Wikipathologica-KDP

 

Diffuse large B-cell lymphoma(DLBCL) びまん性大型B細胞リンパ腫†

 
DLBCL35.jpg

DLBCLは悪性リンパ腫のなかでも最も頻度の高い病型(図; 古くなった統計であるが)で, 現在 Non-Hodgkin lymphoma診断の約30～40%を占めている.

臨床的には中悪性度(治療を行わない/治療が奏功しない場合, 月単位で進行悪化)あるいは高悪性度(同じく週単位で進行悪化する)リンパ腫であり, 急速な腫瘍の進展があるため診断後早期の治療介入が必要となる.

大細胞の定義は, 組織内に存在する小リンパ球とくらべて2倍以上の大きさ (以前はいろんな細胞；内皮や組織球など,と比べる説があったが今はこれ小リンパ球)

DLBCLは生物学的, 形態学的, 遺伝学的および臨床的に非常に不均一で多彩な疾患単位である.
近年の遺伝子発現解析により２つの大きなsubtypeに分類された. さらにNGSを用いた網羅的遺伝子解析により特徴的な遺伝子異常をもつ臨床的また分子病態が異なる4から5個群のグループに再分類され, 将来的な個別化医療の適応への応用が期待されている.

WHO 4th revised*1

→ 個々の疾患亜型における詳細を記載

→DLBCLの個別化

→ grey zone lymphomaの理解;intermediate typeを廃止, high-grade B-cell lymphomaの疾患単位を樹立.

→ 新規治療戦略

 
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DLBCLの臨床像†

↑

DLBCL, Not Otherwise Specified†

Common morphologic variants (* それぞれの特徴をもつ細胞が90%以上を占める病変に用いる)

Centroblastic (胚中心芽球型)
Immunoblastic (免疫芽球型)
Anaplastic (退形成/ 未分化細胞型)
Rare morphologic variants

Centroblastic および immunoblastic variantが通常多く認められる他に, multilobulatedや anaplastic variantが認められている,しかし, これら細胞形態による臨床的意義については評価が定まっていない.*28

画像を追加する

Centroblastic variant(胚中心芽球型)

  • 最も多くみられるtype.腫瘍細胞は胚中心, centroblastに似る. (核膜に付着するように核小体が2～4個認められる)
  • 核はほぼ均一な大きさのことが多いが, ときに大小不同がめだつこともある.まれに分葉ないし多核に見える細胞が混在.
    免疫芽球が混在することもある.
  • 分葉構造がめだつことがあり, 節外性に多い. GCBが多い.
 

血液病理学者が腫瘍細胞形態に基づいてDLBCLをサブタイプ化しようと試みたが,観察者および観察者群間の再現性が乏しく, 結果として, WHOリンパ性腫瘍組織分類においてDLBCLとして単一の診断カテゴリーにまとめられている.*29

 

Molecular subgroupe, COO

Germinal cener B-cell-like
Activated B-cell-like

Immunohistochemical subgroups

CD5+ DLBCL
Germinal center B-cell-like
Non-germinal center B-cell-like

DLBCL Subtypes

T-cell/ histiocyte-rich B-cell lymphoma
Primary DLBCL of the central nervous system
Primary cutaneous DLBCL, leg type
EBV+ DLBCL of the elderly→→WHO 4th revisedでは EBV-positive diffuse large B-cell lymphoma, NOS

Other lymphoma of Large B Cells
Primary mediastinal(thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
ALK+ large B-cell lymphoma
Plasmablastic lymphoma
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease
Primary effusion lymphoma
HHV8- and EBV-associated germinotropic lymphoproliferative disorder( not listed in the WHO classification)

High-grade B-cell lymphoma(新疾患単位として記載)

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement-->High-grade B-cell lymphomaのページをみる.
High-grade B-cell lymphoma, NOS

B-cell lymphoma, unclassifiable
B-cell lymphoma, unclassifiale, with features intrmediate between DLBCL and classical Hodgkin's lymphoma

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Diffuse large B-cell lymphomaの分子診断--治療, 予後に直結する, これからのDLBCL分類†

B-cell Malignancy Academy_血液病理検鏡会in関東 2019の遠西先生の講演から.

&ref(): File not found: "mark-dg-25.gif" at page "Diffuse large B-cell lymphoma WHO 4th classification revised Ed"; 今後の個別化医療の指標になるのはmolecular baseの biomarkers.

↑

1.Cell-of-origin (COO)†

&ref(): File not found: "mark-dg-25.gif" at page "Diffuse large B-cell lymphoma WHO 4th classification revised Ed"; mRNA発現解析によるDLBCL腫瘍のcell-of-origin（COO)設定.

● 2000年 Stanford大学のグループよりmicroarrayを使ったgene expression profilingによりDLBCLのmolecular subtypesが提唱され, GCB(germinal center cell-like), およびABC(activated B-cell-like)に分類された.
いわゆるcell of originの始まり. *30

● mRNA解析は実臨床レベルでは実際的ではないことから--免染によるCOO分類(Hans分類が代表的;2004)を行うが差異が10-20%ほど出てしまう.*31*32

●ABC-DLBCLは, germinal center(GC)を通過し, plasmablastにコミットする, B細胞より発生すると考えられ, NF-kappaB活性が高く, NF-kappaB経路に関わる遺伝子, BCR経路の上流部分の遺伝子に変化が起こり, 最終B細胞分化が混乱していると考えられている.*33*34*35*36

●GCB-DLBCLは,胚中心明調帯(light-zone)B細胞由来と考えられ*33, chromatin-modifying酵素やPI3Kシグナル, Ga-migration経路の遺伝子に変化を来し, しばしばBCL2の構造変化(SVs)を伴っている.*33*37*38

●ABC-DLBCLは, GCB-DLBCLに比較して治療への反応が悪いとされているが,検討されるべき, 付加的遺伝子異常がのこっており, これらの遺伝子変異を選択しターゲット解析をおこなう必要がある.*39*40*41*42*43

●rituximabによる治療時代になってもGCB-like subtypeが予後が良いという報告(New England J Med 2008)*44

&ref(): File not found: "mark-dg-25.gif" at page "Diffuse large B-cell lymphoma WHO 4th classification revised Ed"; これからのCell of origin解析のゴールドスタンダード.

nanoストリング; デジタルカウント遺伝子発現解析（nCounter）タカラ社のWeb page--nCounter Analysis Systemを用いた高感度発現解析

  • nanoストリングテクノロジーによるFFEPからの遺伝子プロファイリングが今後のスタンダードになっていく.
  • ナノストリング社（NanoString Technologies Inc.;ナノストリング社はmRNAの発現解析を新規な技術で製品化した米国ワシントン州シアトルに本拠を置くベンチャー企業）の論文が米国の権威ある科学雑誌“nature biotechnology”の(2008年3月号：26-3）に掲載され、イメージ写真がその表紙を飾った.
  • ナノストリング社の技術はmRNAの発現解析を、これまで必須としていた酵素反応や増幅反応を不要とし、1回の測定で10-1000の遺伝子を直接定量できる大変ユニークで新規な技術.
  • ナノストリング社は、発現解析システムとして2種の自動化システムを組み合わせた「ｎCounter Gene Expression system」を販売.その液体ハンドリング部である「ｎCounter Prep Station」はPSS社より供給される.
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2. MYCとBCL2の発現-Double Hit and Double expressor†

ABC-GCB-Double.jpg

&ref(): File not found: "mark-dg-25.gif" at page "Diffuse large B-cell lymphoma WHO 4th classification revised Ed";DLBCLの第二のbiomarker；MYCとBCLの発現

1. protein レベルでMYCとBCL2の両者を発現するlymphoma--Double-protein expressor(DPE)

  • DPEはDHIT(double-hit lymphoma)を含んでいる.
     
  • DLBCLの形態を示すlymphomaの約30%がDEP.
     
  • DPEの腫瘍の多くは,ABCのmolecular subtypeに認められる
     
  • R-CHOPによる治療では, 予後不良の群になる.
     

2. MYCとBCL2遺伝子のtranslocationが認められる--FISHや核型による確認.:Double-HIT lymphoma(DHL)

  • DLBCLでMYCとBCL2および/あるいはBCL6の再構成を認めるもの.
     
  • DLBCLの形態をとるリンパ腫の約8%
     
  • BCL2転座腫瘍(High grade B-cell lymphoma(HGBL)-DH/TH-BCL2)は,ほぼ全例が GCB molecular subtypeである.
     
  • R-CHOP治療では予後が不良.
↑

3. COOを基盤とした新規mRNA発現プロファイルによるDLBCLの分類 2018～†

&ref(): File not found: "mark-dg-25.gif" at page "Diffuse large B-cell lymphoma WHO 4th classification revised Ed";NGSを使った遺伝子検索

DLBCL-NIHsubtype.jpg

2011 Morin RD et al*45

  • 113リンパ腫例, RNAseq, クロマチン修飾遺伝子の変異が検出された.
     
  • 標本に臨床情報が連結していないため治療や予後と関連付けができなかった.

2018 Schmitz R et al.; NIHのグループ*46

  • COOがsubtypigの基盤として生き残っている
     
  • 少ない遺伝子を取り上げ, DLBCLを4つのグループにわけた, 予後に結びついたsubtypingが可能であった.
    • MCD; MYD88L625P変異, CD79B変異が同時に認められるsubgroup.
    • BN2; BCL6 fusionとNOTCH2変異
    • N1; NOTCH1変異
    • EZB; EZH2変異とBCL2転座がある.
  • MCDとN1 subgroupeは予後が悪く, BN2とEZBは治療効果があり予後良好であった.
     
  • MCDとBN2は腫瘍進展に「chronic active」B-cell receptor signanling pathwayが関与しており治療のターゲット遺伝子として可能性がある.
     

2018 Chapuy B et al.; Dana-Farbar cancer instituteグループ*47

304例のprimary DLBCL. についてrecurrent mutation, somatic copy number alterations(SCNAs), structural variants(SVs)などの低頻度の変化を見落とさず, 有用な予後データと関連のあるものを決定. DLBCLのclusteringにおいて, コンセンサスの得られているgenetic driverと統合し, 新規のclusteringを行い, 5つの明確な DLBCL subtypeを確認した.

clusteringにより いままで認識されなかった, 以下のsubgroupを発見した.

  • extrafollicular/marginal zone 細胞由来の low-risk ABC-DLBCLs
     
  • 予後がことなる, 治療ターゲットになりうる遺伝子異常がことなる2つの GCB-DLBCL subsets
     
  • ABC/GCB, COO分類とは独立した, TP53の両アレルが不活化, CDKN2A lossと関連した遺伝子不安定のあるグループ
     

&ref(): File not found: "mark-dg-25.gif" at page "Diffuse large B-cell lymphoma WHO 4th classification revised Ed";DLBCLは, 遺伝子的にヘテロな疾患であり, 低頻度の多数の遺伝子変異, SCNAs, SVsが認められる.

&ref(): File not found: "mark-dg-25.gif" at page "Diffuse large B-cell lymphoma WHO 4th classification revised Ed";現在DLBCLは Germinal centerを通過する抗原暴露B細胞(antigen-exposed B-cell)由来と考えられている.*33*48*49*50*51*52*53*54

&ref(): File not found: "mark-dg-25.gif" at page "Diffuse large B-cell lymphoma WHO 4th classification revised Ed";胚中心の環境, 高増殖領域であること, AID(activation-induced cytidine deaminase)による免疫グロブリン編集と異常なsomatic hypermutation(SHM)が腫瘍化に機序と考えられる.*33

 
 

Cluster 5(C5);

Cluster1(C1);

Cluster 3(C3)

Cluster4(C4);

Cluster2(C2)

Cluster0 (C0)

 
 
left
 
 
 
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