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림프종은 림프계와 백혈구(WBCs)의  B cell 및 T cell population에 영향을 미칩니다. 림프종은 림프구의 악성 변형으로 발생합니다. 대부분의 림프종은 B cell에서 발생하며, 10–15%  정도만  T cell 및 NK cell에서 발생합니다.1 

 

림프종의 원인은?

다른 암과 마찬가지로 여러 유형의 림프종에서 유전적 변화가 확인되었으며, 질병의 가족력이 전체 사례의 5%를 차지했습니다. 림프종 발병을 촉진하는 위험 요인이 몇 가지 있습니다.  방사선 치료 및 인간면역결핍바이러스(HIV), 인간 T cell 림프친화바이러스 1형,  C형간염 바이러스, 엡스타인바 바이러스(EBV)와 같은 면역결핍 및 바이러스 감염 등이 위험요인에 포함됩니다.2 

림프종의 유형

 

70종 이상의 림프종이 설명되어 있으며, 림프종은 크게 호지킨 림프종과 비호지킨 림프종으로 분류됩니다.

 

 

호지킨 림프종
 

대부분 호지킨 림프종(HL)의 경우 neoplastic cell은 성숙한 B cell에서 유래합니다. 호지킨 림프종은 20 세에서 34 세 사이의 젊은 성인에서 많이 발생합니다. Hodgkin Reed-Sternberg (HRS) cell은호지킨 림프종의 특징입니다. HRS cell은 호지킨 림프종의 클론 종양 pool을 형성하는 거대한 multinucleated cell입니다. CD30은 HL 및 HRS cell surface marker의 특징입니다.3

 

 

비호지킨 림프종
 

비호지킨 림프종(NHL)은 가장 흔한 형태의 림프종 중 하나입니다.4 노인에게 많이 발생하며 호지킨 림프종보다 치료 반응이 좋지 않습니다. CD20 및 CD19와 같은 표면  marker는 B 림프구에서 파생된 NHL 에서 발현됩니다.5 유세포 분석을 기반으로 한 NHL의 immunophenotypic 분석은 B cell 및 T cell의 특정 lineage marker의 측정에 따라 달라집니다. 

림프종에 대한 유세포 분석 기반의 assay

 

유세포 분석을 기반으로 한 immunophenotyping은 림프구에서 항원의 비정상적인 발현을 추적하기 위해 marker의 panel을 실행할 수 있기 때문에 림프종의 유형을 결정할 수 있는 솔루션입니다. 

 

유세포 분석은  확산성 거대 B cell 림프종 (DLBCL), 여포성림프종(FL), 외투세포림프종(MCL), 변연부림프종(MZL), 버킷림프종(BL) 및 림프형질세포림프종(LPL) 6 과 같은 림프종의 subtype 진단을 지원할 수 있습니다. 고감도 유세포 분석 assays를 이용해 진단시 말초혈액에서 순환종양세포를 측정할 수 있을 뿐만 아니라, 질환의 진행 예후 marker 역할도 합니다. 7

 

 

Immunophenotyping

임상 평가 이후에도 림프증식성 장애 가능성이 상당히 존재하는 경우, 림프구의 세포 표면 및 세포내 phenotyping을 할 수 있습니다.
 

유세포 분석을 통해 PBMC, 골수, CSF와 같은 체액을 스크리닝하여 특정 항원에 양성인 림프구 비율 뿐만 아니라 항원의 밀도도 모니터링 가능합니다. 정상적인 PBMC는 대략 B cell 10%, T cell 80%, NK cell 10%로 구성되어 있습니다. 이러한 세포 population의 변화로 림프증식성 질환을 의심하게 됩니다.  특정 유세포 분석 panel을 실행하여 각각의 population을 평가할 수 있습니다. 림프절과 피부, 기관, 뇌, 채액 등 다른 림프세포 및 조직의 phenotyping에도 유세포 분석을  이용할 수 있습니다. 

 

 

확산성 거대 B cell 림프종

확산성 거대 B cell 림프종(DLBCL)은 림프종에서 가장 큰 범주이며, 서방 국가의 경우  성인 NHL의  30 ~ 40 %가 DLBCL입니다.  DLBCL 은 여포성림프종 (FL) 또는 만성 림프구성백혈병 (CLL)과 같은 다른 림프성 악성 종양이 진행되어 발생한 것일 수 있습니다. 유세포 분석으로 측정되는 거대 림프구를 특징으로 합니다. DLBCL에 대한 immunophenotyping panel 에는  pan-B  cell marker (CD19, CD22, CD79a), germinal center marker CD10및 proliferation marker Ki67이 포함됩니다. Ki67이 높다는 것은 악성 림프종 cell 증식이 증가했다는 것을 의미합니다.8,9

 

 

T cell/NK cell neoplasms

CD2, CD3, CD5, CD7와 같은 pan T cell 항원의 이상은 T cell 림프종 증식성 장애를 나타냅니다10. T cell 비호지킨림프종(T cell NHL)은 모든 호지킨 림프종의 약 12%를 차지합니다. 11

 

T/NK cell neoplasms은 림프종에서 차지하는 비율이 크지 않습니다. 비정상적인 T cell 또는 NK cell phenotype을 보여줍니다.  NK cell의 만성 림프증식성장애(CLPD-NK)는 말초 혈액에서 NK cell이 지속적으로 확장되어 CD16과 낮은 수준의 CD56 및 CD57을 발현하는 보기 드문  드문 이질적인 악성종양이며 전체 림프종의 15% 미만을 차지합니다.13  

 

 

유세포 분석 기반의 진단 응용분야

BD Biosciences는 광범위한 특이성과 dye를 갖춘 single-color antibody CE-IVD 시약 포트폴리오를 제공하여 혈액 종양 특성화를 지원합니다. 이러한 panel은 검사실에서 확인하고 검증해야 합니다. 

 

또한 BD Biosciences는 광범위한 시약, setup beads, 프로토콜, assay template으로 구성된 BD OneFlow™ Solution을 제공하여 백혈병 및 림프종 immunophenotyping의 표준화를 지원합니다. 이를 통해 검사실은 효율성을 개선하고 결과의 신뢰성과 정확도를 향상시킬 수 있습니다.14,15 

참고문헌

  1. Jiang M, Bennani MN, Feldman AL. Lymphoma classification update: T-cell lymphomas, Hodgkin lymphomas and histiocytic/dendritic cell neoplasms. Expert Rev Hematol. 2017;10(3):239-249. doi: 10.1080/17474086.2017.1281122

  2. Morton LM, Slager SL, Cerhan JR, et al. Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014;2014(48):130-144. doi:10.1093/jncimonographs/lgu013   

  3. Küppers R, Hansmann ML. The Hodgkin and Reed/Sternberg cell. Int J Biochem Cell Biol. 2005;37(3):511-517. doi:10.1016/j.biocel.2003.10.025

  4. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390. doi:10.1182/blood-2016-01-643569 

  5. Sarkozy C, Baseggio L, Feugier P, et al. Peripheral blood involvement in patients with follicular lymphoma: a rare disease manifestation associated with poor prognosis. Br J Haematol. 2014;164(5):659-667. doi:10.1111/bjh.12675

  6. van Dongen JJ, Lhermitte L, Böttcher S, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukaemia. 2012;26(9):1908-1975. doi:10.1038/leu.2012.120 

  7. Aujla A, Aujla R, Liu D. Inotuzumab ozogamicin in clinical development for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Biomark Res. 2019;7:9. doi:10.1186/s40364-019-0160-4

  8. Abuelgasim KA, Rehan H, Alsubaie M, et al. Coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma with antecedent chronic lymphocytic leukemia: a case report and review of the literature. J Med Case Rep. 2018;12(1):64. doi:10.1186/s13256-018-1612-4 

  9. Friedberg JW, Fisher RI. Diffuse large B-cell lymphoma. Hematol Oncol Clin North Am. 2008;22(5):941-ix. doi:10.1016/j.hoc.2008.07.002

  10. Pulitzer M. Cutaneous T-cell lymphoma. Clin Lab Med. 2017;37(3):527-546. doi:10.1016/j.cll.2017.06.006 

  11. Park HS, McIntosh L, Braschi-Amirfarzan M, Shinagare AB, Krajewski KM. T-cell non-Hodgkin lymphomas: spectrum of disease and the role of imaging in the management of common subtypes. Korean J Radiol. 2017;18(1):71-83. doi:10.3348/kjr.2017.18.1.71

  12. Zambello R, Teramo A, Barila G et al. Activating KIRs in chronic lymphoproliferative disorder of NK cells: Protection from viruses and disease induction? Front Immunol. 2014;5:72. doi: 10.3389/fimmu.2014.00072 

  13. D’Amore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093-3099. doi: 10.1200/JCO.2011.40.2719

  14. van der Velden VHJ, Flores-Montero J, Perez-Andres M, et al. Optimization and testing of dried antibody tube: The EuroFlow LST and PIDOT tubes as examples. J Immunol Methods. 2019;475:112287. doi: 10.1016/j.jim.2017.03.011 

  15. Moloney E, Watson H, Barge D, et al. Efficiency and health economic evaluations of BD OneFlow™ Flow Cytometry Reagents for diagnosing chronic lymphoid leukemia. Cytometry B Clin Cytom. 2019;96(6):514-520. doi: 10.1002/cyto.b.21779

BD OneFlow™ 제품 및BD single-color antibody reagent는 유럽 체외용 진단의료기기 Directive 98/79/EC에 부합하는 CE인증을 받은 제품입니다. 체외진단용입니다.