遺伝性非ポリポーシス大腸癌の臨床病理と分子異常―孤発性MSI陽性大腸癌との比較

Clinicopathological Findings and Molecular Alterations of Hereditary Non-polyposis Colorectal Cancer─Comparison of Sporadic MSI-high Colorectal Cancer

要旨　遺伝性非ポリポーシス大腸癌（HNPCC）と孤発性MSI陽性大腸癌の臨床病理および分子異常について述べる．両者の共通の分子異常はMSIである．HNPCCはミスマッチ修復遺伝子の生殖細胞レベルの変異が原因であるが，孤発性MSI陽性大腸癌では体細胞レベルでのMLH-1のメチル化が原因とされている．MSI陽性大腸癌の共通の病理像は，右側発生，粘液癌/低分化腺癌，髄様所見，腫瘍内リンパ球浸潤（TIL）であるが，特にTILの有無が最も重要である．HNPCCと孤発性MSI陽性大腸癌との臨床病理学的鑑別も重要である．両者の最大の鑑別点は，年齢と癌の多発性の有無である．HNPCCは60歳以下（50歳以下であればほぼ確実）で癌の多発傾向があるのに対して，孤発性MSI陽性大腸癌は明らかに高齢発生（65歳以上がほとんど）である．両者の臨床病理学的所見の違いは相対的であるが，粘液癌や圧排性増殖の所見は孤発性MSI陽性大腸癌に多いとされている．HNPCCと孤発性MSI陽性大腸癌は厳密に鑑別されるべきで，両者の臨床病理学的所見と分子異常の違いを理解することが重要である．

　HNPCC（hereditary non-polyposis colorectal cancer）is one of the representative types of familial CRC（colorectal cancer）. HNPCC is characterized by distinctive clinicopathological features and molecular alterations. However, this disease is sometimes missed in routine medical examinations. Pathologic examination of biopsy specimens can help in identification of such unsuspected cases of certain forms of hereditary CRC due to characteristic morphologic findings. The most important of these are tumor proximal location, lymphocytic infiltration, mucin secretion and poor differentiation. These features are apparent in both sporadic MSI-H CRC and CRC occurring in hereditary non-polyposis colorectal cancer. Whereas inactivation of the mismatch repair gene MLH1 due to promoter methylation causes sporadic MSI positive CRC, HNPCC results from a germline mutation in MMR（mismatch repair）genes. In addition, immunohistochemical and molecular studies can then provide a definitive diagnosis. Finally, HNPCC CRC arises almost exclusively within adenomatous precursor lesions, in contrast to sporadic MSI positive CRC where at least half of the cancers develop in serrated polyps. Distinguishing HNPCC from sporadic MSI CRC by clinicopathological and molecular features can be of assistance in the diagnosis of HNPCC.