Tumor Budding Correlates With the Protumor Immune Microenvironment and Is an Independent Prognostic Factor for Recurrence of Stage I Lung Adenocarcinoma
アメリカからの報告．
＜背景＞
腫瘍カプセルの崩壊や腫瘍の出芽に関連した免疫細胞浸潤は，大腸がんにおいて浸潤，転移，予後不良を反映するといわれている．
われわれは腫瘍の出芽が肺腺がんにおける予後や免疫微小環境における関連を調べた．
＜方法＞
切除されたステージ１の肺腺がんの腫瘍標本が腫瘍出芽の評価の目的で調べられた（トレーニングで５２４例，検証コホートで５１４例）．
腫瘍や基質で構築された組織マイクロアレーを解析してＣＤ３+，forkkhead box P3+(FoxP3+)リンパ球，ＣＤ６８＋マクロファージ，ＩＬ－７受容体，ＩＬ－１２β２受容体を調べた．
＜結果＞
トレーニングコホートにおいて腫瘍出芽が多い群では少ない群よりも再発リスクが高かった（ｐ＜０．００１）．
これは検証コホートでも認められた（ｐ＝０．００５）．
腫瘍出芽の再発に対する層別リスクは腺房優位で２２％ vs ９％，乳頭状優位で２２％ vs １３％，固形優位で３９％ vs １９％であった．
腫瘍出芽は，FoxP3+リンパ球浸潤の多さ，基質のFoxP3/CD3の高さ，腫瘍や基質のCD68+マクロファージの浸潤，ＩＬ－７受容体の過剰発現と相関していた．
腫瘍出芽があると，多変量解析にて独立して再発と関連していた．
＜感想＞
腫瘍出芽があると再発しやすく，腫瘍周囲の免疫微小環境と関連しているという結論のようです．
切除しきれたと思っても，腫瘍出芽の像が見られたらより慎重な経過観察が必要と思われます．
BACKGROUND: Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma.
METHODS: Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor β2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method.
RESULTS: In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P < .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P < .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression (P < .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008).
CONCLUSIONS: Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness.