Carcinoma do cólon ou recto em jovens: caracterização clínico-patológica e vias de carcinogénese

 

I. Claro¹, S. Ferreira¹, P. Lage¹, M. Salazar¹, I. Francisco², B. Filipe², C. Albuquerque², P. Chaves³, M. Cravo¹, C. Nobre Leitão^1,2

 

Resumo

Introdução: A instabilidade de microssatélites, marcador da via mutadora, é detectada em 15% dos carcinomas do cólon ou recto esporádicos e numa percentagem mais elevada em doentes jovens (idade < 45 anos). Aceita-se que a maioria dos restantes carcinomas do cólon ou recto siga a via supressora.

Objectivos: Em doentes com carcinoma do cólon ou recto em idade inferior a 45 anos: 1) Avaliar a prevalência das vias mutadora e supressora; 2) Correlacionar as características clínico-patológicas e a sobrevivência com a via seguida.

Doentes e Métodos: Incluíram-se 42 doentes (19 homens/23 mulheres, média de idades: 35,5±6,0 anos). A via mutadora foi caracterizada com os marcadores de Bethesda, considerando-se ser a via seguida pelo tumor na presença instabilidade de alto grau. A via supressora foi avaliada através da análise das perdas de heterozigotia (genes APC, p53, DCC e SMAD4); considerou-se que o tumor seguia a via supressora quando existiam alterações em pelo menos 2 (50%) desses genes. Analisaram-se ainda: localização, diferenciação, produção de muco, estádio, ocorrência de recidiva do carcinoma do cólon ou recto e sobrevivência.

Resultados: 14/42 (33%) carcinomas do cólon ou recto seguiram a via mutadora e 16/42 (38%) a via supressora. Em 12/42 (29%) carcinomas do cólon ou recto terá sido seguida uma via alternativa. No entanto, considerando dois grupos, com idade inferior ou igual e superior a 35 anos, nos mais jovens os carcinomas do cólon ou recto seguiram a via mutadora em 53,3%, a via supressora em 13,3% e a via alternativa em 33,3% (p=0,03). Registou-se uma localização preferencial dos carcinomas do cólon ou recto que seguiram a via mutadora ao nível do cólon proximal e dos que seguiram a via alternativa no recto (p<0,001). Os carcinomas do cólon ou recto da via supressora apresentaram menor produção de muco (p=0,03). A probabilidade cumulativa de sobrevivência aos 8 anos foi: 70% na via mutadora, 69% na via alternativa e 50% na via supressora.

Conclusões: 1) A via mutadora só foi preferencialmente seguida nos casos com carcinoma do cólon ou recto em idade inferior a 35 anos; 2) Uma percentagem importante dos carcinomas do cólon ou recto em jovens seguiu uma via alternativa, ainda não caracterizada; 3) Nestes últimos casos, verificou-se uma localização predominante dos carcinomas no recto e uma sobrevivência elevada, semelhante à da via mutadora; 4) Admitimos a existência de uma via alternativa em jovens com carcinoma do cólon ou recto, com características próprias e associada a eventos genéticos ainda não esclarecidos.

 

Summary

Background: Microsatellite instability, a hallmark of the mutator pathway in colorectal carcinogenesis, is present in 15% of sporadic colorectal cancers and in a higher percentage of young patients (< 45 years). The majority of the remaining colorectal cancers may follow the classic suppressor pathway.

Aims: In patients with colorectal cancers diagnosed at an age < 45 years: 1) to evaluate the prevalence of the mutator and suppressor pathways; 2) to analyse the clinic and pathological characteristics and survival of the two pathways.

Patients and Methods: Forty-two patients (19 male and 23 female, mean age: 35.5 ± 6.0 yrs) were included. The mutator pathway was analysed using the Bethesda markers. Colorectal cancers presenting microsatellite instabilityhigh were classified as following the mutator pathway. To study the involvement of the suppressor pathway, loss of heterozigoty was evaluated at the following loci: APC, p53, DCC and SMAD4 genes. When loss of heterozigoty was detected in 2 (50%) or more loci, suppressor pathways was assumed. The cancer location, pathological characteristics, stage and recurrence were also recorded.

Results: 14/42 (33%) and 16/42 (38%) of colorectal cancers followed the mutator and the suppressor pathway, respectively. In 12/42 (29%) an alternative pathway of carcinogenesis may have been followed. However, if we divide the patients into two groups according to whether the age at time of diagnosis was before or after 35 years, in the younger group the mutator pathway was observed in 53.3%, the suppressor pathway in 13.3% and an alternative pathway in 33.3% of colorectal cancers (p=0.03). Colorectal cancers following the mutator pathway tended to be located at the proximal colon, while those following the alternative pathway tended to be at the rectum (p<0.001). Colorectal cancers following the suppressor pathway showed less mucous production (p=0.03). The cumulative survival rate at 8 years was: 70% for mutator, 69% for alternative and 50% for suppressor pathways.

Conclusions: 1) The mutator pathway was preferentially followed only in colorectal cancer patients under the age of 35; 2) A significant number of cases followed an alternative pathway yet to be described; 3) In the latter cases, colorectal cancers were predominantly located at the rectum and patients had a high survival rate, similar to that of the mutator pathway; 4) Our results suggest that there might be an alternative pathway for colorectal cancers in young patients that presents specific characteristics and is associated with genetic events not yet known.

 

 

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Correspondência:

Isabel Claro

Serviço de Gastrenterologia

Instituto Português de Oncologia de Lisboa de Francisco

Gentil, E.P.E.

Fax: 217 229 855

e-mail: iclaro@netcabo.pt

 

 

(1) Serviço de Gastrenterologia

(2) Centro de Investigação de Patobiologia Molecular

(3) Serviço de Anatomia Patológica Instituto Português de Oncologia de Lisboa de Francisco Gentil, E.P.E., Lisboa, Portugal.

 

 

Recebido para publicação: 03/10/2006

Aceite para publicação: 06/12/2006