大腸鋸歯状病変の臨床病理学的特徴および分子病理学的意義

Clinico-pathological and Molecular Alterations of Serrated Lesion of the Colorectum

要旨　鋸歯状ポリープは，過形成性ポリープ，鋸歯状腺腫，SSA/P（sessile serrated adenoma/polyp），混合型ポリープに分類されるのが一般的である．これらのポリープの病理診断は，本邦ではいまだ一定のコンセンサスを得るには至っていないが，特にSSA/Pの診断の混乱は目立っている．SSA/Pの病理組織像の特徴は，（1）腺管底部のL字状所見，逆T字状所見，（2）腺管の拡張，（3）不規則な分岐像，などである．このポリープの分子発生メカニズムは，BRAF変異，CIMP（CpG islands methylation phenotype）-high，MSI（microsatellite instability）で特徴づけられる．一方ki-ras変異，CIMP-low，MSS（microsatellite stable）と密接に関連している別経路も指摘されている．鋸歯状ポリープの最終的な病変はMSI陽性大腸癌とされてきたが，近年の検討で，MSS癌の場合もあることが明らかになってきた．鋸歯状ポリープは臨床病理学的，分子病理学的にも従来のadenoma-carcinoma sequenceとは異なった経路である．

　Conventional adenomas were known to represent a precursor to conventional colorectal cancer, whereas hyperplastic polyps were considered as nonneoplastic, having no potential for progression to malignancy. We recognize, however, that the lesions diagnosed as hyperplastic polyps in the past represent a heterogeneous group of polyps, some of which are harmless, and others that actually have a significant risk for a specific colorectal cancer. Recent studies have revealed the concept of the“serrated neoplastic pathway”that is characterized by microsatellite instability, DNA hypermethylation status and BRAF mutation. A subset of hyperplastic polyps and sessile serrated polyps show BRAF mutations and abnormal DNA methylation, which can ultimately affect microsatellite instability. On the other hand, an alternate pathway that is closely associated with ki-ras mutation, low methylated status and MGMT methylation has been suggested. This review describes the clinicopathologic and molecular features of serrated polyps and discusses the current data regarding their biologic significance.