鋸歯状病変の分子異常とその病理診断への応用

Recent Advances in Molecular Alterations of Serrated Lesions and their Application to Clinicopathology

要旨●鋸歯状病変は大きく過形成性ポリープ（HP），鋸歯状腺腫（TSA），SSL（sessile serrated lesion），SSLD（SSL with dysplasia）に分類される．HPはMVHP（microvesicular variant HP）とGCHP（goblet cell rich variant HP）に2分類されるが，分子異常の観点から前者はBRAF変異と，後者はKRAS変異との関連性が指摘されている．TSAは前駆病変の違いに基づいてBRAF型とKRAS型に亜分類される．BRAF型はMVHPから進展することが示唆され，KRAS型はSuSA（superficially serrated adenoma）との関連性が指摘されている．SSLの組織学的特徴は，腺底部の走行異常が本質的所見である．SSLの分子異常はBRAF変異，CIMP（CpG island methylator phenotype）によって特徴付けられる．SSLDはMSI（microsatellite instability）型（75%）とMSS（microsatellite stable）型（25%）の分子病型に亜分類される．分子異常については，MSI型はMLH1遺伝子のプロモーター領域のメチル化が初期異常とされているが，MSS型はTP53変異との関連性が指摘されている．Wntシグナル経路の異常とp16の不活化は両者に共通する異常と考えられている．SuSAの増殖領域は陰窩の中央部分に限局していることが多く，KRAS変異がみられる．さらにPTPRK/RSPO3の癒合遺伝子が本疾患を特徴付けている．鋸歯状病変はその概念の輪郭は明瞭になってきているが，分子異常においてはいまだ不明の部分もある．今後の発展が期待される．

　Colorectal serrated lesions are broadly classified into hyperplastic polyps（HP）, traditional serrated adenomas（TSA）, sessile serrated lesions（SSL）, and SSL with dysplasia（SSLD）. HP is further divided into two subtypes：the microvesicular variant, characterized by BRAF mutations, and the goblet cell-rich variant, associated with KRAS mutations. TSA is categorized into BRAF-type and KRAS-type based on differences in their precursor lesions. Although the histological features of these lesions have received limited attention, borderline, and early-stage cases merit further investigation. In the 2019 revision of the WHO classification, sessile serrated adenoma/polyp（SSAP）was renamed SSL. However, the term SSAP, as used in Japan, may not fully align with the definition of SSL. SSLD is further subclassified into two molecular phenotypes：microsatellite instability（MSI）type（75%）and microsatellite stable（MSS）type（25%）. The MSI phenotype is characterized by MLH1 gene promoter methylation as the initiating abnormality, whereas the MSS phenotype is linked to TP53 mutations. Both phenotypes share common molecular features, including abnormalities in the Wnt signaling pathway and p16 inactivation. Recently, Sekine et al. identified a new lesion, superficial serrated adenoma（SuSA）, which may be integrated into the existing classification system. SuSA is defined by proliferative activity limited to the intermediate part of the crypts and is strongly associated with KRAS mutations. Furthermore, the fusion gene PTPRK/RSPO3 is a defining feature of SuSA, with an occurrence rate of approximately 90%. Although the conceptual framework of serrated lesions has become increasingly clear, the identification of new entities highlights the dynamic and evolving nature of this field. Further research is needed to refine our understanding of these lesions.