Ann Lab Med.  2020 Sep;40(5):361-369. 10.3343/alm.2020.40.5.361.

Diagnostic Approach for Double-Hit and Triple-Hit Lymphoma Based on Immunophenotypic and Cytogenetic Characteristics of Bone Marrow Specimens

Affiliations
  • 1Department of Laboratory Medicine, Korea Cancer Center Hospital, Seoul, Korea
  • 2Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Abstract

Background
High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (BCL2/BCL6), also known as double-hit lymphoma (DHL) and/or triple-hit lymphoma (THL), is a new entity of B-cell lymphoma in the 2017 WHO Classification. We retrospectively investigated D/THL and their clinico-laboratory features among cases of large B-cell lymphoma involving the bone marrow (BM), including diffuse large B-cell lymphoma, Burkitt lymphoma, and B-cell lymphomas with medium to large lymphoid cells, by additional FISH analysis of BM aspirates.
Methods
A total of 111 patients diagnosed with aggressive B-cell lymphomas or B-cell lymphoma involving the BM with medium to large-sized malignant lymphocytes were reviewed from January 2000 to January 2018. Patients with available BM aspirates were evaluated by immunophenotyping by flow cytometry, chromosome, and FISH analysis for MYC and/or BCL2/BCL6 rearrangements.
Results
In total, 23/111 (20.7%) showed MYC rearrangement, and eight (7.2%) were reclassified as D/THL on BM after FISH analysis for MYC and BCL2/BCL6. The detection of CD5(-)/CD10(+) based on flow cytometry was strongly associated with D/THL. A complex karyotype with aberrations related to regions in MYC and BCL2/BCL6 was significantly associated with D/THL. When the MYC FISH results of 28 BM aspirates and formalin-fixed paraffin-embedded tissue specimens were compared, 14% were discrepant.
Conclusions
Immunophenotypic and cytogenetic characteristics facilitate the diagnosis of D/THL in the cases with BM-involving aggressive B-cell lymphomas.

Keyword

Double-hit lymphoma; Triple-hit lymphoma; Diffuse large B-cell lymphoma; Burkitt lymphoma; Aggressive B-cell lymphoma; MYC; BCL2; BCL6

Reference

1. Swerdlow SH, Campo E, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. revised 4th ed.Lyon: International Agency for Research on Cancer (IARC);2017. p. 335–41.
2. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011; 117:5019–32.
Article
3. Said JW. Aggressive B-cell lymphomas: how many categories do we need? Mod Pathol. 2013; 26:S42–56.
Article
4. Lindsley RC, LaCasce AS. Biology of double-hit B-cell lymphomas. Curr Opin Hematol. 2012; 19:299–304.
Article
5. Snuderl M, Kolman OK, Chen YB, Hsu JJ, Ackerman AM, Dal Cin P, et al. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol. 2010; 34:327–40.
6. Oki Y, Noorani M, Lin P, Davis RE, Neelapu SS, Ma L, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014; 166:891–901.
Article
7. Li S, Lin P, Fayad LE, Lennon PA, Miranda RN, Yin CC, et al. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol. 2012; 25:145–56.
8. Merron B, Davies A. Double hit lymphoma: how do we define it and how do we treat it? Best Pract Res Clin Haematol. 2018; 31:233–40.
Article
9. Carbone A, Gloghini A, Kwong YL, Younes A. Diffuse large B cell lymphoma: using pathologic and molecular biomarkers to define subgroups for novel therapy. Ann Hematol. 2014; 93:1263–77.
Article
10. Friedberg JW. How I treat double-hit lymphoma. Blood. 2017; 130:590–6.
Article
11. Nabhan C, Mato AR. Emerging strategies in treating double hit lymphomas. Clin Lymphoma Myeloma Leuk. 2017; 17:563–8.
Article
12. Sakr H, Cook JR. Identification of “Double Hit” lymphomas using updated WHO criteria: insights from routine MYC immunohistochemistry in 272 consecutive cases of aggressive B-cell lymphomas. Appl Immunohistochem Mol Morphol. 2019; 27:410–5.
13. Sesques P, Johnson NA. Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. Blood. 2017; 129:280–8.
14. Aukema SM, Siebert R, Schuuring E, van Imhoff GW, Kluin-Nelemans HC, Boerma EJ, et al. Double-hit B-cell lymphomas. Blood. 2011; 117:2319–31.
Article
15. Scott DW, King RL, Staiger AM, Ben-Neriah S, Jiang A, Horn H, et al. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood. 2018; 131:2060–4.
16. Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, et al. Diffuse large B-Cell lymphoma version 1.2016. J Natl Compr Canc Netw. 2016; 14:196–231.
17. Bain BJ. Bone marrow trephine biopsy. J Clin Pathol. 2001; 54:737–42.
Article
18. Talaulikar D, Dahlstrom JE. Staging bone marrow in diffuse large B-cell lymphoma: the role of ancillary investigations. Pathology. 2009; 41:214–22.
Article
19. Lee SH, Erber WN, Porwit A, Tomonaga M, Peterson LC. International Council for Standardization in Hematology. ICSH guidelines for the standardization of bone marrow specimens and reports. Int J Lab Hematol. 2008; 30:349–64.
Article
20. Mazur G, Hałoń A, Wróbel T, Jeleń M, Kuliczkowski K. Contribution of flow cytometric immunophenotyping and bone marrow trephine biopsy in the detection of lymphoid bone marrow infiltration in non-Hodgkin’s lymphomas. Neoplasma. 2004; 51:159–63.
21. Kim B, Lee ST, Kim HJ, Kim SH. Bone marrow flow cytometry in staging of patients with B-cell non-Hodgkin lymphoma. Ann Lab Med. 2015; 35:187–93.
Article
22. Morice WG, Kurtin PJ, Hodnefield JM, Shanafelt TD, Hoyer JD, Remstein ED, et al. Predictive value of blood and bone marrow flow cytometry in B-cell lymphoma classification: comparative analysis of flow cytometry and tissue biopsy in 252 patients. Mayo Clin Proc. 2008; 83:776–85.
Article
23. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004; 103:275–82.
Article
24. Jaffe ES, Campo E, Harris NL, Pileri SA, Stein H, Swerdlow SH. Introduction and overview of the classification of lymphoid neoplasms. Swerdlow SH, Campo E, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. revised 4th ed.Lyon: International Agency for Research on Cancer (IARC);2017. p. 190–8.
25. Dorfman DM. Clinical flow cytometry: state-of-the-art and new approaches. Clin Lab Med. 2017; 37:xiii–xiv.
Article
26. Wu D, Wood BL, Dorer R, Fromm JR. ‘Double-Hit’ mature B-cell lymphomas show a common immunophenotype by flow cytometry that includes decreased CD20 expression. Am J Clin Pathol. 2010; 134:258–65.
Article
27. Roth CG, Gillespie-Twardy A, Marks S, Agha M, Raptis A, Hou JZ, et al. Flow cytometric evaluation of double/triple hit lymphoma. Oncol Res. 2016; 23:137–46.
Article
28. Schniederjan SD, Li S, Saxe DF, Lechowicz MJ, Lee KL, Terry PD, et al. A novel flow cytometric antibody panel for distinguishing Burkitt lymphoma from CD10+ diffuse large B-cell lymphoma. Am J Clin Pathol. 2010; 133:718–26.
Article
29. Copie-Bergman C, Cuillière-Dartigues P, Baia M, Briere J, Delarue R, Canioni D, et al. MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study. Blood. 2015; 126:2466–74.
30. de Jonge AV, Roosma TJ, Houtenbos I, Vasmel WL, van de Hem K, de Boer JP, et al. Diffuse large B-cell lymphoma with MYC gene rearrangements: current perspective on treatment of diffuse large B-cell lymphoma with MYC gene rearrangements; case series and review of the literature. Eur J Cancer. 2016; 55:140–6.
31. Landsburg DJ, Falkiewicz MK, Petrich AM, Chu BA, Behdad A, Li S, et al. Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable. Br J Haematol. 2016; 175:631–40.
32. Ventura RA, Martin-Subero JI, Jones M, McParland J, Gesk S, Mason DY, et al. FISH analysis for the detection of lymphoma-associated chromosomal abnormalities in routine paraffin-embedded tissue. J Mol Diagn. 2006; 8:141–51.
Article
33. May PC, Foot N, Dunn R, Geoghegan H, Neat MJ. Detection of cryptic and variant IGH-MYC rearrangements in high-grade non-Hodgkin’s lymphoma by fluorescence in situ hybridization: implications for cytogenetic testing. Cancer Genet Cytogenet. 2010; 198:71–5.
34. Muñoz-Mármol AM, Sanz C, Tapia G, Marginet R, Ariza A, Mate JL. MYC status determination in aggressive B-cell lymphoma: the impact of FISH probe selection. Histopathology. 2013; 63:418–24.
35. Chong LC, Ben-Neriah S, Slack GW, Freeman C, Ennishi D, Mottok A, et al. High-resolution architecture and partner genes of MYC rearrangements in lymphoma with DLBCL morphology. Blood Adv. 2018; 2:2755–65.
36. Sarkozy C, Traverse-Glehen A, Coiffier B. Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas. Lancet Oncol. 2015; 16:e555–67.
Article
Full Text Links
  • ALM
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr