肝細胞癌について

肝・胆・膵

肝細胞癌の病態と検査

肝細胞癌の定義

肝臓を構成している細胞が癌化して発生したものを「原発性肝癌」という。

「原発性肝癌」は肝細胞が癌化した肝細胞癌と肝内胆管細胞が癌化した肝内胆管癌に分けられる。

「原発性肝癌」のうち肝細胞癌が約94%を占めて、残りを肝内胆管癌が占める。

肝細胞癌の成因

長期にわたって肝細胞の破壊と再生を繰り返すことが肝細胞癌の成因だと考えられており、わが国では肝細胞癌の患者の約80%が肝硬変または慢性肝炎を合併している。

また、肝細胞癌患者のうち約80%がB型肝炎ウイルスまたはC型肝炎ウイルス陽性の感染者となっている。最大の原因はC型肝炎ウイルスである。

しかし、近年C型肝炎に対する抗ウイルス治療薬としてインターフェロン・リバビリン(核酸アナログ製剤)に加えて直接作用型抗ウイルス薬(DAA)が登場したことも影響して、2015年以降はC型肝炎ウイルスによる新規発生肝細胞癌は50%以下に減少して非B非C型(非ウイルス型)の肝細胞癌が30~40%まで増加していることから傾向が変わってきていることにも注意する必要がある。

加えて、アスペルギルス属のカビが産生するカビ毒であるアフラトキシンは肝毒性を持ち、肝細胞癌の誘発因子となることは知っておくべきである。

肝細胞癌のサーベイランス

B型慢性肝炎・C型慢性肝炎・肝硬変のいずれかが存在する肝細胞癌の高危険群に対してはサーベイランス(定期的なスクリーニング検査)を行う。

サーベイランスは3~6ヶ月の間隔で腹部超音波検査と腫瘍マーカー測定を行う。

肝細胞癌の腫瘍マーカーとしてはAFP・PIVKA-Ⅱ・AFP-L3分画の3種が保険収載となっている。
(従来は肝シンチグラムが用いられていたこともあったが、肝シンチグラムによる肝細胞癌検出率は超音波検査に比べて明らかに低いため、現在では肝細胞癌の画像診断において推奨されていない。)

サーベイランスで異常が指摘された場合にはdynamic CT・細胞外液性 Gd 造影dynamic MRI・Gd-EOB-DTPA 造影 MRIのいずれかを測定して鑑別診断をする。

腹部超音波検査における肝細胞癌の所見

モザイクパターン

腫瘍結節内部に分化度の異なる細胞が混在している場合にモザイク状のエコー像(モザイクパターン)を認める。これはnodule in nodule appearanceとも呼ばれる。

ハロー

外周に線維性被膜を有している肝細胞癌の場合には腫瘍周囲の被膜部が低エコー帯を呈してハローと呼ばれる。

PIVKA-Ⅱ

血液凝固因子:Ⅱ,Ⅸ,Ⅶ,ⅩはビタミンK依存性に肝臓で合成される。

これらの因子はビタミンKが欠乏すると凝固因子活性をもたない蛋白、PIVKA(Protein Induced by Vitamin K absence or antagonist)として存在するようになる。

PIVKAはそれぞれの凝固因子に対応してPIVKA-Ⅱ,Ⅸ,Ⅶ,Ⅹと呼ばれる。

このうちPIVKA-Ⅱは昔は主にビタミンKの腸管における合成や腸管での吸収障害の指標として使われていた。

つまり、腸内細菌によって合成されて胆汁酸に伴って吸収される脂溶性のビタミンKが抗生剤などの投与による正常腸内細菌の抑制や胆汁分泌不全によって吸収されないことで、PIVKA-Ⅱの値が上昇することをビタミンK欠乏の指標として検査に利用していたということである。

現在ではPIVKA-Ⅱが肝細胞癌で高率に出現することが見出されたため、肝細胞癌における代表的な腫瘍マーカーであるα-フェトプロテイン(AFP)に並ぶ腫瘍マーカーとして位置付けられている。

肝細胞癌の血流診断(確定診断)

動脈相(早期相)において濃染されて高吸収域となり、門脈・平衡相(後期相)では周囲肝実質と比較して相対的に低吸収域=低信号域(wash out)として描出された場合に典型的肝細胞癌であると判断して治療方針決定に進む。

肝血管腫

動脈相(早期相)で濃染して高吸収域となったにも関わらず、門脈相・平衡相(後期相)でwash outを認めない場合には肝血管腫などが鑑別に挙がる。

このような場合、医師国家試験問題においては肝血管腫が答えになると思われる。肝血管腫は良性腫瘍であるので経過観察でよい。

肝細胞癌と肝血管腫の鑑別

通常の肝組織は門脈血:約70%と動脈血:約30%によって栄養されているのだが、肝細胞癌はほぼ100%動脈血のみから栄養されている。

このため、肝細胞癌には血流が豊富になり造影剤がすぐに入っていきすぐに出ていく。

これを反映した結果、肝細胞癌は動脈相(早期相)において「多血化」による濃染を認め、門脈・平衡相において低吸収域=低信号域(wash out)として描出される。

動脈に造影剤が多く流れるタイミングである動脈相ではよく染まるが、門脈に造影剤が多く流れるタイミングである門脈相では周辺の正常な肝組織よりも染まらないということである。

動脈相(早期相)において「多血化」による濃染を認めて肝細胞癌との鑑別が必要となる疾患として肝血管腫が挙げられる。

肝血管腫も肝細胞癌のようにすぐに造影剤が入るのだが、血管腫内の血流速度が極めて遅いため造影剤がしばらく出ていかない。

このため、肝血管腫は動脈相で濃染するものの門脈・平衡相において低吸収域=低信号域とならずにwash outを認めないことで肝細胞癌と区別して鑑別することができる。

肝嚢胞

肝嚢胞は単純CTで低吸収域としてみえる。また、造影CT・MRIで造影剤増強効果を認めず低吸収域のままとなる。

肝嚢胞は液体成分を内部に含む袋状の構造物が存在するという良性疾患であり、経過観察でよい。

造影CT・MRIにおける注意点

腎機能低下患者(血清クレアチニン値:2.0mg/dL以上)にヨード造影剤やGd造影剤を投与すると造影剤腎症が引き起こされる危険性がある。

また、近年Gd造影剤(ガドリニウム造影剤)特有の副作用として腎性全身性線維症(Nephrogenic Systemic Fibrosis:NSF)が注目されており、平成30年度版医師国家試験出題基準において造影磁気共鳴画像検査<造影MRI>の造影剤と副作用の備考として追記された。

造影剤を投与する前にヨードアレルギーや喘息の既往などアレルギーに関して質問することも重要である。

肝細胞癌の治療アルゴリズム

肝細胞癌の治療アルゴリズムは肝予備能・肝外転移・脈管侵襲・腫瘍数・腫瘍径の5因子に基づいて決められる。肝予備能評価はChild-Pugh分類によって行い、肝外転移・脈管侵襲・腫瘍数・腫瘍径は治療前画像診断によって判定する。

医師国家試験問題において肝細胞癌の治療を選ぶ問題を解くコツ

肝癌診療ガイドラインに記載されている肝細胞癌の治療アルゴリズムの図のみを覚えて、それを辿りながら医師国家試験問題において治療を選ぶという方法もあるが、この方法では時間がかかることに加えて問題が解けないという状況に陥ることがしばしばある。

なぜならガイドラインに記載してある肝細胞癌の治療アルゴリズムの図は例外規定まで記載していないので、例外規定が問題で問われた場合にはどうやっても答えに辿り着くことができないためである。

医師国家試験問題を効率よく正確に解くためには状況と治療を1対1で対応させて覚えた方が良いのかもしれない。医師国家試験問題で問われる状況というのはある程度決まっているからである。

Child-Pugh分類の語呂

Child-Pugh分類:A,B←腫瘍数と腫瘍径によって決まる

腫瘍数1個の場合は腫瘍径にかかわらず肝切除が第一選択となる。
腫瘍数2,3個で腫瘍径3cm以内の場合は肝切除またはラジオ波焼灼療法が第一選択となる。
腫瘍数2,3個で腫瘍径3cm超の場合は第一選択が肝切除、第二選択が肝動脈塞栓療法(TACE/TAE)となる。
腫瘍数4個以上の場合は第一選択が肝動脈塞栓療法、第二選択が肝動注化学療法または分子標的治療薬(全身薬物療法)となる。

塞栓療法

肝細胞癌に栄養を供給している肝動脈を塞ぐことによって癌を「兵糧攻め」する治療法である。

塞栓剤のみが投与されるものを肝動脈塞栓療法:TAEと呼び、塞栓剤に加えて細胞障害性抗がん剤が投与されるものを肝動脈化学塞栓療法:TACEと呼ぶ。

塞栓療法の特徴

正常な肝臓組織も多少は障害されるため肝予備能に影響する。

門脈に腫瘍や血栓がある場合に動脈血流を塞ぐと肝臓全体の血流が乏しくなって肝機能が急激に悪化する可能性があるため、門脈本幹に腫瘍栓を有する症例には禁忌となっている。

肝両葉に腫瘍が多発している多発肝細胞癌の場合でも適応となり得る。

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