臨床検査67巻7号

2023年07月発行

今月の特集 造血器・リンパ系腫瘍のWHO分類　第5版

T/NK細胞腫瘍3—未分化大細胞リンパ腫/節性T濾胞ヘルパー細胞リンパ腫/その他の末梢性T/NK細胞リンパ腫

著者： 井上典仁¹² 津山直子¹² 竹内賢吾¹²³

所属機関： ¹公益財団法人がん研究会がん研究所病理部 ²公益財団法人がん研究会有明病院臨床病理センター ³公益財団法人がん研究会がん研究所分子標的病理プロジェクト

ページ範囲：P.772 - P.779

Point

●未分化大細胞リンパ腫（ALCL）ファミリーには，未分化リンパ腫キナーゼ（ALK）陽性ALCL，ALK陰性ALCL，乳房インプラント関連ALCL（BIA-ALCL）の3つのエンティティが含まれる．原発性皮膚ALCLは，原発性皮膚T細胞リンパ増殖症およびリンパ腫のファミリーに属している．

●WHO分類改訂第4版において“血管免疫芽球性T細胞リンパ腫および他のT濾胞ヘルパー細胞起源性リンパ腫”であったリンパ腫は，ファミリーの名称と各エンティティの名称が変更された．それぞれの類似点が多いことから，“節性T濾胞ヘルパー細胞リンパ腫（nTFHLs）”が共通用語として採用されている．

●末梢性T細胞性リンパ腫（PTCL）には，TBX21およびGATA3の生物学的バリアントが認められるが，サブタイプとするには現時点でのデータが不十分とされている．

●節外性NK/T細胞性リンパ腫は，鼻以外の全身の節外に出現することが周知となったため，“鼻型”という言葉は削除された．また，EBV陽性NK/T細胞リンパ腫のエンティティとして，節性TおよびNK細胞性リンパ腫が新たに定義された．

参考文献

1）Alaggio R, Amador C, Anagnostopoulos I, et al：The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia　36：1720-1748，2022

2）Irshaid L, Xu ML：ALCL by any other name: the many facets of anaplastic large cell lymphoma. Pathology　52：100-110，2020

3）Pina-Oviedo S, Ortiz-Hidalgo C, Carballo-Zarate AA, et al：ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas. Cancers (Basel)　13：4667，2021

4）Benharroch D, Meguerian-Bedoyan Z, Lamant L, et al：ALK-positive lymphoma: a single disease with a broad spectrum of morphology. Blood　91：2076-2084，1998

5）Pittaluga S, Wlodarska I, Pulford K, et al：The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements. Am J Pathol　151：343-351，1997

6）Leventaki V, Bhattacharyya S, Lim MS：Pathology and genetics of anaplastic large cell lymphoma. Semin Diagn Pathol　37：57-71，2020

anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood　96：3681-3695，2000

8）Eyre TA, Khan D, Hall GW, et al：Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease. Eur J Haematol　93：455-468，2014

9）Foss HD, Anagnostopoulos I, Araujo I, et al：Anaplastic large-cell lymphomas of T-cell and null-cell phenotype express cytotoxic molecules. Blood　88：4005-4011，1996

10）d'Amore ES, Menin A, Bonoldi E, et al：Anaplastic large cell lymphomas: a study of 75 pediatric patients. Pediatr Dev Pathol　10：181-191，2007

11）Boi M, Rinaldi A, Kwee I, et al：PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma. Blood　122：2683-2693，2013

12）Lobello C, Tichy B, Bystry V, et al：STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma. Leukemia　35：1500-1505，2021

13）Richardson AI, Yin CC, Cui W, et al：p53 and β-Catenin Expression Predict Poorer Prognosis in Patients With Anaplastic Large-Cell Lymphoma. Clin Lymphoma Myeloma Leuk　19：e385-e392，2019

14）Liang HC, Costanza M, Prutsch N, et al：Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma. Nat Commun　12：5577，2021

15）Pedersen MB, Hamilton-Dutoit SJ, Bendix K, et al：DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study. Blood　130：554-557，2017

16）Hapgood G, Ben-Neriah S, Mottok A, et al：Identification of high-risk DUSP22-rearranged ALK-negative anaplastic large cell lymphoma. Br J Haematol　186：e28-e31，2019

17）King RL, Dao LN, McPhail ED, et al：Morphologic Features of ALK-negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements. Am J Surg Pathol　40：36-43，2016

18）Ravindran A, Feldman AL, Ketterling RP, et al：Striking Association of Lymphoid Enhancing Factor (LEF1) Overexpression and DUSP22 Rearrangements in Anaplastic Large Cell Lymphoma. Am J Surg Pathol　45：550-557，2021

19）Scarfò I, Pellegrino E, Mereu E, et al：Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. Blood　127：221-232，2016

Systemic T-Cell Lymphomas With Anaplastic Morphology. Am J Surg Pathol　45：895-904，2021

21）Miranda RN, Aladily TN, Prince HM, et al：Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients. J Clin Oncol　32：114-120，2014

22）Oishi N, Brody GS, Ketterling RP, et al：Genetic subtyping of breast implant-associated anaplastic large cell lymphoma. Blood　132：544-547，2018

23）Blombery P, Thompson ER, Jones K, et al：Whole exome sequencing reveals activating JAK1 and STAT3 mutations in breast implant-associated anaplastic large cell lymphoma anaplastic large cell lymphoma. Haematologica　101：e387-e390，2016

24）Laurent C, Nicolae A, Laurent C, et al：Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL. Blood　135：360-370，2020

25）Letourneau A, Maerevoet M, Milowich D, et al：Dual JAK1 and STAT3 mutations in a breast implant-associated anaplastic large cell lymphoma. Virchows Arch　473：505-511，2018

26）Di Napoli A, Jain P, Duranti E, et al：Targeted next generation sequencing of breast implant-associated anaplastic large cell lymphoma reveals mutations in JAK/STAT signalling pathway genes, TP53 and DNMT3A. Br J Haematol　180：741-744，2018

27）Los-de Vries GT, de Boer M, van Dijk E, et al：Chromosome 20 loss is characteristic of breast implant-associated anaplastic large cell lymphoma. Blood　136：2927-2932，2020

28）Quesada AE, Zhang Y, Ptashkin R, et al：Next generation sequencing of breast implant-associated anaplastic large cell lymphomas reveals a novel STAT3-JAK2 fusion among other activating genetic alterations within the JAK-STAT pathway. Breast J　27：314-321，2021

29）Breitfeld D, Ohl L, Kremmer E, et al：Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med　192：1545-1552，2000

30）Kim CH, Lim HW, Kim JR, et al：Unique gene expression program of human germinal center T helper cells. Blood　104：1952-1960，2004

31）Huang Y, Moreau A, Dupuis J, et al：Peripheral T-cell lymphomas with a follicular growth pattern are derived from follicular helper T cells (TFH) and may show overlapping features with angioimmunoblastic T-cell lymphomas. Am J Surg Pathol　33：682-690，2009

32）Dobay MP, Lemonnier F, Missiaglia E, et al：Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. Haematologica　102：e148-e151，2017

33）Sakata-Yanagimoto M, Enami T, Yoshida K, et al：Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet　46：171-175，2014

34）Cairns RA, Iqbal J, Lemonnier F, et al：IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood　119：1901-1903，2012

35）Odejide O, Weigert O, Lane AA, et al：A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood　123：1293-1296，2014

) cells. Blood　109：4952-4963，2007

37）Dorfman DM, Brown JA, Shahsafaei A, et al：Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol　30：802-810，2006

38）Marafioti T, Paterson JC, Ballabio E, et al：The inducible T-cell co-stimulator molecule is expressed on subsets of T cells and is a new marker of lymphomas of T follicular helper cell-derivation. Haematologica　95：432-439，2010

39）Grogg KL, Attygalle AD, Macon WR, et al：Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells?. Blood　106：1501-1502，2005

40）Attygalle A, Al-Jehani R, Diss TC, et al：Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood　99：627-633，2002

41）Roncador G, García Verdes-Montenegro JF, Tedoldi S, et al：Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. Haematologica　92：1059-1066，2007

42）Dorfman DM, Shahsafaei A：CD200 (OX-2 membrane glycoprotein) is expressed by follicular T helper cells and in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol　35：76-83，2011

43）Murakami YI, Yatabe Y, Sakaguchi T, et al：c-Maf expression in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol　31：1695-1702，2007

44）Ree HJ, Kadin ME, Kikuchi M, et al：Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma. Hum Pathol　30：403-411，1999

45）Vallois D, Dobay MP, Morin RD, et al：Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas. Blood　128：1490-1502，2016

46）Watatani Y, Sato Y, Miyoshi H, et al：Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Leukemia　33：2867-2883，2019

47）Miyoshi H, Sakata-Yanagimoto M, Shimono J, et al：RHOA mutation in follicular T-cell lymphoma: Clinicopathological analysis of 16 cases. Pathol Int　70：653-660，2020

48）Iqbal J, Wright G, Wang C, et al：Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood　123：2915-2923，2014

49）Heavican TB, Bouska A, Yu J, et al：Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood　133：1664-1676，2019

50）Amador C, Greiner TC, Heavican TB, et al：Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by immunohistochemistry. Blood　134：2159-2170，2019

51）Tse E, Au-Yeung R, Kwong YL：Recent advances in the diagnosis and treatment of natural killer/T-cell lymphomas. Expert Rev Hematol　12：927-935，2019

52）Bi XW, Wang H, Zhang WW, et al：PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma. J Hematol Oncol　9：109，2016

53）Song TL, Nairismägi ML, Laurensia Y, et al：Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood　132：1146-1158，2018

54）Jiao W, Ji JF, Xu W, et al：Distinct downstream signaling and the roles of VEGF and PlGF in high glucose-mediated injuries of human retinal endothelial cells in culture. Sci Rep　9：15339，2019

55）Lim JQ, Huang D, Tang T, et al：Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma. Leukemia　34：3413-3419，2020

56）Kim SJ, Lim JQ, Laurensia Y, et al：Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. Blood　136：2754-2763，2020

57）Kuo TT, Chen MJ, Kuo MC：Cutaneous intravascular NK-cell lymphoma: report of a rare variant associated with Epstein-Barr virus. Am J Surg Pathol　30：1197-1201，2006

58）Cerroni L, Massone C, Kutzner H, et al：Intravascular large T-cell or NK-cell lymphoma: a rare variant of intravascular large cell lymphoma with frequent cytotoxic phenotype and association with Epstein-Barr virus infection. Am J Surg Pathol　32：891-898，2008

59）Liu Y, Zhang W, An J, et al：Cutaneous intravascular natural killer-cell lymphoma: a case report and review of the literature. Am J Clin Pathol　142：243-247，2014

60）Alegría-Landa V, Manzarbeitia F, Salvatierra Calderón MG, et al：Cutaneous intravascular natural killer/T cell lymphoma with peculiar immunophenotype. Histopathology　71：994-1002，2017

61）Klairmont MM, Cheng J, Martin MG, et al：Recurrent Cytogenetic Abnormalities in Intravascular Large B-Cell Lymphoma. Am J Clin Pathol　150：18-26，2018

62）Fujikura K, Yamashita D, Yoshida M, et al：Cytogenetic complexity and heterogeneity in intravascular lymphoma. J Clin Pathol　74：244-250，2021

63）Jeon YK, Kim JH, Sung JY, et al：Epstein-Barr virus-positive nodal T/NK-cell lymphoma: an analysis of 15 cases with distinct clinicopathological features. Hum Pathol　46：981-990，2015

64）Jung KS, Cho SH, Kim SJ, et al：Clinical features and treatment outcome of Epstein-Barr virus-positive nodal T-cell lymphoma. Int J Hematol　104：591-595，2016

65）Ng SB, Chung TH, Kato S, et al：Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes. Haematologica　103：278-287，2018

diseases. Cancer Sci　109：2599-2610，2018

67）Wai CMM, Chen S, Phyu T, et al：Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS. Haematologica　107：1864-1879，2022