differentiation would lay in the fact that hypophosphatemia presents more severe general and skeletal manifestations. Fermin & Carranza, in 1986, reported that Meleda disease differs from Papillon-Lefèvre syndrome for presenting hyperkeratosis of fingers and palms and no periodontitis (Ullbro et al, 2003).

Management consists of strict scaling and root and crown planing of all dental elements, encouraging and orienting patients to perform an adequate oral hygiene, as well as splinting of affected teeth to provide better oral health conditions. Systemic treatment should be prescribed by physicians.

CONCLUSIONS

Participation of a multidisciplinary team is crucial for treating and following-up patients affected with Papillon-Lefèvre syndrome. Dentists play an important role in diagnosis considering it is a disease with severe oral manifestations;

When making diagnosis, the clinical examination should be detailed, ordered and complete. A meticulous clinical examination is the basis for a reliable diagnosis;

Diagnosis of oral diseases very often depends on knowledge and choice of relevant laboratory tests that may confirm or rule out diseases with similar clinical picture and progression.

REFERENCES

Allegra, F; Gennari, P.U. As doenças da mucosa bucal. 1a ed. Santos livraria editora: São Paulo, 2000.
Allende LM; Moreno A; de Unamuno P A genetic study of cathepsin C gene in two families with Papillon-Lefèvre syndrome. Mol Genet Metab; 79(2):146-8, 2003 Jun.
Fermin, A; Carranza, JR; Dr. Odont. Periodontia clínica de Glickman. 5a ed. Editora Guanabara S.A.: Rio de Janeiro, 1986.
Ghaffer KA; Zahran FM; Fahmy HM; Brown RS. Papillon-Lefèvre syndrome: neutrophil function in 15 cases from 4 families in Egypt. Oral Surg Oral Med Oral Pathol Oral Radiol Endod; 88(3):320-5, 1999 Sep.
Hart PS; Zhang Y; Firatli E; Uygur C; Lotfazar M; Michalec MD; Marks JJ; Lu X; Coates BJ; Seow WK; Marshall R; Williams D; Reed JB; Wright JT; Hart TC Identification of cathenpsin C mutations in ethnically diverse Papillon-Lefèvre syndrome patients. J Med Genet; 37(12):927-32, 2000 Dec.
Hewitt C; McCormick D; Linden G; Turk D; Stern I; Wallace I; Southern L; Zhang L; Howard R; Bullon P; Wong M; Widmer R; Gaffar KA; Awawdeh L; Briggs J; Yaghmai R; Jabs EW; Hoeger P; Bleck O; Rüdiger SG; Petersilka G; Battino M; Brett P; Hattab F; Al-Hamed M; Sloan P; Toomes C; Dixon M; James J; Read AP; Thakker N The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat; 23(3):222-8, 2004 Mar.
Mahajan VK; Thakur NS; Sharma NL Papillon-Lefèvre syndrome. Indian Pediatr; 40(12):1197-200, 2003 Dec
Neville, B.W; Damm, D.D; White, D.K. Atlas colorido de patologia oral clínica. 2nd ed. Guanabara Koogan S.A.: Rio de Janeiro, 2001.
Pratchyapruit WO; Kullavanijaya P. Papillon-Lefèvre syndrome: a case report. J Dermatol; 29(6):329-35, 2002 Jun.
Regezi, JA, Sciubba, JJ. Patologia Bucal. Correlações Clinicopatológicas. 3a. Ed. Guanabara Koogan Rio de Janeiro, 2002
Robertson KT A microbiological study of Papallon-Lefèvre syndrome in two patients. J Clin Pathol; 54(5):371-6, 2001 May.

LEGENDS OF FIGURES

FIGURE 1 – Tooth migration

FIGURE 2 – Panoramic X-ray with extensive bone reabsorption

FIGURE 3 – Periapical X-ray – “floating tooth”

FIGURE 4 – Hyperqueratosis

BURNING MOUTH SYNDROME

Carlos Eduardo Xavier dos Santos Ribeiro da Silva 1
Rodrigo Alarcon Cerri2
Silvia Cristina de Oliveira Bressan3
Artur Cerri 4
Francisco Octávio Teixeira Pacca5

Resumo

A Síndrome da Ardência Bucal (SAB) é uma condição caracterizada pela sensação de queimação da mucosa bucal, sem que uma causa física possa ser detectada. Afeta principalmente mulheres na pós-menopausa, com mais de 50 anos. Diversos fatores são apontados como possíveis desencadeadores dessa patologia e muito se discute sobre a importância de fatores psicogênicos, como ansiedade e depressão, na sua etiologia. Não há tratamentos estabelecidos e padronizados, sendo necessário na maioria das vezes, abordagem multidisciplinar.

Descritores:

Mucosa Bucal. Etiologia. Diagnóstico. Terapia.

1.Professor Titular da Disciplina de Estomatologia da Universidade de Santo Amaro (UNISA); Doutor pela UNIFESP

2.Especialista em Estomatologia pela Universidade de Santo Amaro (UNISA).

3.Estagiária da Disciplina de Estomatologia da Faculdade de Odontologia da UNISA.

4.Diretor da Escola de Aperfeiçoamento Profissional da APCD. Especialista, Mestre e Doutor em Estomatologia pela USP.

5. Especialista, Mestre e Doutor em Estomatologia pela USP.

Revisão de Literatura

A síndrome de Ardência Bucal (SAB) ou da “Queimação Bucal” pode ser definida como uma entidade clínica caracterizada pela dor e sensação de ardor (queimação), localizada em qualquer região da mucosa bucal, sem que se possa detectar qualquer alteração ou lesão fora dos padrões de normalidade e com achados laboratoriais normais17. A sinonímia encontrada na literatura abrange distesia oral, estomatopirose, estomatodinia7. Nos casos onde a sensação de ardência é restrita à língua são utilizados termos como glossodínia, glossopirose ou glossalgia18.

A SAB é mais prevalente em mulheres após a menopausa acima dos 50 anos de idade5,6,13,17. Sua manifestação antes dos 30 anos de idade é rara11. Os sintomas mais comuns relatados pelos pacientes são: xerostomia6,13, paladar alterado6,13, sede13, sensação de queimação na língua17 e nos lábios13. Marcucci 200511,relata que a xerostomia é a queixa bucal secundária mais frequente entre os portadores de SAB, ocorrendo em cerca de 60% dos casos. As localizações mais afetadas são ponta, borda e dorso da língua, lábios e mucosa bucal13. Terci el al18 2007, cita ainda regiões como palato e rebordo alveolar superior. Mucosa jugal, assoalho bucal e orofaringe são localizações menos frequentes11.

Segundo Nascimento et al12 2006, a bilateralidade usual da sensação dolorosa, acrescida ao fato de não respeitar a anatomia dos nervos responsáveis pela degustação, são importantes indicativos para excluir-se uma neuropatia.

Nenhuma diferença significativa em relação à idade, sexo, tempo de duração da doença ou locais de queimação foi encontrada entre os indivíduos que apresentaram a remissão parcial ou total, comparados com aqueles que continuam com o problema17.

Não é incomum paciente portador de SAB relatar dificuldade para dormir à noite e queixar-se de sono interrompido. Relatos de mudanças de humor tais como irritabilidade e diminuição no desejo de relacionamento, podem ser relacionados com padrões alterados de sono17.

A ingestão de bebidas e alimentos em temperaturas muito quentes ou muito frios, agravam os sintomas de ardência e sensação de queimação da SAB, além de alimentos condimentados e ácidos16.

Silverman et al17 2004, afirma que a remissão parcial da SAB é observada em aproximadamente dois terços dos casos dos pacientes após período de 6 a 7 anos.

Etiologia

A etiologia da SAB é desconhecida6,11,13 e dividida por diversos autores em fatores locais, sistêmicos e psicogênicos, o que evidencia o seu caráter multifatorial.

Dentre os fatores locais, podemos destacar o fumo, o álcool, o refluxo esofágico, hábitos parafuncionais (bruxismo) e próteses mal adaptadas como agentes irritantes da mucosa oral6,17. A maioria dos estudos não sustenta a irritação química ou reação alérgica aos materiais dentários como causas significativas da SAB17, porém o diagnóstico da alergia pode ser facilmente confirmado quando removido o contato do material com o tecido bucal18. Para Drage et al7 2003, o teste alérgico deve ser realizado em todos os pacientes.

As infecções bacterianas, fúngicas e virais também são apontadas como fatores locais. Dentre elas, destacam-se as infecções fúngicas causadas por Cândida albicans, maior responsável pela sensação de ardor nos portadores de próteses9.

Cavalcanti5 2003, analisou trinta e um pacientes com SAB. Nenhuma associação foi observada entre a SAB e a prevalência de leveduras do gênero Cândida. Ressaltou ainda a possível relação da síndrome com uso crônico de medicamentos, depressão, climatério e cancerofobia.

Recentes relatos de queimação bucal decorrente do uso de inibidores da enzima conversora de angiotensina (ACE), como o captropil, enalapril e lisinopril, indicaram a remissão após a descontinuação da medicação17.

A disfunção das glândulas salivares pode levar a um quadro de xerostomia, ressecando as mucosas bucais, causando desconforto e ardência15.

Bogetto et al3 1998, afirma que existem alguns fármacos que podem diminuir o fluxo salivar e com isso causar o aparecimento dos sintomas da SAB, tais como os antiespasmódicos, antidepressivos, antipsicóticos, relaxantes músculos-esqueléticos, antiparkinsonianos, antiarrítmicos, antihistamínicos, anticonvulsivantes, ansiolíticos, moderadores de apetite, diuréticos e anti-hipertensivos.

Como fatores sistêmicos, estão associados a SAB o diabetes18, Síndrome de Sjoegren17,18, anemias18, deficiências hormonais (TSH)17, radioterapia, deficiências de nutricionais de vitaminas do complexo B17,18 e de ferro17,18 e o climatério18.

Nascimento et al12 2006, afirma que pacientes diabéticos são mais susceptíveis a infecções oportunistas, podendo levar a SAB devido às infecções fúngicas. O percentual de pacientes diabéticos que relatam o sintoma de ardência bucal varia de 2% a 10%.

Blachman et al1 2001, relata uma amostra de 40 pacientes com a Síndrome da Boca Ardente (SBA) em relação aos aspectos físicos e psicológicos, encontrando-se para 95 por cento deles uma deficiência de lítio sérico. Concluiu-se, mediante análise estatística, que essa relação deva ocorrer em até 88,1 por cento dos pacientes com essa síndrome.

Deficiências nutricionais prejudicam o reparo tecidual, podendo gerar despapilação da língua e conseqüentemente provocando sensação de ardor e queimação12.

Nos fatores de origem psicogênica, estão incluídos indivíduos ansiosos, desconfiados, deprimidos, cancerofóbicas e os psicóticos maníacos depressivos.

Rodriguez et al16 2007, realizaram um estudo em 83 pacientes portadores de SAB onde 63% apresentavam transtornos psicológicos, com destaque para ansiedade, depressão e alterações durante o sono.

Diagnóstico

O diagnóstico da ardência bucal é eminentemente clínico. Frente à presença de qualquer lesão, estará descartada a hipótese de SAB. Além da anamnese detalhada, procura-se traçar um perfil psicológico do paciente. Patologias como o líquen plano, língua geográfica e a estomatite protética produzem sensações semelhantes às da SAB13,18.

Exames complementares como cultura para Cândida albicans, hemograma completo, glicemia em jejum, níveis de ferro sérico, níveis de vitamina B, dosagem hormonal, níveis de secreção salivar e os testes sorológicos para anticorpos da Síndrome de Sjoegren são amplamente utilizados13,15.

Tratamento

Apesar de não constituir uma doença grave e não representar risco à vida do indivíduo, a SAB é um transtorno que leva boa parte da população acometida à busca de um tratamento que ainda não existe6.

O uso de antidepressivos tricíclicos (TCA), alivia a queimação bucal em alguns pacientes. Os mais usados são a amitriptilina (TryptanolR), desipramina, nortriptilina, imipramina (ImipraR) e clomipramina (AnafrilR), embora apenas a amitriptilina tenha sido avaliada em experimentos clínicos17.

Benzodiazepínicos, como o clorazepam, podem ser eficazes para alterações dolorosas como a SAB17.

O controle do consumo do fumo e do álcool deve ser promovido, bem como o balanceamento da dieta alimentar, evitando-se alimentos condimentados e de alto teor ácido. Hidratação constante da mucosa oral serve de grande alívio para os sintomas de ardência.

A prescrição de vitamina B é bastante citada na literatura como um recurso utilizado na melhoria das ardências, obtendo-se excelentes resultados9.

Nos casos onde a cultura de fungos for positiva para Cândida albicans, aplicações tópicas de Nistatina e eventual troca da prótese produzem resultados clínicos satisfatórios.

Na aplicação da laserterapia, a sintomatologia da queimação é diminuída proporcionando alívio da dor e controle da inflamação ao paciente. Os efeitos terapêuticos são imediatamente relatados pelo paciente logo após a aplicação10. A aplicação deve ser feita logo após a área acometida ser limpa e seca, com auxílio de gaze e durante a irradiação deve manter-se o campo isento de umidade, a forma de aplicação de ser pontual, com dosimetria de 4-5 J/cm² durante 2 a 3 sessões semanais, com intervalos de 48 horas até a remissão dos sintomas4.

Blom et al2 1992, afirma que a acupuntura é largamente utilizada para diferentes finalidades médicas, também representando possível método de tratamento para SAB, podendo, além de agir em terminações nervosas, gerar um aumento do fluxo salivar.

O ácido alfa-lipóico é um potente antioxidante. Essa substância apresenta uma possível ação neuroprotetora e tem mostrado eficácia no tratamento da SAB11. Femiano etal8 2004 realizaram um estudo com 192 pacientes portadores de SAB e concluíram que o uso do ácido alfa-lipóico pode ser usado como um complemento junto com outros agentes psicoterápicos, necessitando ainda de novos estudos para comprovação da sua real eficácia.

Em pacientes com estado de ansiedade e depressão, a avaliação psicológica e psicoterapia são recomendadas como parte do tratamento6,11.

A capsaicina tem tido seu uso diminuído pelo incômodo de aumentar a sensação de ardor no início do tratamento, pelos efeitos colaterais gerados pelo uso sistêmico (irritação gástrica) e pela baixa efetividade no controle dos sintomas12. Petruzzi et al14 2004, após pesquisa com o uso sistêmico da capsaicina a 0,25% afirma que seu uso é efetivo em curto prazo, mas que devido a irritações gastrointestinais provocadas pelo uso em longo prazo, se faz necessário ainda estudos para comprovação da posologia e tempo de uso ideal da substância.

Diante das diversas possibilidades de tratamento, é de grande importância, que o cirurgião-dentista seja realista e não mostre ao paciente grande otimismo e nem ofereça solução fácil, pois este poderá ter que aceitar e aprender a conviver com a doença, no caso de um tratamento sem sucesso.

Conclusões

A Síndrome de Ardência Bucal é uma condição com múltiplos fatores etilógicos, sendo que as condições de origem psicogênicas (depressão, ansiedade e cancerofobia) estão entre as principais causas.
Novos estudos fazem-se necessários a fim de que se elucide a causa da SAB para proporcionar melhor qualidade de vida aos pacientes.
È importante o cirurgião-dentista fazer com que o paciente entenda a complexidade da síndrome e aceitar a conviver com sua sintomatologia.

Referências Bibliográficas:

1- Blachman IT, Salgado CM, Silva OMP. A carência do nível sérico de lítio e a síndrome da boca ardente: da observação à ação. Ver Odontol UNIFESP 2001;30(2):271-5.

2- Blom M, Dawidson I, Angmar-Manson B. The effect of acupunture on sw rates in patients with xerostomia. Oral Surg Oral Med Oral Pathol 1992;73(3):293-8.

3- Bogetto F, Maina G, Ferro G, Carbone M, Gandolfo S. Psychiatric comorbidity in patients with burning mouth syndrome. Psychosom Med 1998; 60: 378-85.

4- Brugnera Junior A, Santos AECG, Bologna ED, et al. Atlas de laserterapia aplicada à clínica odontológica. São Paulo: Santos, 2003.

5- Cavalcanti D. Síndrome de ardência bucal: perfil clínico de pacientes e prevalência de leveduras gênero do Cândida (tese de mestrado). São Paulo: Faculdade de Odontologia da USP; 2003.

6- Cherubini K, Maidana JD, Weigert KL, Figueiredo MA. Síndrome da ardência bucal: revisão de cem casos. Revista Odonto Ciência 2005;20(48):109-112.

7- Drage LA, Rogers RS. Burning mouth syndrome. Dermatol Clin 2003;21:135-45.

8- Femiano F, Gombos F, Scully C. Burning Mouth Syndrome: open trial of psychotherapy alone, medication with alpha-lipoic acid (thioctic acid), and combination therapy. Med Oral 2004;8(1):8-13.

9- Hugoson A, Thorstensson B. Vitamin B status and response to replacement therapy in patients with BMS. Acta. Odontol. Scand 1991;49 :367-75.

10- Ladardo TC, Brugnera Juior A, Takamoto M et al. A laserterapia no tratamento da Síndrome de Ardência Bucal-Relato de Caso Clínico. 20º Congresso Internacional de Odontologia de São Paulo 2002.

11- Marcucci G. Fundamentos de Odontologia – Estomatologia. Guanabara Koogan;2005.

12- Nascimento TD, Bordini CA, Speciali JG. Síndrome da ardência bucal: diagnóstico diferencial e revisão de tratamento. Migrâneas cefaléias 2006; 9(3):80-83.

13- Nery FS, Lauria RA, Sarmento VA, Oliveira MGA. Avaliação da ansiedade e depressão da terceira idade e sua relação com a Síndrome da Ardência Bucal. R Ci Med Biol 2004;3(1):20-29.

14- Petruzzi M, Lauritani D, Benedittis M, Baldoni M, Serpico R. Systemic capsaicin for burning mouth syndrome: short-term results of a pilot study. J Oral Pathol Med 2004; 33(2):111-4.

15- Rapoport PB, Cerchiari DP, Moricz RD, Sanjar FA, Moretti G, Guerra MM. Síndrome da boca ardente: etiologia. Rev Bras Otorrinolaringol 2006; 72(3):419-24.

16- Rodríguez RC, López LJ, Chimenos EK, Sabater RMM. Estúdio de uma muestra de pacientes con síndrome de boca ardiente. Av Odontoestomatol 2007; 23(3):141-151.

17- Silverman S, Eversole LR, Truelove EL. Fundamentos de Medicina Oral. Guanabara Koogan;2004.

18- Terci AO, Pacífico A, Braga FPF, Wienfeld I, Birman EG. Atualizando-se sobre a Síndrome de Ardência Bucal. Ver Odontol Univ Santo Amaro 2007;12(1):32-35.

Abstract

The Burning MouthSyndrome (BMS) is a condition characterized by burning sensation of the oral tissues withouta physical cause. This condition affects especially mild menopausal woman over 50 years old. Many Factors have been suggested as possible etiology of this condition. The importance of psycological factors such as anxiety and depression on the development of this condition. There is not an established treatments, nevertheless, a multidisciplinary approach is recomended.

Descriptors:

Mouth mucosa. Etiology. Diagnosis. Therapy.

The importance of histopathological exam.

Authors:

1. Carlos Eduardo Xavier dos Santos Ribeiro da Silva1
2. Artur Cerri
3. Francisco Octávio Teixeira Pacca
4. Luc Louis Maurice Weckx
5. Patrícia Silva

1. Professor at Santo Amaro University – UNISA ; Department of Otorhynolaringology and Head and Neck Surgery at Federal University of São Paulo – UNIFESP – Brazil
2. Professor at Santo Amaro University – UNISA
3. Professor at Santo Amaro University – UNISA
4. Chief of Department of Otorhynolaringology and Head and Neck Surgery at Federal University of São Paulo – UNIFESP – Brazil
5. Dental Surgeon

Address for Correspondence: Rua Pelotas, 358 – Vila Mariana – CEP 04012-010 – São Paulo – SP – Brazil
55 (11) 5571-1736 – dreduardosilva@terra.com.br

Keywords: Ameloblastoma – Periodontal Cyst – Odontogenics Cysts

Abstract

The ameloblastoma is a benign neoplasia, locally very aggressive tumor, arising from odontogenic epithelium of the jaws. By means of a radiographic examination, it can be classified as uni- or multi-cystic. The uni-cystic ameloblastoma is less aggressive and with a reduced potential for relapses after treatment. It prevails primarily amongst younger patients, regardless of sex or race, at the posterior area of the mandible, and it is generally associated with the third non-erupted molar. The authors report a case of a 25 years old patient, S. A, Caucasian, carrier of a radiolucent lesion in the area of tooth 46, which was absent and had not involved tooth 45. We proceeded surgical removal of the lesion suspecting a residual cyst or a periapical cyst of tooth 45. An anatomo-pathological exam revealed follicular ameloblastoma. Our purpose, with this case history, was to call the attention to the importance of a histopathological examination of all material collected from the mouth cavity, even though clinically and radiographically pathognomic signs indicate another pathology. The patient is presently under preventive surveillance, and shows signs of local bone reconstruction.

Introduction

The ameloblastoma is a benign locally aggressive neoplasia with a behavior affecting exclusively the jawbones (Kramer et al., 1992)9.

Guzak first described it, in 1826, and the first scientific publication on the subject was by Broca in 1868. In 1879, Falkson performed a histological description (Shafer et al., 1985)17.

It arises in the odontogenic epithelium. There are some doubts about the histogenesis, specially regarding the proliferation of epithelial remainders of the enamel producing organ, the proliferation of the epithelium that encases the ontogenic cysts or even the cells of the basic mucous mouth layers (Iordanidis, 1999; Kawai, 1999)5,7.

The ameloblastoma is a locally invasive neoplasia with frequent relapse after treatment that can eventually deteriorate into metastasis. (Adou, 2001)1.

According to Neville (1988)12 10% out of 30% of all odontogenic tumors are ameloblastomas.

The histological characteristics are well known to be benign in spite of the fact that quite rarely metaplasia may occur within the limits of the lesion, such as dysplasia and malignant transformation. These facts lead some authors to question its benign nature. (Maia Campos, 1990; Wilson)10.

Usually, the ameloblastoma is an asymptomatic pathology with a slow evolution, occurring at any age. The most frequent multicystic variant occurs from the thirties throughout the seventies and the unicystic ameloblastoma is more frequent in the twenties. (Kim et al, 2001)8.

The occurrence of this lesion is independent of sex or ethnic origin, affecting approximately 80% of the cases in the posterior area of the jawbone at the molars and the upper branch. (Gardner, 1984) 4.

According to WHO- World Health Organization classification in 1992, the ameloblasts are histologically classified into the following types: plexiform, follicular, granulocytes, cystic, decompensated and inflammatory (Santos et al., 2000)13,16.

The ameloblastoma is called plexiform when the epithelial cells arrange themselves in a networklike shape being limited by layers of cylindrical cells (Isacsson, G et al., 1986)6.

Radiographically, they may be described as ostelithic lesions in one site or several sites with areas of ostheogenesis forming the septa that gives the ameloblastoma the aspect of “soap bubbles” or “honeycombs”. Although it is a benign neoplasia, the root reabsorption of the involved teeth occurs frequently. (Regezi & Sciubba, 1989; Reichart et al.;1995) 14,15.

Curi et al. (1997)2 advocate that at the time to choose therapy, patient’s morbidity and quality of life must be taken into account. The reason is that extensive resections provoke problems to the patient such as chewing difficulties, mutilation, facial deformity and abnormal mandibular movements.

The same authors also observed the response in view of the surgical enucleation followed by cryosurgery in 46 cases of solid ameloblasts. The surgical complications were evaluated by clinical and X-ray follow-up, and only in 30.6% of the cases, there was a local relapse.

In 1995, Feinberg and Steinberg3 , along with Neville (1998)12, claimed that the relapse ratio for solid ameloblasts were around 15% to 25%, whenever they were treated with more radical measures.

IIt proves that less invasive approaches may be successful and are comparable to the more radical ones, enhancing the importance of a conservative therapy for amelobasts.

In spite of the fact that it is a benign neoplasia , researchers have been discussing the therapy for the ameloblastoma due to its local very aggressive behavior. Extensive resections have been chosen for the ameloblastoma in several sites, whereas the unicystical ones were treated via enucleation. However, a certain tendency seems to exist among researchers to adopt less aggressive procedures since the relapse ratios of the lesion are similar when compared with conservative therapies (enucleation and cryosurgery) and with radical ones (segmental resection with or without bone reconstruction).

Nakamura et al.,.11 in 2002, described a conservative therapy by means of marsupialization and posterior enucleation that turned out to be quite efficient and with few relapses.

Radiotherapy, as an auxiliary therapy for ameloblastoma, was recommended in the past, and then discarded because the lesion is resistant to radiotherapy, besides the risk of bone necrosis caused by X-rays and malignant transformation (Santos et al., 2000)16.

Case Report

The 25 year old, female, Caucasian patient S.A, was referred to the Mouth Surgery Department of the University of Santo Amaro – UNISA (São Paulo – Brazil ), by the Orthodontics Department to be evaluated for a radiolucent lesion, in the area of the missing first inferior pre-molar. During the anamnesis the patient did not report any relevant information regarding the medical history, family antecedents and/or orthodontics history and neither did she mention the use of any medication. Facial symmetry and normal texture of the skin and lubrication were observed, upon physical examination of the face.

When examining head and neck limphonodes only an inflammatory process of the right hand sub-mandibular area was observed. The remaining lymphonodes were normal.

Blood pressure was 120X80 mmHg and the radial pulse frequency was 88 beats per minute.

Upon the clinical examination, the patient had the loss of limits of the furrow bottom in the area, and normal color of the smooth, brilliant and well-hydrated mucous membrane. The palpation revealed clicking of the vestibular bone wall, which was quite thin. Radiographically, the lesion was a radiolucent area, circumscribed to one area, well characterized by the radiopaque halo, quite visible at the borders, with a diameter of about two centimeters, extending from the root of the second molar to the root of the second premolar including the latter. The lesion caused a dislocation of the alveolar channel toward the cortical base of the mandible.

No symptoms were reported at all. The lesion was perforated to eliminate the suspicion of hemangioma in the bone, and the presence of clear brownish liquid confirmed our clinical hypothesis of a cyst.

Since the lesion radiographically revealed the involvement of the roots of tooth 45, vitality tests were done and there was no pulpar reaction to heat, cold and impact. Thus, before surgery, root canal treatment was requested, with the filling exaggerated at the apex to facilitate the detection of the tooth tip in the process of enucleation of the lesion.

Figure 1 – Initial aspect of the lesion.

Standard procedures for intra- and extra-oral sterilization were carried out with 0.12% chlorexidine and the surgical field was sterilized. By means of a pterygomandibular technique the patient was anesthetized in the right side with bupivacaine. An incision was made from the distal portion of the third inferior molar to the mesial region of the canine, alleviating at this site. Much care was taken to preserve the nerve insertions. After release of the muco-periostal sheet it was possible to see the thin bone flange with reactive enlargement, which was removed with a scalpel. The cavity was full of liquid having a fibrous envelope around its borders. The withdrawal was carried out very carefully in a piece to insure complete removal. The remaining bone tissue showed normal color and consistency without any clinical signs of lesion. After replacement of the sheet, it was sutured with 4-0 silk threads and the patient received the routinely post surgical instructions, besides antibiotics and anti-inflammatory drugs. The removed material was maintained in 10% formaldehyde and sent to the anatomopathological laboratory.

The histopathological diagnosis is follicular ameloblastoma with cystic area. Since the clinical diagnosis was not in accordance with the obtained results, the material was forwarded to another pathology laboratory, which confirmed the first result.

X-ray observation of the patient to control eventual relapse of the lesion was chosen since the lesion had a well-defined cystic envelope and the complete removal was possible. Presently, she is under follow-up for twelve months, without any signs of relapse and with bone restoration in the affected area.

Discussion

I Our intention in this particular case, although the X-ray findings suggesting a periapical or residual cyst, was to show that in fact it was a unicystic ameloblastoma.

Since the ameloblasts are known for their great potential of relapse, it is fundamental for the Dental Surgeon to maintain a regular and careful follow-up of this patien,t for at least three years.

The diagnosis was only possible because the anatomopathologic examination was performed in the removed material. It reinforces the requirement that every material removed from the patient must be examined, regardless of the unquestionable type of clinical diagnosis.

If the removed evidence had been discarded, we would not have had the opportunity to establish the correct diagnosis and to carry out the necessary follow-up.

Conclusions

Conclusions of the present study are as follows:
The radiolucid lesions of the jaw-bone complex shall be better understood by the C.D.;
The ameloblastoma reveals a variable prognosis and depends on a number of clinical and histological aspects;
The histopathological analysis is fundamental for an adequate treatment and prognosis;
Detailed and complete medical history in addition to complementary tests are fundamental for a better treatment of the patient.
All of the removed materials have to be examined by a pathologist

REFERENCES

1. Adou, et.al. Ameloblastoma. Odontostomatol Trop, Dakar. V.24, n.94, p.42-44,2001.
2. Curi MM, Dib LL, Pinto DS. Management of solid ameloblastoma of the jaws with liquid nitrogen spray cryosurgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endond, v.84, n.4, p.339-344, 1997.
3. Feinberg SE, Steinberg B. surgical management of ameloblastoma: current status of the literature. Oral surg Oral Med Oral Pathol, v.81, p.383-388, 1996.
4. Gardner DG. Some current concepts on the pathology of ameloblastomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endond, v.82, n. 6, p. 660-669 Dec 1996.
5. Iodarnidis,S. et al. Ameloblastoma of the maxilla. Case report. Aust Dent J, v.44, n.1, p.51-55,1999
6. Isacsson G. et. Al. Diagnosis and treatment of the unicystic ameloblastoma. Int. J. Oral Maxillofac Surg, v.15, p.759-764, 1986.
7. Kawai T et al. A unique case of the desmoplastic ameloblastoma of the mandibule: report of a case and brief review of the English language literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, v.,87, n.2, p.258-263,Feb. 1999.
8. Kim SG, Jang HS, Kwang-Ju. Ameloblastoma: A clinical, radiograph and histopathologic analysis of 71 cases. Oral Surg Oral Med Oral Path, St. louis, v.91.n.6,p.649-653, Jun.2001.
9. Kramer IRH, Pindborg JJ, SHEAR M. Internacional Histological Classification of Tumours. Histological Typining of Odontogenic Tumours. 2a. ed. Heidelberg: Springer – Verlag,1992. p. 11-14
10. Maia Campos G. Ameloblastoma, a Behavioral and histological Paradox (A Philosophical Aproach). Braz Dent J., Ribeirão Preto, v.1, n.1, p.5-15, 1990.
11. Nakamura, N. et al. Marsupialization of cystic ameloblastoma: a clinical and histopatologic study of the growth characteristics before and after marsupialization. J Oral Maxillofac Surg, v. 53, p.748-754,1995
12. Neville BW. et. Al. Patologia Oral e Maxilo Facial. Rio de Janeiro: Guanabara Koogan, 1998, 705p.
13. Regezzi JA, Sciuuba JJ. Oral pathology: clinical pathologic correlations. Philadelphia: Saunders; 1989.554p.
14. Reichart PA, Philipsen HP, Sonner S. Ameloblastoma: Biological Profile of 3677 cases. Oral Oncol, Eur J. Câncer, Oxford, v.31.3, n.2, p.86-99,1995.
15. Santos JN et.al. Odontogenic tumors: analysis of 127 cases. Pesqui odontol Bras, v.15, n.4, p.308-313, out/dez.2001
16. Shafer WG, Hine MK, Levy BM. Tratado de patologia bucal 4ª ed. Rio de Janeiro, Interamericana; 1985 p.255-263
17. WHO – World Health Organization, 1992.

* Prof. Dr. Carlos Eduardo Xavier dos Santos Ribeiro da Silva

** Prof. Dr. Artur Cerri

*** Prof. Dr. Francisco Octávio Teixeira Pacca

**** Prof. Dr. João Ferreira dos Santos Junior

DECRITORES: Xerostomia – Saliva – Terapia – Boca – Glândulas Salivares

RESUMO:

A xerostomia é uma alteração quantitativa e/ou qualitativa da saliva que causa a sensação de boca seca. Neste trabalho além de ser discutida sua etiologia, diagnóstico, alterações da cavidade bucal e tratamento da xerostomia, os autores apresentam revisão de literatura de uma droga recém aprovada pelo FDA denominada cevimelina. A cevimelina é um sialogogo que possui a capacidade de incrementar o fluxo salivar. Esta é apresentada como uma alternativa para o tratamento dos pacientes portadores desta condição que em muito piora a qualidade de vida dos pacientes.

REVISÃO DE LITERATURA

A saliva exerce um papel essencial na manutenção da saúde oral. Alterações na função e/ou quantidade salivar levam ao comprometimento dos tecidos da cavidade oral e suas funções, e tem um grande impacto na qualidade de vida do paciente. Reduções do fluxo salivar se manifestam mais comumente com sintomas de boca ressecada. Essa queixa subjetiva de boca seca é denominada de xerostomia, ao passo que alterações objetivas na quantidade de saliva, são referidas como hipossalivação¹.

Para alguns autores, a xerostomia seria caracterizada pela secura evidente das mucosas, enquanto que a hiposalivação seria a diminuição do fluxo salivar e conseqüentemente menores efeitos colaterais que a xerostomia10,11.

As estruturas anatômicas responsáveis pela produção e secreção da saliva são as glândulas salivares e estão divididas em dois grupos distintos. As glândulas salivares maiores ( paródita, sub-mandibular e sub-lingual ) e as menores, que estão dispersas por toda a cavidade bucal e podem ser classificadas funcionalmente pelo seu produto de secreção ( serosa, mucosa ou mista ). O volume de secreção salivar diário é de aproximadamente 1,5 litros por dia.

* Especialista e Mestre em Estomatologia

Doutor pelo Depto de ORL/CCP da UNIFESP

Prof. Dr. das Disciplinas de Estomatologia e Pacientes Especiais da UNISA

** Especialista, Mestre e Doutor em Estomatologia pela USP

Prof. Titular da Disciplina de Estomatologia da UNISA

*** Especialista, Mestre e Doutor em Estomatologia pela USP

Prof. Dr. da Disciplina de Estomatologia da UNISA

***** Especialista em Cirurgia Bucomaxilofacial

Mestre e Doutorando pelo Depto de ORL/CCP da UNIFESP

Prof. Dr. da Disciplina de Pacientes Especiais da UNISA

A produção da saliva e o seu fluxo são modulados pelo sistema nervoso autônomo, por meio da ação do neurotransmissor acetilcolina ( parassimpático )13.

No que diz respeito a sua composição, a saliva é formada basicamente por água, eletrólitos, peptídeos, glicoproteínas, lipídeos, lisozimas, lactoferrina, imunoglobulinas, histamina, leucócitos fagocitários, fluoretos e mucina.

Dentre as múltiplas funções da saliva, destacam-se a proteção antibacteriana da cavidade bucal e do epitélio gastrointestinal, lubrificação das mucosas, auxílio na formação e deglutição do bolo alimentar, manutenção do equilíbrio ácido-básico ( ph ), retenção de próteses totais, função digestiva , auxílio na fonação e percepção do paladar.

Como pode ser notada, a função normal da saliva é importante para muitos aspectos da saúde oral. Adicionalmente, a saúde geral pode ser prejudicada quando a função salivar está afetada¹.

Existem numerosas causas de xerostomia, sendo o mais comum o uso de medicamentos. São mais de 500 drogas associadas com sintomas de boca seca¹, destacando-se os antidepressivos, anti-hipertensivos, anticolinérgicos, anti-histamínicos, diuréticos, antiinflamatórios, antineoplásicos, ansiolíticos, analgésicos, antipsicóticos, relaxantes musculares, anticonvulsivos e outras. Nos Estados Unidos, dos 200 medicamentos mais prescritos pela classe médica em 1999, 63% apresentavam potencial para causar xerostomia13.

A radioterapia que inclui as glândulas salivares no seu campo de tratamento, leva a uma profunda e permanente perda da função secretora¹,5,12,14.

Emoções4,12 ( como o estresse, depressão e ansiedade ) e certas doenças sistêmicas, como a doença de Parkison7,12, hepatite C6, hipotireoidismo¹,4, HIV¹,5,14, doença de Mikulicz³, síndrome de Sjogren¹,³,5,7,12,14 , doenças neurológicas5, tumores7 e diabetes¹,5,8 podem levar o paciente a apresentar boca seca, além de infecções de origem viral e bacteriana¹,7,8, menopausa5, anorexia8, respiração bucal14, bulimia8, alcoolismo8,, fumo14 e hipovitaminose A³ e a idade14.

Alterações eletrolíticas do organismo, como vômitos7, diarréia7, sede7 e hemorragias7, são causadoras de ressecamento bucal leve, que também se ocorre em pacientes portadores de respiração bucal³.

A redução do fluxo salivar apresenta um aumento de incidência três vezes maior no idoso do que no indivíduo adulto. Essa sintomatologia pode estar relacionada a algumas doenças sistêmicas ou a medicamentos usados no seu tratamento²,7. Mulheres são mais comumente afetadas do que os homens14.

Como consequências causadas pela xerostomia temos o aumento do índice de cáries ( particularmente envolvendo o terço cervical ou as bordas das cúspides ), doenças periodontais e candidíses, dificuldades de fonação e deglutição, diminuição na retenção de próteses totais, sensação de queimação na boca, alterações na sensibilidade gustativa, halitose, mucosas desidratadas e susceptíveis a traumas, fissuras na mucosa bucal, disfagia ( dificuldade de deglutição ), disfasia ( dificuldade em ordenar palavras ), disgeusia ( erro na percepção das sensações gustativas ), “ problemas digestivos ”, aumento da saburra no dorso lingual e ressecamento labial.

O diagnóstico de um paciente portador de xerostomia contém um princípio básico, focado em uma anamnese detalhada, investigando a fundo os fatores causadores da xerostomia, de preferência com uma série de perguntas específicas para pacientes com suspeita de boca seca. Apesar de a xerostomia sintomática não ser suficiente para o diagnóstico da disfunção salivar, algumas perguntas são úteis para identificar indivíduos que podem apresentar fluxo salivar diminuído: ressecamento na boca ao comer, necessidade de ingerir líquidos para a deglutição de alimentos secos, dificuldade para engolir e sensação de que há pouca saliva na boca9. O exame físico pode detectar mucosas ressecadas, língua fissurada e avermelhada, viscosidade salivar, doenças fúngicas, cáries e alterações de consistência das glândulas salivares. Saliva acumulada normalmente no assoalho da boca não será vista9. Exames como coleta de saliva ( sialometria ), ressonância magnética, sialografia e biópsia de glândulas salivar podem ser solicitados, além de exames específicos quando a suspeita de Síndrome de Sjogren.

O tratamento da xerostomia consiste na eliminação de suas causas, desde que seja possível e no uso de substâncias que confiram ao paciente conforto e alívio dos sintomas, que apenas podem ser controlados.

Em pacientes com ressecamento bucal leve, pode ser indicada ingestão de líquido várias vezes ao dia, além mascar de chicletes sem açúcar e cubos de maçã com gotas de limão, para alívio da sintomatologia. Deve-se evitar alimentos ácidos e condimentados, umidificadores de ambiente, ar condicionado ou aquecedores e substâncias alcalóides como a cafeína. O uso de hidratantes labiais é essencial. Em casos mais severos, o uso de substâncias químicas que aumentam o fluxo salivar, como o Cloridrato de Pilocarpina a 2% pingado sobre a língua ou ingerido em cápsulas de 5 mg podem ser efetivos para alguns pacientes. O Salivan® ( carmelose sódica ) e o Oral Balance®, que são substituidores de saliva, também podem ser utilizados.

Recentemente, um novo sialogogo, o hidrocloreto de cevimelina, foi aprovado pelo FDA ( Food and Drug Administration – USA)15 para alívio dos sintomas de boca seca em pacientes com Síndrome de Sjogren¹. A cevimelina é um anti-colinérgico que se liga a receptores muscarínicos. Os agonistas muscarínicos em doses sufucientes podem aumentar a secreção de glândulas exócrinas como as salivares e sudoríparas. A cevimelina é rapidamente absorvida possuindo um pico de concentração que varia de uma hora e meia a duas horas. Quando administrada junto com alimentos ocorre uma redução da sua absorção, com decréscimo de aproximadamente 17,3% de sua dose. A dose recomendada de cevimelina é de 30mg, três vezes ao dia. Ainda não existe informação suficiente para permitir o uso de doses acima de 90mg/dia. Os principais efeitos colaterais da cevimelina são caracterizados por sintomas parassimpáticos15. Esses incluem dor de cabeça, lacrimejamento, sudorese, náuseas, vômitos, diarréia e tremores. Os pacientes devem ser informados que a cevimelina pode causar distúrbios visuais, especialmente à noite, onde podem ser impedidos de dirigir com segurança. Outra recomendação necessária é que em pacientes com transpiração excessiva quando do uso de cevimelina devem consumir maior quantidade de líquido para prevenir a desidratação. Suas principais indicações estão embasadas nos quadros de redução do fluxo salivar, como em pacientes idosos, portadores da Síndrome de Sjogren e pacientes submetidos à radioterapia na região de cabeça e pescoço. Nos pacientes portadores de doenças cardiovasculares como história de infarto do miocárdio e angina pectoris, o uso da cevimelina deve ser feito sob acompanhamento cuidadoso15.

Instruções de higiene oral e dieta alimentar, evitando alimentos maciços, condimentados ou ácidos, bebidas alcoólicas e carbonadas, assim como o tabaco. Como os quadros de xerostomia podem contribuir para acréscimo do índice de cáries, é indicada aplicação tópica de flúor e/ou recomendações para o uso diário de soluções de fluoreto de sódio a 0,05%, bem como o uso diário de soluções de gluconato de clorexidina a 0,012%12.

CONCLUSÃO

A Cevimelina parece ser uma droga promissora para o melhora da qualidade de vida dos pacientes portadores de xerostomia.

Por tratar-se de um medicamento com pouco tempo de utilização clínica, requer ainda maiores estudos para se determinar com segurança à dose terapêutica, bem como seus efeitos colaterais.

REFERÊNCIAS BIBLIOGRÁFICAS

1-SILVERMAN S. J., EVERSOLE L. R, TRUELOVE E. L. Fundamentos de Medicina Oral. Editora Guanabara Koogan, 2004.

2- LOESCHE W. J. et al. Xerostomia, xerogenic medications ans food avoidances in selectes geriatric groups. J Am Geriatric Soc, v. 43, n.04, p. 401-447, Apr. 1995.

3- DAWES C. Physiological factors affecting salivary flow rate, oral clearance and the sensation of dry mounth in man. J Dent Res, v.66, Spec. No, p.648-653, Feb. 1987.

4- ASTOR F. C. et al. Xerostomia: a prevalent condition I the elderly. Ear Nose Throat, v.78, n.7, p. 476-467, July 1999.

5- ESCALONA L. A., ACEVEDO A. M. Xerostomia: diagnostico y tratamiento. Acta Odontol Venez, v. 28, n.1, p.37-40, ene 1990.

6- TORRES S. R., et al. Relação entre fluxo salivar e contagem de Cândida na saliva. Pesquisa Odontologia bRasileira, v.14, suppl., p. 138, set 2000.

7- ETTINGER R. L. Review: xerostomia: a symptom which acts like a disease. Age Ageing, v. 25, n.5, p. 409-412, Sept. 1996.

8- NAVAZESH M. et al. Salivary gland disease in human immunodeficiency virus-positive women from the WHIS study. Woman´s Interagency HIV Study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, v. 98, n.6, p. 702-709, June 2000.

9- FOX P. C. Differentiaton of dry mounth etiology. Adv Dent Res, v.10, n. 1, p. 13-16, Apr. 1996.

10-MONN F., GUTTENBERGER R. Treatment of Xerostomia tollowing radiotherapy: doses age matter? Support Care Cancer, v. 10 (6), p. 5005-8, Sep. 2002.

11- BRENNAN M. T., et al. Treatment of Xerostomia: a systematic review of therapeutic trials. Dent Clin North Am. V. 46, n. 4, p. 847-56, Oct 2002.

12- COELHO C. M. P., et al. Implicações clínicas da xerostomia: Abordagens sobre o diagnóstico e tratamento. Rev APCD. V. 56, n. 4, p. 295-289. Jul/Ago 2002.

13- WYNN R. L., MEILLER T. F. Drugs and dry mounth. Gen Dent, v. 49, n. 1, p. 10-123, Jan/Fev 2001.

14- NEVILLE D. D. S. et al. Patologia Oral e Maxilofacial. Editora Guanabara Koogan, 1998.

15- www.fda.gov ; Acesso em Maio de 2008

Endereço Institucional dos autores:

Universidade de Santo Amaro – UNISA
Rua Enéas de Siqueira Neto, 340 – Jd. Das Imbuias
São Paulo – SP

Endereço de todos os autores para correspondência:
Rua Pelotas, 358 – Vila Mariana – São Paulo – SP – CEP 04012-001
dreduardosilva@terra.com.br

Declaração de Responsabilidade

Certifico que participei da concepção do trabalho para tornar pública minha responsabilidade pelo seu conteúdo, não omitindo quaisquer ligações ou acordos de financiamento entre os autores e companhias que possam ter interesse na publicação deste artigo;

Certifico que o manuscrito é original e que o trabalho, em parte ou na íntegra, ou qualquer outro trabalho com conteúdo substancialmente similar, de minha autoria, não foi enviado a outra Revista e não o será, enquanto sua publicação estiver sendo considerada pela RGO, quer seja no formato impresso ou no eletrônico.

Carlos Eduardo X. S. Ribeiro da Silva

Francisco Octávio Teixeira Pacca

Artur Cerri

João Ferreira dos Santos Junior
02/06/2008

Transferência de Direitos Autorais

Declaro que, em caso de aceitação do artigo, a RGO – Revista Gaúcha de Odontologia passa a ter os direitos autorais a ele referentes, que se tornarão propriedade exclusiva da Revista, vedado a qualquer reprodução, total ou parcial, em qualquer outra parte ou meio de divulgação, impressa ou eletrônica, sem que a prévia e necessária autorização seja solicitada e, se obtida, farei constar o competente agradecimento à Revista”.

Assinaturas do(s) autor(es) :

Carlos Eduardo X. S. Ribeiro da Silva

Francisco Octávio Teixeira Pacca

Artur Cerri

João Ferreira dos Santos Junior

02/06/2008

Contribuição de cada autor no trabalho

Sob a coordenação do Prof. Dr. Carlos Eduardo X. S. Ribeiro da Silva, os Professores Francisco Octávio Teixeira Pacca; Artur Cerri e João Ferreira dos Santos Junior realizaram a pesquisa bibliográfica correspondente ao assunto, traduzindo-a e interpretando-a.

CD ROSIENE DE FREITAS LIMA

Prof. Eduardo Ribeiro da Silva
Prof. Francisco Pacca
Prof. Artur Cerri

Características Clínicas

As UAR caracterizam-se por lesões ulceradas superficiais, de forma regular, única ou múltiplas, limites nítidos, halo eritematoso, leito fibrinoso branco-amarelado, podendo atingir até 1cm de diâmetro;

Recidivantes;

Dor intensa e linfoadenopatia do tipo inflamatório.

Características

As lesões aftosas são encontradas mais comumente na mucosa jugal, labial, na mucosa alveolar ou na superfície ventral da língua.

Regiões não queratinizadas.

Fatores Etiológicos

Agentes infecciosos

Pequenos traumas

Alterações hematológicas

Alterações hormonais

Hereditariedade

Autoimunidade

Fatores Psicogênicos

Classificação

Úlcera Aftosa Minor ou Afta Recorrente de Mikulicz & Kummel

Úlcera Aftosa Major ou Periadenite Mucosa Necrótica Recorrente de Sutton

Herpetiforme

DIAGNÓSTICO

Clínico

História Evolutiva do Quadro

Análise Histopatológica por Biópsia.

Terapêutica

Terapêutica Local: bochechos antissépticos (Clorexidina), anestésicos tópicos, tetraciclina tópica e corticosteróides de uso local.

Terapêutica Sistêmica: Benzodiazepínicos, Corticosteróides, Talidomida, controle hormonal e dietético.

LEVAMISOL

Levamisol é um antihelmíntico e agente imunomodulador
Renoux & Renoux (1971): primeiro a evidenciar seu efeito imunomodulador.

Restaurador da função de células imunodeficientes (fagócitos, linfócitos T e linfócitos B)

Dose adulto:
50 mg de 8 / 8 horas por 3 dias consecutivos, por 2 semanas.
50 mg por dia por 10 dias.

Dose Pediátrica:
3 mg / kg

Efeitos do Levamisol na UAR

Frequência e duração média dos surtos,
Severidades das aftas e conseqüentemente a sintomatologia dolorosa,
Número de aftas.

Principais Efeitos Colaterais

Cefaléia
Náuseas
Depressão
Diminuição da libido
Insônia
Paranóia
Xerostomia
Diarréia

CONCLUSÃO

O Levamisol mostra-se eficaz na terapêutica das Ulcerações Aftosas Recorrentes, diminuindo a freqüência, duração e severidade dos surtos

• Carlos Eduardo Xavier dos Santos Ribeiro da Silva
• Ismael Dale Cotrim Guerreiro da Silva
• Artur Cerri
• Luc Louis Maurice Weckx Oral Surgery
• Oral Medicine
• Oral Pathology
• Oral Radiology and Endodontics
• October 2007 (Vol. 104, Issue 4, Pages 497-500)

ABSTRACT

Oncogenic human papillomaviruses (HPVs) are important agents in the genesis of gynecological cancer, and have also been implied in the genesis of oral cancer. With the purpose of evaluating the relation between HPV and squamous cell carcinoma (SCC) of the tongue a case-control study was performed. 50 Caucasian male patients who were smokers and had the histological diagnosis of SCC of the tongue were selected. The control group was comprised of 10 matched patients with no clinical evidence of tongue lesions. Polymerase chain reaction (PCR) was used to detect the presence of HPV genome in fresh-frozen tissue specimens from SCC of the tongue margin. Thirty seven patients (74%) had a positive PCR for oncogenic papillomavirus, and only one specimen (10%) of the control group was positive for non-oncogenic papillomavirus. Based on the statistical analysis of this study there was a 25.6 higher risk for SCC of the tongue to harbor oncogenic HPV than the healthy control tongur tissue.

INTRODUCTION

Human papillomavirus (HPV) is a virus of the Papillomavirus genus, of the Papovaviridae family, with more than 120 subtypes identified up to the moment, and is composed of a genome of 8000 base pairs of double-stranded DNA forming a complex similar to a chromosome encased by a 55nm non-enveloped outer capsid protein.1 The cleavage site of viral DNA circular molecules is specific, that is, it is always cleaved at the same site between E1 and E2 genes. E2 is responsible for repressing transcription of the E6 and E7 viral genes. Once E2 is inactivated by cleavage of the viral molecule, a dysregulated expression of the E6 and E7 genes occurs.1

The oncogenic potential of the HPV is related to gene products that interact and inactivate cell proteins derived from suppressor genes of p53 and p105-RB and promote degradation of these genes, thus blocking their function. Oncogenicity, among other conditions, will depend directly on the degree of affinity between proteins derived from tumor suppressor genes and viral proteins derived from the E6 and E7 genes. 1 Thus, “high risk� E6 and E7 gene products have a high affinity for p53 and p105-RB derived proteins, whereas “low risk� viral gene derived products have a low affinity for these proteins. The result of viral penetration is the immortalization of cells in which HPV had integrated. These cells morphologically exhibit abnormal mitosis, nuclear pleomorphism, aneuploid DNA content consistent with abnormal chromosome number, and chromosome architectural changes.1 However, these cells only start to generate tumors when the E6 and E7 transforming genes are exposed to activated cell oncogenes1. However, HPV may not operate alone in oncogenesis. In theory, other factors such as the host’s immune status, nutritional deficiency, and cigarette and alcohol consumption operate together favoring and potentializing tumor onset. The association of these factors with oncogenic HPV subtypes is extremely important in the genesis of malignant tumors, since cigarette and alcohol operate as inducing factors and papillomavirus operates in the tumor progression phase.

In fact, recent evidence suggests that HPV can be present in up to 100% of patients with cervical carcinoma.2 The different types of HPV are divided into two groups depending on their oncogenic potential. HPVs considered non-oncogenic are the 6, 11, 42 and 54 subtypes, usually present in verrucous lesions, papillomas and condylomas.3 The oncogenic subtypes are the 16, 18, 31, 33, 35, 39, 45, 51, 55, 56, 58, 66, and 68, which are frequently found in patients with malignant neoplasms.3,4 The mere presence of oncogenic HPV may increase the relative potential for the development of cervical intraepithelial neoplasm by up to 116 times.5 The Word Health Organization considers HPV a carcinogen. Oral cavity cancer is a major cause of mortality and morbidity in Brazil. According to INCA (Brazilian National Cancer Institute)6 data, the estimated incidence of new cases for 2005 ranks it as the eighth most frequent type of cancer in males and ninth in females, with 9985 and 3895 cases, respectively. The most prevalent type of cancer of the oral cavity is the squamous cell carcinoma (SCC) accounting for approximately 95% of all malignant neoplasms of this site. The principal risk factors for oral cancer are smoking, excessive alcohol consumption, and exposure to sun radiation (for neoplasm of the lower lip).

Some authors have associated the presence of HPV, particularly of type 16 as factors contributing to the onset of squamous cell carcinoma (SCC) of the ororpharynx, but its role in oral cavity cancer is controversal.7,8 and 4 The prevalence of HPV in oral cavity cancer has been variable in the literature, mainly due to variations in site and mixture with oropharynx sample size, population studied and sensitivity of the techniques used. The previous results were very debatable and we believed that the methods used in previous research were inadequate. Such studies have used in situ hybridization and the hybrid capture as HPV detection methods, and such methods are substantially less sensitive than PCR. Besides, while the fresh-frozen tissue has a higher preservation rate of viral DNA, many studies have used material from paraffin blocks. A study conducted in 1996 demonstrated that the presence of HPV is more frequent when the sample is tested by PCR (37,1%) than when tested by in situ hybridization (16,9%) and that it is also more frequent when frozen oral tissue is tested (51,6%) than when paraffin-embedded tissue is (21,7%).9Â A meta-analysis of 4680 samples of oral SCC has come to the conclusion that the presence of HPV is more frequent in carcinomatous epithelium and is an independent significant risk factor for oral SCC.10 The objective of the present study is to evaluate the presence of human papillomavirus (HPV) genome both oncogenic and non-oncogenic types in fresh tissue specimens from oral tongue SCC, using polymerase chain reaction (PCR), and to compare these results with those obtained in tissue specimens of a similar site removed a control group of cancer-free individuals.

METHODS

Sixty fresh tissue specimens from the oral tongue were used in this study. Fifty were from patients with squamous cell carcinoma (SCC) of the oral tongue and 10 were from volunteers ( from the hospital staff ) of the control group who had no clinical evidence of disease. and no one had history of cancer The patients were selected at the Outpatient Service of Oral Medicine, of the Federal University of Sao Paulo – UNIFESP, and at the Oupatient Service of the Discipline of Oral Medicine of the Santo Amaro University – UNISA. The material was collected only after approval of the Research Ethics Committees of both UNIFESP and UNISA. All of those patients readied and signed the informed consent.

All subjects participating in the study were males, older than 40 years, Caucasian and smokers. These criteria were used because they are statistically related to the group with a higher incidence of oral cavity cancer according to the Brazilian National Cancer Institute.6 We performed anesthesia followed by incisional biopsy of the lesion, from which a small fragment of tissue was removed using a number-5 biopsy punch (diameter of approximately 5.0mm). For patients with no clinical signs of disease (control group), a small amount of anesthetic agent was infiltrated in the lateral oral tongue, and the tissue was removed with a number-2 biopsy punch (diameter of 2.00 mm).

The tissue removed with a diagnostic hypothesis of SCC was divided into two fragments, one of which was immersed in 10% formalin for pathological examination to confirm the diagnosis, and the other was immersed in an Eppendorf tube with 0.9% saline solution and frozen at minus 20ºC in the Laboratory of Molecular Gynecology of UNIFESP. A similar method was used for the control group. For the SCC group, all patients had squamous cell carcinoma confirmed by histopathological examination.

The “Phenol-Chloroformâ€? protocol for DNA extraction was used for the 60 fresh frozen specimens collected (50 in the SCC group and 10 in the control group). For polymerase chain reaction (PCR), a commercial kit for the detection of HPV (BIOPAP kIT) was used. BIOPAP KIT is manufacturated by Biotools B & M Labs S.A. – Madrid, Spain. According to the manufacturer this kit is able to detect the presence of HPV and separate it into two groups named oncogenic – 16, 18, 31, 33, 35, 52, 58 and 67 and non-oncogenic – 6, 11, 13, 16, 18, 30, 31, 32, 33, 34, 35, 39, 40, 42, 43, 44, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 64, 66, 67, 68 and 69   (manufacture’s nomenclature) according to its oncogenic potential. It needs only 10 copies of the HPV DNA to be positive. For each assay a negative control (DNA replaced by water) and another molecular weight marker were amplified in addition to the specimens and the positive control included in the commercial kit was performed to certificate the method. The visualization of the bands under ultraviolet transillumination enabled determining the presence or absence of HPV DNA in the specimens. In the cases where the reaction was positive thanks to the difference in the number of base pairs between the “oncogenicâ€? (250bp) and the “non-oncogenicâ€? (450 bp) groups, the classification of the specimens in one of these groups was also possible.

The Fisher’s exact test was used to evaluate whether the presence of HPV was associated with oral cancer. To quantify this association, the odds ratio was estimated whenever possible, that is, the likelihood of a patient with HPV to have oral cavity cancer when compared to a patient without HPV using a univariate logistic regression model. The response variable in this model was the presence of cancer (yes or no), and the explanatory variable was the presence of HPV (yes or no).

RESULTS

Of the 50 specimens of squamous cell carcinoma of the lateral oral tongue analyzed by polymerase chain reaction (PCR) to detect human papillomavirus DNA, 37 (74%) were positive for the “oncogenic� subtypes. None of the specimens (0%) was exclusively positive for “non-oncogenic� subtypes. Of the 10 specimens of normal tissue from the control group analyzed with this method, only one (10%) was positive for “non-oncogenic� subtypes and no specimens (0%) were positive for “oncogenic� subtypes.

The prevalence of HPV was not similar in the two groups (p≤0.01). Logistic regression model analysis demonstrate that patients with SCC of the tongue had 25.6 higher odds (95%CI = 3.0 – 222.2) of having oncogenic HPV than the controls. Since none of the patients without oral cancer had oncogenic HPV, estimates using the logistic regression model for odds ratio could not be obtained.Â

DISCUSSION

An interesting study has demonstrated the presence of HPV 16 in 69.2% of oral SCC cases and of HPV 18 in 28% of them by utilizing a combination of PCR with in situ hybridization and has shown also that the same samples tested negative when tested with isolated hybridization11. In our study we have used two groups with different numbers of individuals, being 50 with tongue SCC and 10 without the disease, following the orientation of the Research Ethics Committee – regarding biopsy in patients with no evidence of disease. Despite the different sizes of the material collected in the biopsies (5 mm for SCC cases and 2 mm for the control group), the material used in the PCR had practically the same size, for the fragments of the SCC cases were cut in half to allow the histopathological analysis. We observed that out of a total of 50 specimens of squamous cell carcinoma removed from the lateral oral tongue, 74% were positive for oncogenic subtypes of HPV. These results are similar to those obtained by other authors: 78%12;72.5%;13 72.5%14; 91%15, and 74%16. These results suggest that oncogenic HPV should be considered as a risk factor for oral tongue cancer.

On the other hand, our results are not in agreement with those obtained by several authors such as Chang et al. (1990) who found HPV in 27.5%17 of the oral cavity SCC specimens analyzed; and other authors in 8.4%18; 31%19; 12.5%20 and 42%21. The discrepancy of results is attributed to the fact that in most cases in which the prevalence of HPV was low, a viral DNA amplification from paraffin blocks was performed, whereas in the studies where the prevalence of HPV was higher, like in ours, the DNA was amplified from fresh tissue (frozen immediately after biopsy). The material is usually fixed in 10% formalin prior to being embedded in a paraffin block. Formalin fixation, paraffin embedding, and subsequent deparaffinization can lead to degradation of viral DNA making its detection impossible or difficult9. Secondly, the high-sensitivity and specificity BIOPAP kit (Spain) was used for this study. This kit has the property to detect the presence of HPV genome and to discriminate its potential into the oncogenic and non-oncogenic groups.

Of the 10 specimens of the control group which presented a clinically normal mucosa, only one (10%) was positive for the non-oncogenic subtype, and none of the specimens was positive for oncogenic subtypes. In this sense, our study corroborates many other studies conducted by this authors with 0%14; 11.1%22; and 0%20. Chang et al17. (1990) analyzed 40 specimens of normal tissue and found no evidence of HPV. Based on our findings and on the analysis of other authors’ studies we believe that the tongue is the not the only place in the mouth where oncogenic HPV can be found and we believe that other places in the mouth may have the SCC risk increased by the presence of HPV.

CONCLUSIONS

The study conducted with fresh-frozen specimens of oral tongue squamous cell carcinoma using PCR allowed us to conclude that oncogenic human papillomavirus is present in 74% of cases, whereas the control group had a prevalence of none (only 10% non-oncogenic). These rates suggest that oral cavity cancer HPV positive rates may be higher than previously suspected. More studies are needed to know if the simple presence of HPV in oral cavity can increase the risk of oral cancer.

KEYWORDS: Papillomavirus, Mouth Neoplasms, Head and Neck Neoplasms, Oncogenic viruses, Polymerase Chain Reaction

REFERENCES

1. Syrjanen K, Syrjanen S, Lamberg M, Pyrhonen S, Nuutinen J. Morphological and immunohistochemical evidence suggesting human papillomavirus (HPV) involvement in oral squamous cell carcinogenesis. Int J Oral Surg 1983;dec;12(6):418-24.

2. zur Hausen H. Papillomavirus causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000; 92(9), 690-8.

3. Villa LL. Human papillomavirus and cervical cancer. Advanc Canc Res. V.71, p.321-341, 1997

4. Watts SL; Brewer EE; Fry TL. Human papillomavirus types in squamous cell carcinomas of the head and neck. Oral Surg Oral Med Oral Pathol; 71(6):701-7, 1991 Jun.

5. Rozendal AL, Walboomers JMM, van der Linden JC, Voorhost FJ, Kenemans P, Helmerhost TJM, Ballegooijen M. PCR based high-risk HPV test in cervical cancer screening gives objective risk assessment of women with cytomorphologically normal cervical smears. Int J Cancer; v.68, p.766-9, 1996.

6. Brazilian National Cancer Institute www.inca.gov.br/cancer. Access in 15/04/2006.

7. Gillison, ML et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. Journal of the National Cancer Institute 2000;92(9):709-20.

8. Mineta H, Ogino T, Amano HM, Ohkawa Y, Araki K, Takebayashi S, Miura K. Human papilloma virus (HPV) type 16 and 18 detected in head and neck squamous cell carcinoma. Anticancer Res 1998;nov-dec;18(6B):4765-8.

9. Miller CS, White DK. Human papillomavirus expression in oral mucosa, premalignant conditions, and squamous cell carcinoma: a retrospective review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997 Feb;83(2):187-8

10. Miller CS; Johnstone BM. Human papillomavirus as a risk for oral squamous cell carcinoma: a meta-analysis, 1982-1997. Oral Surg Oral Med Oral Pathol Oral Radiol Endod; 91(6):622-35, 2001 Jun.

11. Miller CS; Zeuss MS; White DK. Detection of HPV DNA in oral carcinoma using polymerase chain reaction toguether with in situ hybridization. Oral Surg Oral Med Oral Pathol; 77(5):480-6, 1994 May

12. Woods KV, Shillitoe EJ, Spitz MR, Schantz SP, Adler-Storthz K. Analysis of human papillomavirus DNA in oral squamous cell carcinomas. J Oral Pathol Med 1993;mar;22(3):101-8.

13. Nielsen H, Norrild B, Vedofte P. Human papillomavirus in oral premalignant lesions. Eur j Cancer B Oral Oncol 1996;(32):264-70.

14. Cao J, Zhang ZY, Zhang YX. Human papillomavirus infection and p 53 alteration in oral squamous cell carcinoma. Chin Dent Res 2000;nov;3(3):44-9.

15. Bouda M, Gorgoulis VG, Kastrinakis NG, Giannoudis A, Tsoli E, Danassi-Afentaki D, et al. “High risk” HPV types are frequently detected in potentially malignant and malignant oral lesions, but not in normal oral mucosa. Mod Pathol 2000;jun;13(6):644-53.

16. Balaram P, Nalinakumari KR, Abraham E, Balan A, Hareendran NK, Bernard HU, Chan SY. Human papillomaviruses in 91 oral cancers from Indian betel quid chewers-high prevalence and multiplicity of infections. Int J Cancer 1995;may; 16; 61(4):450-4.

17. Chang F, Syrjanen S, Nuutinen J, Karja J, Syrjanen K. Detection of human papillomavirus (HPV) DNA in oral squamous cell carcinomas by in situ hybridization and polymerase chain reaction. Arch Dermatol Res 1990;282(8):493-7.

18. Kansky AA, Poljak M, Seme K, Kocjan BJ, Gale N, Luzar B, Golouh R. Human papillomavirus DNA in oral squamous cell carcinomas and normal oral mucosa. Acta Virol 2003;47(1):11-6.

19. Koppikar P, deVilliers EM, Mulherkar R. Identification of human papillomaviruses in tumors of the oral cavity in an Indian community. Int J Cancer 2005;mar;113(6):946-50.

20. Sand L, Jalouli J, Larsson PA, Hirsch JM. Human papilloma viruses in oral lesions. Anticancer Res 2000;mar-apr;20(2B):1183-8.

21. Ibieta BR, Lizano M, Fras-Mendivil M, Barrera JL, Carrillo A, Ma Ruz-Godoy L, Mohar A. Human papilloma virus in oral squamous cell carcinoma in a Mexican population. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;mar;99(3):311-5.Â

22. Summersgill KF, Smith EM, Kirchner HL, Haugen TH, Turek LP. p53 polymorphism, human papillomavirus infection in the oral cavity and oral cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90(3):334-9

* Carlos Eduardo Xavier dos Santos Ribeiro da Silva
** Artur Cerri
*** Francisco Octávio Teixeira Pacca
**** José Augusto Ferrari Cestari

. DDS, PhD Associate Prof of Oral Medicine- Santo Amaro University – Unisa, Brazil
** DDS, PhD, Chairman of Oral Medicine- Santo Amaro University – Unisa, Brazil
… DDS, PhD Associate Prof of Oral Medicine- Santo Amaro University – Unisa, Brazil
…. DDS, Specialist in Oral Medicine- Santo Amaro University – Unisa, Brazil

Mail address:

Rua Pelotas, 358 – Vila Mariana – SP- Brasil – 04012-010
dreduardosilva@terra.com.br
55 (11) 5571-1736

ABSTRACT

The Peutz-Jeghers (PJS) is an autossomal dominant condition. It´s predominant clinical features are melanosis in the oral mucosa and intestinal polyposis, with a tendency for malignant transformation. The dentists could be the first professional to detect the oral lesions, and aid in early diagnosis of the condition. Earlier is the diagnosis better is the prognosis since the intestinal polyposis could lead to malignant transformation. This publication is a case report from a patient that presented to the dentist for routine evaluation of the mouth, although later, she was diagnosed as a case of PJS.

INTRODUCTION

The Peutz-Jeghers (PJS) is an autossomal dominant condition, which prevalence is 1 in 8300 to 29000 births in USA (Bishop, Loftis e Nowicki, 2004 ). There is no sex or race predilection. Although this is a genetic autossomal dominant disease, just half of the patients give a positive family history during anamnesis.

The evolution of PJS during life, exposes the patient to a predisposition to developing malignant neoplasias, mainly in the small bowel, ceccum, rectum, as well as pancreatic adenocarcinomas. Other more rare carcinomas could occur in the breast, uterus, testicles and ovarium. The risk for cancer of those patients is 18 times higher in comparison with the general population, and as high as the number of intestinal polyps the higher is the chance for malignant transformation (Lindor, 2004). The first case of PJS, was presented by Hutchinson in 1896, when he described a case of twins with diffuse labial pigmentation. Peutz presented in 1921 a case of intestinal familial polyposis associated with hyperpigmentation of skin and mucosa in general. In 1949, Jeghers et al. complemented the association of pigmentation and intestinal polyposis and confirmed the familiar origin of the disease (Schreibman et al., 2005). Since then, these features together were denominated Peutz-Jeghers Syndrome (PJS). The Involved chromossome is 19p13.3 with apparent mutation in the locus (STK11) LKB1 with the enzyme serin/treonin kinase functionally inhibiting the tumoral supressor genes ( Doxey, Kuwada e Burt, 2005 ).

The melanotic pigmentation could be present at birth or appearing later in childhood, with characteristic distribution in the perioral mucosa (Pereira et al., 2005). It is important to emphasize that they are spots-like and not plaques, with alteration in color but not in the surface of the lesions. In the mouth, the main area of occurrence is the labial mucosa as well as the buccal mucosa, but they can also be found on the tongue, gingiva and hard palate, and are variable in number as well as in shape (Ciçek & Ertas, 2003 ). In the skin they occur in general on the dorsum of the hands and feet, and also the fingers. The lesions are very dark or dark blue, with a diameter ranging from 1 to 12 mm. When the melanotic spots are localized on the face, the diameter of the spots rarely are larger than 2 mm (Afolabi, 2003 ).

The skin lesions could disappear during puberty but the lesions in the mouth persists forever. The histological evaluation show higher amounts of melanin in the basal layer of the epithelium close to the basal lamina. The hamartomatous polyps are the main characteristic of the syndrome and they could vary in their shape, size, number and anatomical distribution, being found in different areas of gastrointestinal tract. In older patients, during colonoscopy multiple polyps are mainly found in the final bowel region. The polypus could be sessiles or pedunculated, with a diameter varying between 1 to 3 cm, and they could be considered capable to transformation in real cancer depending on the histological aspects seen in microscopy.

Approximatelly 35% of the patients with PJS were diagnosed in childhood or during puberty (Bronner, 2003 ). In general they complain of abdominal pain, compression of abdominal area, mainly in the region of intestinal colum, blood in the feces and frequent muscular spasm after ingestion of meals. There is alternating diarrhea and intestinal constipation. The symptoms of intestinal obstruction and/or hemorrage start to appear at 20 and 30 years of age. (Bronner, 2003 ).

When there is a suspaician of PJS, the gastrointestinal tract of the patient needs to be evaluated and examined by gastric endoscopy and colonoscopy, as well as the intestinal transit of fecal material by contrast radiographies. Other investigations are reactive proteín C, ferritin and hemogram, to detect inflammation and lost of blood in the feces (Schreibman et al., 2005 ). The histological examination of the oral pigmentation include large amounts of melanin in the basal layer of the epithelium. Considering the features of PJS, the differential diagnosis are: Crohn, Albright and Addison diseases .The gastroenterologist is the indicated professional to treat the disease more suitably.

CASE REPORT

A 24 years old single caucasian female, patient from São Paulo, attended in the Department of Oral Medicine of the School of Dentistry at Santo Amaro-Unisa, Brazil) for routine dental treatment. The clinical intra-oral exam revelead dark pigmented spots, painless, and varying in size and number, in the right and left sides of buccal mucosa and in the lips (Figs. 1,2). The general condition of oral hygiene was reasonable, although mild gingivitis was observed. The other aspects of the oral cavity were within normal limits.

Some inflammatory submandibular lymphnodes were observed bilaterally. During Medical history she did not mentioned any disease except some childhood diseases. Some lab investigations such as glycemia, hemogram, urine type I were within normal range.

The patient had never observed the pigmentation in the cheek and did not know the cause of them. The arterial blood pressure at the time of consultation was 120 x 80 mm Hg, the pulse was 85 bpm and the body temperature was 36.5° C. The color and the face was normal and without any pigmentation as well as in other regions of the body. The patient´s younger brother and deceased parents had no such symptoms.

The patient mentioned gastrointestinal problems such diffuse pain and intestinal constipation of many years duration, but she had never visited a gastroenterologist for consultation. All signs and symptoms were suggestive of Peutz-Jeghers Syndrome and so, the patient was advised to make an appointment with a gastroenterologist. We first asked for a dosage of ACTH to eliminate the possibility of Addison disease. An incisional biopsy was also accomplished in one of the pigmented spots. The microscopic result was melanotic pigmentation (fig 3). To investigate the possibility of Albright syndrome, radiographic from the femur, in different positions (front and lateral) were done, and the results showed normal bone aspects for the patient´s age. All the exams results were given to the patient in order to show to the gastroenterologist. The physicians requested for a colonoscopy and the result was positive for colon diverticular polyposis (fig.4), and the diagnosis of PJS have made. Currently the patient is under dental and medical treatment.

DISCUSSION

The dentist must guide the patient when any unusual signs and/or symptom are observed during an anamnesis and clinical examination.

Additionally the oral cavity is considered a part of the gastrointestinal tract of the individual. Any experienced clinician knows that a detailed examination of the oral cavity may show signs of many systemic diseases, for example anemia, leukemias, dermatological diseases, systemic diseases and several syndromes. Considering PJS particularly or any other disease, early diagnosis is very important for the patient and subsequent treatment. The dentist as a health professional, may have the opportunity to diagnose many systemic diseases, since many signs or symptoms of these disease may appear first in the mouth. In this specific case presented, the multiple pigmented lesions in childhood or puberty, scattered in the mouth and periorally, PJS must be considered in the diagnosis. Nowadays the dentists are well informed and have studied much more than in the past and know more about general pathology. Thus it is essential to establish an integration between all health professionals, mainly, dentists and physicians. Such interchangeable experiences and knowledge are of fundamental importance in diagnosis that would benefit the common patient. Thus always an early diagnosis could sometimes aid in management of the disease, thereby reducing morbidity and mortality of our patients.

CONCLUSIONS

The dentist must be capable of recognizing the characteristic signs and symptoms of Peutz-Jeghers Syndrome (PJS) in oral cavity and ascertain early diagnosis in connection with the patient physician.

Although it is a rare syndrome, if let alone, it could promote a gastrointestinal carcinoma, that could be lethal to the patient´s life.

In addition to an oral examination the dentist should request for further investigations if there is suspicion of any systemic disease with oral manifestations.

Unfortunately the biopsy is still not an investigation procedure routinely used by the dentist, but this conception must be changed.

– A patient suspected of PJS, should visit a gastroenterologist to confirm the diagnosis before any dental treatment has been started.

– Any alteration in color and/or pigmentation in the oral cavity, even without any other symptoms, should, in principle, be always investigated.

IMAGES

REFERENCES

Afolabi, O.O. Oral melanosis: a case report of Peutz-Jegher’s Syndrome in Suva, Fiji. Pac Health Dialog;10(1):55-6, 2003 Mar.
Bishop, P.; Loftis S; Nowicki M; What syndrome is this? Peutz-Jeghers syndrome.; Pediatr Dermatol;21(4):503-5, 2004 Jul-Aug.
Bronner, M.P.; Gastrointestinal polyposis syndromes.; Am J Med Genet A;122(4):335-41, 2003 Nov 1.
Ciçek, Y.; Ertas, U.; The normal and pathological pigmentation of oral mucous membrane: a review.; J Contemp Dent Pract;4(3):76-86, 2003 Aug 15
Doxey, B.W.; Kuwada, S.K.; Burt, R.W,; Inherited polyposis syndromes: molecular mechanisms, clinicopathology, and genetic testing.; Clin Gastroenterol Hepatol;3(7):633-41, 2005 Jul.
Lindor, N.M.; Recognition of genetic syndromes in families with suspected hereditary colon cancer syndromes.; Clin Gastroenterol Hepatol;2(5):366-75, 2004 May.
Pereira, C.M.; Coletta, R.D.; Jorge, J.; Lopes, M.A.; Peutz-Jeghers syndrome in a 14-year-old boy: case report and review of the literature. Int J Paediatr Dent;15(3):224-8, 2005 May.
Schreibman, I.R.; Baker, M.; Amos, C.; McGarrity, T.J.; The hamartomatous polyposis syndromes: a clinical and molecular review.; Am J Gastroenterol;100(2):476-90, 2005 Feb.

Eduardo Kazuo Sannomiya, DDS, MSc, PhD
Marcelo de Queiroz Nogueira, DDS
Marli de Carvalho Diniz, DDS
Francisco Octavio Teixeira Pacca, DDS, MSc, PhD
Gisele da Silva Dalben, DDS, MSc

ABSTRACT

The dentigerous cyst is the most common developmental odontogenic cyst of the jaws.
The purpose of this artide was to report the case of a dentigerous cyst associated with a permanent maxillary central incisor in a 5-year-old boy whe had suffered severe facial trauma at age 4. Panomaric and periapical radiographs revealed a well-defined radiolucent area with radiopaque borders surrounding the permanent maxillary left central incisor, causing displacement of the tooth buds of the permanent maxillary left lateral incisor and canine and root resorption of the deciduous maxillary left lateral incisor. Treatment was performed by aspiration and enucleation; the permanent maxillary left central incisor was part of the cyst and, thus, was also removed. (J Dent Child 2007;74:161-4)
KEYWORDS: CYST DENTIGEROUS, DENTAL TRAUMA, TOOTH, PRIMARY TOOTH

The dentigerous cyst is the most common developmental odontogenic cyst the jaws and accounts for 20% to 24% of all epirthelium-lined jaw cysts.
It is defined in the literature as a cyst surrounding the unerupted tooth’s crown and adhered to its cervical region.
This diagnosis should not be based only on radiographic evidence. Instead, it should include macroscopic and microscopic examination of the specimen, since various other lesions-such as unicystic ameloblastoma, odontogenic keratocysts, and central giant granuloma-may also occur in this position.

Dr. Sannomiya is professor in Dentomaxillofacial Radiology, Dentomaxillofacial Department of Oral and Maxillofacial Radiology, São Paulo Methodist University, São Paulo, Brazil, and professor of the Post Graduation Program in Orthodontics, São Paulo Methodist University; São Paulo, Brazil; Dr. Nogueira is an orthodontist and Dr. Diniz is a periodontist, both at the São Paulo Dental Association, (APCD); Dr. Pacca is professor or Oral Stomatology, Department of Stomatology, Santo Amaro University (UNISA), São Paulo; and Dr. Dalben is pediatric dentist in orofacial clefts and a a student in oral pathology, Department of Pediatric Dentstry and Community Dentistry, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil.
Correspond with Dr. Sannomiya at eduardosannomiya@hotmail.com

The pathogenesis of dentigerous cyst is still controversial. Some authors have suggested a developmental origin affecting mature teeth usually secondary to tooth impaction.
In this case, it would be initiated by accumulation of fluid within the reduced enamel or between the reduced epithelium and enamel. An inflammatory nature has also been suggested, which would affect immature teeth as a result of inflammation (eg, from a nonvital deciduous tooth), spreading to the region of the tooth follicle.
Most patients diagnosed with dentigerous cyst are younger than 20 years old; the percentage of 6- to 7-year-old patients with dentigerous cysts in only 9%. Associating this finding with tooth trauma would be even less frequent, according to Counts et al, who reported a case of an angressive dentigerous cyst in a 7-year-old child.
Due to the small number of cases at this age range and scarce reports of association with trauma, the purpose of this article was to report the case of a dentigerous cyst involving the permanent central incisor’s tooth bud of a 5-year-old child who had a history of trauma to the maxillary region.

CASE DESCRIPTION

A 5-year, 9 month-old boy presented at the Pediatric Dental Clinic of São Paulo Methodist University, São Paulo, Brazil, for initial screening. Before this, the mother had taken the child to a private dental practitioner. The professionals at São Paulo Methodist University attempted to contact this practittioner, yet he had moved to an unknown address.
During anamnesis, the mother reported that the child had suffered severe trauma to the face at age 4 years, with bleeding and lip wounds, followed by edema without need of suture. The mother did not mobility of any deciduous teeth after the trauma nor did she report any occurrence of alveolar fracture. One year later, they came to the pediatric dental clinic due to appearance of bucal swelling with cortical thinning, with sensitivity of the left anterior teeth (Figure1). Panoramic and periapical radiographs were then obtained, revealing significant root resorption of the primary maxillary left central and lateral incisors with lingual displacement left of the incisors and canine. There was also superior and distal displacement of the permanent maxillary left central and lateral incisors and canine. The radiolucency was diffused, with ill-defined borders. Except for one focal area in the midline, there was no evidence of sclerotic margin (Figure 2). Based on these clinical and radiographic characteristics, differential diagnosis included the hypotheses of dentigerous cyst, central giant cell granuloma or central hemangioma.

Figure 1. Intraoral aspect with mild buccal swelling.

Figure 2a and 2b.

Initial panoramic and periapical radiographs demostrating well-defined radiolucent area with radiopaque borders surrounding the permanent maxillary left central incisor and displacement of tooth buds of the permanent maxillary left lateral incisor and canine.

The patient was then referred to a maxillofacial surgeon. A buccal intrasulcular incision was performed from the deciduous maxillary rigth lateral incisor to the deciduous maxillary left firt molar and two releasing incisions were made from the distal papillae of these teeth to the buccal sulcus. The attached gingiva and alveolar mucosa were thoroughly dissected to allow good surgical access.

The swollen region exhibited a very thin cortical plate, allowing aspiration of the cyst, which revealed a yellowish liquid characteristic of cystic content. Enucleation was then performed by fabrication of a window access on the bucal bone plate. The deciduous maxillary left lateral incisor was also extracted at this time.
During resection, it was noticed that the permanent maxillary left central incisor was part of the cyst. Thus, its removal was necessary (Figure 3). The surgical site was completely curetted for removal of all cystic epithelial remnants and to induce bleeding in the area for new bone formation and healing. The flap was repositioned and sutured with Vicryl 4-0.

Figure 3.

 Removed cyst with tooth bud of the maxillary left central incisor-macroscopic view.

Macroscopic examination revealed that the cyst measured 2.5×2.0×1.8 cm and contained a tooth structure in its interior measuring 1.2×0.8 cm and another on its wall measuring 0.8×0.6 cm. Microscopic examination revealed tooth fragments embedded in a cystic structure lined by nonkeratinized squamous epithelium without atypical figures. The histological examination also revealed the presence of moderate inflammatory infiltrate with lymphocytes and plasma cells and capillary proliferation, which led to a final diagnosis of dentigerous cyst (Figure 4).

Figure 4

Cystic structure lined by nonkeratinized squamous epithelium without atypical figures-microscopic view, hematoxylin-eosin staining, original magnification X10.

Postsurgical follow-up was performed after 8 months. The panoramic radiograph obtained on August 2006 revealed partial repositioning of the maxillary left lateral incisor’s tooth bud. The maxillary left canine’s tooth bud is still located above the tooth buds of the maxillary left first and second premolars (Figure 5).

Figure 5

Follow-up panoramic radiograph after 8 months, demonstrating partial repositioning of the maxillary left lateral incisor and canine.

DISCUSSION

The exact histogenesis of dentigerous cysts is unknown.
Development of a dentigerous cyst, howerer, requires the presence of an unerupted tooth. Regarding its pathogenesis, Al-Talabani and Smith suggested that they may have an extrafollicular or intrafollicular origin, and that the latter may occur by fluid accumulation between the reduced enamel epithelium or within the enamel organ. It has also been suggested that the permanent tooth’s crown may erupt in a periapical cyst related to the respective deciduous tooth.
This phenomenon probably occurs, although not often, because periapical cysts are not common in the deciduous dentition. In the present case, there was a history of trauma to the deciduous maxillary central incisor. At that time, no diagnosis was made regarding impaction of the permanent maxillary central incisor. Kubota et al reported that trauma to deciduous teeth can lead to disturbances in the odontogenesis of the respective permanent teeth. Such disturbances may usually give rise to hypoplastic defects or crown/ root disruption in the permanent teeth, or even deviations from the normal eruption pathway.
This type of dentigerous cyst usually promotes bone expansion, but rarely causes cortical destruction. The growth potential of this cysts is apparently limited, but it

can cause sufficient bone expansion to promote facial asymmetry, as in the present case. Many dentigerous cysts reach great dimensions before being diagnosed. Displacement of impacted teeth to another region, such as the mandibular border, is relatively common. Movement of adjacent teeth or root resorption may also occur. In the present case, the permanent maxillary left lateral incisor’s tooth bud was severely displaced to the region of the maxillary left first and second premolars, and the tooth bud of the permanent maxillary left canine was displaced close to the maxillary sinus above the tooth bud of the permanent maxillary left lateral incisor. There was also root resorption of the deciduous maxillary left lateral incisor.
Even though the dentigerous cyst is the most frequent jaw cyst in the first decade of life, its frequency is lower in the 3 following decades. According to Shear, dentigerous cysts are primarily related to premolars and molars and rarely affect the incisors and the age range reported in the present case.
Selection of the proper surgical technique depends on the dimension of the osteolytic region and its relationship with anatomical structures observed radiographically. Enucleation is the technique of choice for small cysts. In the present case, it was possible to enucleate the entire lesion, despite the extensive bone destruction. Another surgical option would be marsupialization, usually recommended for larger cysts, which can promote decompression and lesion redduction.
In the present case, complete enucleation was preferred due to the need for differential diagnosis with odontogenic keratocyst and the interrupted root development of the central incisor. This type of cyst may be detected by routine radiographic examination. Patients with dentigerous cysts should be submitted to thorough radiographic examination combined with histopathological examination to allow selection of the proper treatment plan.
Treatment planning from now on comprises extraction of the deciduous molars at a later age to facilitate the eruption of premolars. Also, extraction of one premolar will probably be necessary for achievement of space to the maxillary left lateral incisor and canine.

REFERENCES

1. Shear M. Inflammation in dental cysts. Oral Surg 1964;17:756-67.
2. Farman GA, Nortjé CJ, Wood RE. Cysts of the jaws. In: Oral and Maxillofacial Diagnostic Imaging. 1st ed. Sr. Louis, Mo: Mosby Co; 1993:212-6.
3. Benn A, Altini M. Dentigerous cyst of inflammatory origin: A clinicopathologic study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:203-9.
4. Lustig JP, Schwartz D, Shapira A. Odontogenic cysts related to pulpotomized deciduous molars. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:499-503.
5. Takagi S, Koyama S. Guided eruption of an impacted second premolar associated with a dentigerous cyst in the maxillary sinus of a 6-year-old child. J Oral Maxillofac Surg 1998;56:237-84.
6. Counts AL, Kochis LA, Buschman J, Savant TD. An aggressive dentigerous cyst in seven-year-old child. J Dent Child 2001;87:499-503.
7. Al-Talabani N, Smith CJ. Experimental dentigerous cysts and enamel hypoplasia: Their possible significance in explaining the pathogenesis of human dentigerous cysts. J Oral Pathol 1980;9:82-91.
8. Kawamura JY, Magalhães RP,Souza SC, Magalhães MH. Management of a large dentigerous cyst occurring in a 6-year-old boy. J Clin Pediatr Dent 2004;28:355-7.
9. Shibata Y, Asaumi J, Yanagi, Y, Kawai N, Hisatomi M, Matsuzaki H, Konouchi H, Nagatsuka H, et al. Radiographic examination of dentigerous cysts in the transitional dentition. Dentomaxillofac Radiol 2004;33:17-20.
10. Kubota Y, Yamashiro T, Oka S, Ninomiya T, Shirasuna K. Relation between size of odontogenic jaw cysts and the pressure of fluid within Br J Oral Maxillofac Surg 2004;42:391-5.
11. Homem MGN, Simoes WA, Zindel D, Chilvarquer I, Aparecida TA. Dentigerous cyst associated with an upper permanent central incisor: Case report and literature review. J Clin Pediatr Dent 2002;26:187-92.
12. Bodner L. Cystic lesions of the jaws in children. Int J Pediatr Otorhinolaryngol 2002;62:25-9.
13. Singh S, Singh M, Chhabra N, Nagar Y. Dentigerous cyst: A case report. J Indian Soc Pedod Prev Dent 2001;19:123-6.
14. Motamedi MH, Talesh KT. Management of extensive dentigerous cysts. Br Dent J 2005;198:203-6.
15. Jones TA, Perry Rj, Wake MJ. Marsupialization of a large unilateral mandibular dentigerous cyst in a 6-year-old boy: A case report. Dent Update 2003;30:557-61.
16. Takagi S, Koyama S. Guided eruption of an impacted second premolar associated with a dentigerous cyst in the maxillary sinus of a 6-year-old child. J Oral Maxillofac Surg 1998;56:237-9.

Carlos Eduardo Xavier dos Santos Ribeiro da Silva, DDS ; Artur Cerri, DDS; Francisco Octávio Pacca, DDS; Luc Louis Maurice Weckx,DDS; Ines Velez, DDS, MS; Michael A. Siegel, DDS, MS

Learning Objectives

After reading this article, the reader should be able to:
* Describe ameloblastomas and the differences among their classifications.
* Discuss the variety of benign and malignant palatal lesions.
* Describe characteristics of how oral lesions – benign or malignant – may present upon intraoral examination.
* Explain the importance of obtaining histopathologic evaluations of lesion tissue removed from the oral cavity to render accurate diagnoses.

Abstract

Rendering a diagnosis of benign or malignant lesions in the oral environment based solely on clinical and radiographic examination is insufficient to ensure the delivery of proper treatment and the realization of the best long-term prognosis. Because many lesions exhibit characteristics similar to those of either less-aggressive or more destructive pathologies, clinicians must understand the anatomy of the tissues inherent to each area of the oral cavity, as well as the pathologies of different lesions. Additionally, when suspicious lesions are encountered, histopathologic examination should be part of the diagnostic process. This article describes several classifications of benign and malignant lesions found in the oral cavity and presents three cases to demonstrate the manner in which thorough intraoral, head/neck cancer, and histopathologic evaluations were used for diagnosis and treatment planning.

Lesson

Throughout the course of practice, clinicians may encounter patients who present with lesions in the oral cavity. Such lesions may affect the hard or soft tissues – and be either benign or malignant. Correctly diagnosing oral lesions based on clinical and radiographic examination alone may be challenging because their appearance and characteristics initially may be indicative of a different pathology.

Understanding the lesions of the jaw and the hard or soft palate requires appreciation of the different tissues inherent to each area. Knowledge of the complexity of the salivary glands and their structural components is also necessary.

During a vigilant intraoral examination, a high level of knowledge-based suspicion, as well as conducting a thorough head and neck cancer examination, are important to establishing an early and correct diagnosis of the lesion and ensuring the best prognosis for the patient. Additionally, however, microscopic histopathologic evaluation of all tissue removed from the oral cavity is paramount to determining appropriate treatment protocol, particularly when clinical and radiographic findings may suggest another pathology and, therefore, therapy for the lesion in question.

This article describes several classifications of lesions found in the oral cavity (hard/soft palate and jaws) and their respective characteristics. To emphasize the need for thorough intraoral and histopathologic evaluations to ensure the best prognosis for the patient, three cases involving benign and malignant lesions are presented. The process engaged in each case for rendering a differential and definitive diagnosis is also discussed, in addition to any recommended treatment.

Ameloblastoma

The ameloblastoma is a benign, locally aggressive, and invasive neoplasm exclusively affecting the mandible that frequently recurs after treatment.1 Guzak first described it in 1826, and Falkson provided a histological description in 1879.2

Ameloblastoma is derived from odontogenic epithelium, but there are some doubts about its histogenesis. Theories to explain the histogenesis of ameloblastomas postulate that lesions may arise from epithelial remnants of the enamel organ, proliferation of the epithelium that encases the odontogenic cysts, or the cells of the oral mucosa.3,4

According to The World Health Organization, ameloblastomas are classified as conventional, unicystic, and peripheral. Histologic subtypes are desmoplastic, follicular, granular cell, plexiform, and acanthomatous.5,6 Although locally invasive but benign, two related entities can metastasize: the histologically benign ameloblastoma that exhibits malignant behavior (ie, malignant ameloblastoma) and the ameloblastoma with malignant microscopic manifestations (ie, ameloblastic carcinoma).7

The conventional ameloblastoma demonstrates asymptomatic pathology, evolves slowly, and occurs at any age. The most frequent multicystic variant presents in patients anywhere in their 30s through their 70s; the unicystic ameloblastoma is more common in patients who are in their 20s.8

The occurrence of ameloblastoma is independent of sex or ethnic origin, and approximately 80% of cases affect the posterior mandible and ascending ramus.9 It is also commonly associated with an unerupted third molar.

Radiographically, ameloblastomas manifest as osteolytic, well-defined, multilocular lesions showing bone septa, contributing to their soap bubble or honeycomb appearance. Early lesions are unilocular. Root resorption of the involved teeth frequently occurs.10,11

Although ameloblastoma is a benign neoplasm, clinicians have sought suitable treatments because of its typically local, aggressive behavior. Extensive resections have been chosen for solid and multicystic ameloblastomas, whereas those that are unicystic have been treated with enucleation. However, there is a tendency among oral surgeons to adopt less aggressive procedures because the relapse ratios of the lesion are not very different when treated with conservative therapies (eg, enucleation and cryosurgery) compared to radical methods (eg, segmental resection with or without bone reconstruction).

Curi et al advocate that when choosing treatments for ameloblastoma, the patient’s morbidity and quality of life must be considered because extensive resections provoke such problems as chewing difficulties, mutilation, facial deformity, and abnormal mandibular movements.12 Additionally, these authors note that after observing 46 cases of solid ameloblastomas that were treated with surgical enucleation followed by cryosurgery, clinical and radiographic follow-up of the surgical complications showed that – in 30.6% of the cases – there was a local recurrence. Complications included wound dehiscence, paresthesia, infection, and pathologic fracture.12

Feinberg and Steinberg13, along with Neville14, claimed that the recurrence ratios for solid ameloblastomas were between 15% and 25% whenever more radical treatment measures were used. Nakamura et al. described a conservative therapy for cystic ameloblastomas by marsupialization and posterior enucleation that was efficient and resulted in few relapses.15 Radiotherapy, as an auxiliary therapy for ameloblastoma, was recommended in the past but then abandoned because – in addition to the risk of bone necrosis and malignant transformation caused by the radiation – the lesion is resistant to radiotherapy.16

Palatal Lesions
Torus palatinus, the most common palatal entity, presents as an osseous, exophytic, centrally located, midline, and usually symmetric asymptomatic lesion of the hard palate. The epithelial tissues covering tori are attenuated (ie, stretched) because of the underlying bony prominence, subjecting this site to ulcerations of traumatic origin. Inflammatory lesions of dental origin are also common in the hard palate.14

Malignant Squamous Epithelial Neoplasms
Malignant squamous epithelial neoplasms – such as squamous cell carcinoma, verrucous carcinoma, and carcinoma of the maxillary sinus – may also appear in the hard palate. Carcinoma of the maxillary sinus usually remains asymptomatic for long periods of time. Eventually, the tumor grows to fill the sinus and diagnosis is rendered when the lesion has produced a bulge of the palatal or alveolar ridge area. This tumor usually is associated with elderly patients.14
Squamous cell carcinoma of the soft palate is often painful, may cause dysphagia, and offers a worse prognosis than tumors located in more anterior locations. Squamous cell carcinomas extending from the maxillary alveolar ridge onto the hard palate may present a diagnostic challenge because they mimic periodontal disease or pyogenic granulomata. Alveolar and palatal carcinomas are usually painless. Verrucous carcinoma is a type of squamous cell carcinoma that exhibits a papillary, white clinical appearance; behaves indolently; and rarely metastasizes. The most common locations for this lesion are the hard palate and the alveolar ridge; it is often associated with elderly patients wearing complete denture prostheses.14

Salivary Gland Tumors
A wide range of conditions can develop in the numerous small minor salivary glands located within the submucosa of the palate. For example, necrotizing sialometaplasia is a salivary gland condition that usually appears as a crater-like defect of the posterior palate, may be associated with pregnancy, and while ominous in appearance, will usually resolve spontaneously following biopsy confirmation of the diagnosis.14
Salivary gland tumors represent a diverse group of neoplasms; the majority are of ductal or acinic epithelial derivation. Although tumors of salivary glands are not common, they are not rare in occurrence. The biologic behavior of salivary gland tumors is paradoxical. A benign tumor of salivary glands tends to exhibit a more aggressive behavior pattern than the usual benign tumor; a malignant tumor of salivary glands is less aggressive than the usual malignant tumor.17
Minor salivary gland tumors have an affinity for the posterior hard palate and the soft palate and virtually never develop in the midline; this is probably due to the natural distribution of salivary tissues throughout the palate. Both benign and malignant salivary gland neoplasms of the palate appear as well-circumscribed, dome-shaped and smooth-surfaced, nonmovable swellings that exhibit a very slow growth pattern. Pain and ulceration are occasionally seen in adenocarcinomas at this site.17
The most common benign salivary gland tumor of the palate is the pleomorphic adenoma. The most common malignant tumors of the palate are adenoid cystic carcinoma (ie, cylindroma), polymorphous low-grade adenocarcinoma, and mucoepidermoid carcinoma. Most of these tumors, both benign and malignant, are asymptomatic masses or associated with a low level of discomfort. Constant pain in the palate associated with a gradual increase in intensity that is usually present before any noticeable swelling is a common and important characteristic of adenocystic carcinoma. Malignant tumors of the palate may show radiographic evidence of bone destruction and sometimes a radiopacity produced by the neoplastic mass. Intraosseous salivary gland tumors also may develop within the jaws.17
Salivary gland tumors are considered separately from other palatal pathologies because an extensive number of these lesions have been identified. Salivary gland tumors have been classified to include 13 benign tumors and six malignant low-grade, 10 malignant intermediate-grade, and 13 malignant high-grade neoplasms.18

Melanomas
Melanoma is a malignant tumor of melanocytic origin. Although the majority occurs on the skin, they may develop in any site, such as the oral cavity, where melanocytes exist. Significant numbers of melanocytes are normally found in the palatal mucosa. In fact, the most common site for a melanocytic nevus and melanomas of the oral cavity is the palate. Approximately 30% of melanomas develop from previously existing pigmented lesions.14, 19
Oral melanoma appears predominantly on the hard palate or maxillary alveolus and tends to be much more aggressive than its cutaneous counterpart. Early lesions are usually flat and later become nodular and fixed. Most melanomas appear as dark/light brown lesions.14
The prognosis of nonskin melanoma is very poor and primarily dependant on its depth. The “3-D” rule generally can be applied to a melanoma’s prognosis. The darker the melanoma appears clinically, the deeper it is within the epithelium and, therefore, the deadlier the result. It is usually the most aggressive malignant neoplasm of the human body. To clinically differentiate a melanoma from nevus, another pneumonic that can be used is the “ABCD” system, which is widely used by dermatologists: Asymmetry of the lesion; Borders irregularity; Color variation; Diameter greater than 0.6 cm.14

Lymphoma
The posterior palate is also a part of the Waldeyer’s ring and presents numerous aggregates of normal, protective lymphoid tissue that may be the originating site of lymphoma. Lymphoma (ie, lymphosarcoma) encompasses a diverse and complex group of malignancies of lymphoid histogenesis. The most frequent locations of extranodal lymphoma in the head and neck are the posterior hard and soft palate. Lymphomas usually appear as a nontender diffuse mass and are rarely ulcerated. Many salivary gland lymphocytic infiltrates of the palate are actually non-Hodgkin’s B-cell lymphomas of the mucosal associated lymphoid tissue (MALT).14 Sarcomas, malignant tumors of nonepithelial tissue origin, may develop in any location of the human body and usually appear as ulcerated masses in young or middle-aged people.

Case Presentation No. 1: Ameloblastoma
A 25-year-old woman was referred to the Oral Surgery Department of the University of Santo Amaro – UNISA, in São Paulo, Brazil, by the Orthodontics Department for evaluation of a radiolucent lesion in the area of the missing right inferior first molar. During consultation, the patient did not report any relevant information regarding her medical history, family antecedents, dental history, or medication use.

Clinical Examination
Facial symmetry and normal skin texture were observed during the examination of her face. The head and neck examination revealed one inflamed lymph node in the right submandibular area. The remaining lymph nodes were within normal limits.

During the intraoral examination, the patient exhibited expansion of the mandible, as well as normal color of the smooth, brilliant, and well-hydrated mucous membrane. Palpation revealed crepitice of the buccal bone wall, reflecting its thin composition. Radiographically, the lesion in question presented as radiolucent, unilocular, and well-defined by a radiopaque halo. Its diameter measured approximately 2 cm, extending from the root of the mandibular right second molar to the root of the second premolar (Figure 1). The lesion also caused displacement of the right alveolar canal toward the cortical inferior border of the mandible.

No symptoms were reported, but the lesion was aspirated in order to dismiss the possibility of intraosseous hemangioma. The presence of clear, brownish liquid appeared to confirm a clinical/radiographic diagnosis of a cyst.

Since the lesion radiographically revealed the involvement of the root of the second premolar, vitality testing was performed, with negative results to heat and cold. Therefore, prior to surgery, root canal treatment was performed on this nonvital tooth.

Operative Procedure
Standard surgical preparation procedures were completed with 0.12% chlorhexidine. Using a pterygomandibular technique, the patient was anesthetized on the right side with bupivacaine. An incision was made from the distal portion of the third inferior molar to the mesial region of the canine, followed by blunt gingival retraction. Care was taken to preserve nerve integrity.

After release of the mucoperiosteal flap, the thin and expanded cortical plate was visible and removed with a scalpel. The cavity exhibited a fibrous envelope around its borders and was full of fluid.

Enucleation was carefully completed in one piece to ensure complete removal. Remaining bone tissue showed normal color and consistency, without any clinical signs of pathosis. The flap was then replaced and secured with 4-0 silk sutures.

The patient received routine postsurgical instructions and prescriptions for antibiotics and anti-inflammatory medications. The excised tissue was maintained in 10% formaldehyde and sent to the pathology laboratory for evaluation.

Histopathologic Diagnosis
The histopathologic diagnosis was acanthomatous ameloblastoma with cystic component. Because the clinical/radiographic diagnosis did not agree with the results obtained, the tissue was forwarded to another pathology laboratory, which confirmed the previous laboratory’s results (Figure 2).

Follow-Up
Regular radiographic observation of the patient was required in order to monitor the possibility of lesion relapse, particularly because it originally presented with a well-defined capsule and was removed completely. The patient had been seen for 12 months of follow-ups, with no signs of recurrence. Bone regeneration in the affected area was visible after 12 months (Figure 3).

Case Presentation No. 2: Adenocarcinoma
A 19-year-old man presented to the Nova Southeastern University Department of Oral and Maxillofacial Surgery with a chief complaint of a “painful eruption of the wisdom tooth.” The patient was unaware of any present illness until the acute onset of the “painful eruption” approximately 2 months earlier. Medical history, dental history, social history, and family history were unremarkable. There were no extraoral signs of disease present.

Clinical Examination
Intraoral examination showed an exophytic, crater-form, ulcerated, macerated, and well-circumscribed lesion measuring approximately 2.5 cm in diameter and covered by a fibrinopurulent membrane. The lesion was located palatal to the alveolar ridge and extended to the midline of the palate (Figure 4). No radiographic manifestations were seen in panoramic, periapical, and occlusal radiographs. All teeth in the maxillary left quadrant were vital.

Diagnosis
Palatal torus and odontogenic infection were easily dismissed from the differential diagnosis by reviewing the clinical and radiographic manifestations. This lesion appeared as an ulcerated, fast-growing mass in the area where salivary gland tumors are usually located. Malignant salivary gland tumor was the first clinical consideration because of its location, aggressive nature, and rapid growth rate. Necrotizing sialometaplasia, a crater-like ulcer, does not exhibit the large nodular growth presented in this case. Therefore, it was not considered in the differential diagnosis. Conventional squamous cell carcinoma, verrucous carcinoma, and carcinoma of the maxillary sinus were dismissed because of the patient’s young age.

Sarcomas may be present in young people with the clinical characteristics seen in this case. Approximately 40% of rhabdomyosarcomas and 14% of neurogenic sarcomas occur in the head and neck area.19 They were included in the differential diagnosis.

Liposarcoma, fibrosarcoma, and chondrosarcoma are rare in the oral cavity. Osteosarcoma generally will show radiographic changes. Angiosarcoma exhibits a purple/reddish discoloration of the mucosa.14

Melanoma is commonly a dark colored lesion that usually begins as a brown to black macula with irregular borders, but then a lobulated, nonpainful mass develops later. Satellite lesions are commonly seen. However, amelanotic melanomas (ie, without melanin) occur. About 20% of oral melanomas contain so little pigment that they have a normal mucosal color.14 It is for this reason that melanoma is often included in the differential diagnosis of an aggressive lesion because it has a reputation for mimicking other pathologic entities.

MALT lymphoma was not considered in the differential diagnosis of this case. MALT lymphoma, usually a low-grade non-Hodgkin’s lymphoma, may develop into a high-grade tumor with aggressive behavior. It may appear as a diffuse palatal ulcerated mass, with borders that are not clearly delineated.14

The differential diagnosis in this case included malignant salivary gland tumor, sarcoma, and melanoma.

Operative Procedure
An outpatient incisional biopsy was performed using local anesthesia. Microscopic histopathologic examination revealed infiltrating carcinoma with a uniform pattern and duct and gland-like structures, which was not reminiscent of any other malignant neoplasm of salivary glands. Perineural invasion of the nerve sheath was present.

The diagnosis was adenocarcinoma NOS (ie, not otherwise specified). The patient was treated with a wide surgical excision and adjuvant radiation therapy. The prognosis for this tumor was poor: 56% survival at 5 years.20

Case Presentation No. 3: Working Diagnosis of Melanoma

A 38-year-old man was referred to Nova Southeastern University for the diagnosis of a mass in the left lateral palate. The patient noticed the lesion and a slight swelling of the left side of his face approximately 1 month prior to the consultation. No significant medical, dental, family, or social history was presented.

Clinical Examination
Physical examination revealed that the patient was well developed and well nourished, with a small swelling of the left maxillary aspect of his face (Figure 5). No fever, pain, bleeding, or paresthesias were identified. During the intraoral examination, a large, firm mass covered by normal mucosa that completely occupied the left palate was noted (Figure 6).

The lesion extended from the palatal midline medially into the fornix of the vestibule laterally and covered the alveolar ridge in an edentulous area. The borders of this mass were fixed to the surrounding tissues. The remaining teeth in this quadrant were vital. No radiographic changes were observed in the panoramic, occlusal, or periapical radiographs.

Diagnosis
The differential diagnosis included sarcoma, salivary gland tumor, and MALT. An outpatient incisional biopsy was performed under local anesthesia. The histopathologic examination revealed nests of atypical melanocytic cells with high mitotic activity and pleomorphic nuclei.

A working diagnosis of melanoma was rendered, and the patient was referred for positron emission tomography (PET) studies. After medical consultation, PET scanning, and medical laboratory testing, a definitive diagnosis of primary melanoma of the liver was confirmed. The patient refused treatment and returned to his country of origin.

Discussion
The diagnosis of ameloblastoma in Case No. 1 was possible only as a result of the histolopathologic evaluation that was performed. The clinical and radiographic findings initially suggested the presence of a periapical or residual cyst, when in fact the lesion was more aggressive. Likewise, periapical lesions could also visibly present as expansive and extremely large, mimicking the appearance of different, more destructive lesions. Therefore, Case No.1, in particular, reinforces the importance of histopathologic examination of all tissues removed from a patient, regardless of the initial clinical findings, to establish the correct diagnosis and determine the appropriate follow-up treatment.

Unfortunately, given the patient’s young age, the malignant salivary gland tumor component of the differential diagnosis for Case No. 2 was confirmed through histopathologic examination. Despite the poor prognosis of this tumor, the ability to precisely identify the lesion as soon as possible was paramount to initiating surgical excision and appropriate radiation therapy.

Again, diagnosis and proper treatment of palatal lesions requires a combination of astute clinical observation and histopathologic examination. In Case No. 3, the original differential diagnosis was limited to pathologies of the oral environment. However, histopathologic information suggested the need for further testing, subsequently leading to a diagnosis of primary melanoma of the liver.

Conclusion

The cases presented underscore the importance of routinely performing a thorough intraoral examination, head and neck cancer examination, and histopathologic evaluation of suspicious tissues removed from the oral cavity. Knowledgeable and conscientious clinicians should be able to readily identify lesions requiring attention and treatment. However, the specific characteristics and type of lesion – which can only be confirmed histopathologically – ultimately dictate the most appropriate therapeutic protocol to ensure the best long-term prognosis for the patient.

References

1. Kramer IRH, Pindborg JJ, Shear M. Histological typing of odontogenic tumors. International Histological Classification of Tumours. 2nd ed. Heidelberg: Springer-Verlag; 1992: 11-14.

2. Shafer WG, Hine MK, Levy BM. Tratado de patologia bucal. 4th ed. Rio de Janeiro: Interacmericana; 1985:255-263.

3. Iordanidis S, Makos C, Dimitrakopoulos J, et al. Ameloblastoma of the maxilla. Case report. Aust Dent J. 1999;44(1):51-55.

4. Kawai T, Kishino M, Hiranuma H, et al. A unique case of desmoplastic ameloblastoma of the mandible: a report of a case and brief review of the English language literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87(2):258-263.

5. World Health Organization (WHO); 1992.

6. Isacsson G, Andersson L, Forsslund H, et al. Diagnosis and treatment of the unicystic ameloblastoma. Int J Oral Maxillofac Surg. 1986;15(6):759-764.

7. Maia Campos G. Ameloblastoma, a behavioral and histologic paradox (a philosophical approach). Braz Dent J. 1990;1(1):5-15.

8. Kim SG, Jang HS. Ameloblastoma: a clinical, radiographic, and histopathologic analysis of 71 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91(6):649-653.

9. Gardner DG. Some current concepts on the pathology of ameloblastomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82(6):660-669.

10. Regezi JA, Sciubba JJ. Oral Pathology: Clinical-Pathologic Correlations. Philadelphia: Saunders; 1989:554.

11. Reichart PA, Philipsen HP, Sonner S. Ameloblastoma: biological profile of 3677 cases. Eur J Cancer B Oral Oncol. 1995;31B(2):86-99.

12. Curi MM, Dib LL, Pinto DS. Management of solid ameloblastoma of the jaws with liquid nitrogen spray cryosurgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84(4):339-344.

13. Feinberg SE, Steinberg B. Surgical management of ameloblastoma. Current status of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81(4):383-388.

14. Neville, BW, Damm DD, Allen CM, et al. Oral & Maxillofacial Pathology. 2nd ed. Philadelphia: WB Saunders; 2002.

15. Nakamura N, Higuchi Y, Tashiro H, et al. Marsupialization of cystic ameloblastoma: a clinical and histopathologic study of the growth characteristics before and after marsupialization. J Oral Maxillofac Surg. 1995;53(7):748-754, discussion 755-756.

16. Santos JN, Pinto LP, de Figueredo CR, et al. Odontogenic tumors: analysis of 127 cases. Pesqui Odontol Bras. 2001;15(4):308-313.

17. Batsakis JG. Tumors of the Head and Neck: Clinical and Pathological Considerations. 2nd ed. Baltimore: Williams & Wilkins; 1979:1-99.

18. Dardick I. Color Atlas/Text of Salivary Gland Tumor Pathology. New York: Igaku-Shoin Medical Publishers; 1996:33.

19. Pilch BZ. Head and Neck Surgical Pathology. Philadelphia: Lippincott Williams & Wilkins; 2001:389-420.

20. Ellis GL, Auclair PL. Tumors of the Salivary Glands. Washington, DC: Armed Forces Institute of Pathology/Universities Associated for Research and Education in Pathology; 1996:300-73.