Diagnosis and Molecular Pathology of Lymphoblastic Leukemias and Lymphomas in the Era of Genomics and Precision Medicine: Historical Evolution and Current Concepts—Part 2: B-/T-Cell Acute Lymphoblastic Leukemias
Abstract
:1. Introduction
2. Acute Lymphoblastic Leukemia
Epidemiology of Acute Lymphoblastic Leukemia
3. Diagnosis of Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
4. The Classification of Acute Lymphoblastic Leukemia/Lymphoma Requires Genetics
4.1. Historical Overview
4.2. The Genetic Abnormalities in “B-Other” B Lymphoblastic Leukemias/Lymphomas Were Incorporated in the Fifth-Edition WHO Classification in 2022
- (1)
- Upgraded from provisional entities in WHO 2017:
- (2)
- Terminology changes:
- a)
- WHO-HAEM5 includes only the name of the fusion in the names of the types of ALL, and the complete cytogenetic nomenclature is eliminated from the name change. However, as explained in Part 1, WHO-HAEM5 continues to emphasize the importance of cytogenetics throughout the classification [1]. This concern was explained by WHO-HAEM5 editors in a recent publication [38];
- b)
- B-ALL with hyperdiploidy in 2017 is termed B-ALL with high hyperdiploidy in WHO-HAEM5. The ICC uses the same term, B-ALL, hyperdiploid, as in WHO 2017;
- (3)
- B-ALL with ETV6::RUNX1-like features and B-ALL with TCF3::HLF fusion are new types of B-ALL in WHO-HAEM5;
- (4)
- WHO-HAEM5 created a new subgroup, B-ALL with other defined genetic features, which includes seven new types of B-ALL, as shown in Table 1;
- (5)
- If comprehensive testing in a case of B-ALL does not identify any of the genetic abnormalities now defined by WHO-HAEM5, the diagnostic subtype would be B-ALL, not otherwise specified (NOS);
- (6)
- However, if complete testing cannot be performed, the diagnostic term B-ALL/LBL, not further classified, should be used, not B-ALL, NOS [36]. This distinction in diagnostic terminology is a desirable change from WHO 2017, which should ideally be applied throughout the fifth-edition WHO classification for all tumors, as many countries will not have the resources to use advanced genomics methods to define tumor types. It is essential to differentiate between any cancer that is genuinely NOS and cannot be diagnosed as a specific cancer type after comprehensive testing versus a tumor that cannot be determined to be a particular genetic type because it was not possible to test for any reason, as previously discussed [39].
WHO-HAEM5 2022 Classification [7,36] | International Consensus Classification [37] |
---|---|
B-lymphoblastic leukemias/lymphomas B-lymphoblastic leukemia/lymphoma a B-lymphoblastic leukemia/lymphoma with high hyperdiploidy B-lymphoblastic leukemia/lymphoma with hypodiploidy B-lymphoblastic leukemia/lymphoma with iAMP21 b B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features b B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features b B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion b B-lymphoblastic leukemia/lymphoma with other defined genetic alterations b B-lymphoblastic leukemia with DUX4 rearrangement B-lymphoblastic leukemia with MEF2D rearrangement B-lymphoblastic leukemia with ZNF384 rearrangement B-lymphoblastic leukemia with PAX5alt B-lymphoblastic leukemia with PAX5 p.P80R B-lymphoblastic leukemia with NUTM1 rearrangement B-lymphoblastic leukemia with MYC rearrangement B-lymphoblastic leukemia/lymphoma, not otherwise specified Precursor T-cell neoplasms T-lymphoblastic leukemia/lymphoma T-lymphoblastic leukemia/lymphoma, not otherwise specified Early T-precursor lymphoblastic leukemia/lymphoma b | B-acute lymphoblastic leukemia (B-ALL) B-ALL with recurrent genetic abnormalities B-ALL with t(9;22)(q34.1;q11.2)/BCR::ABL1 with lymphoid only involvement b with multilineage involvement b B-ALL with t(v;11q23.3)/KMT2A rearranged B-ALL with t(12;21)(p13.2;q22.1)/ETV6::RUNX1 B-ALL, hyperdiploid B-ALL, low hypodiploid B-ALL, near haploid B-ALL with t(5;14)(q31.1;q32.3)/IL3::IGH B-ALL with t(1;19)(q23.3;p13.3)/TCF3::PBX1 B-ALL, BCR::ABL1–like, ABL-1 class rearranged b B-ALL, BCR::ABL1–like, JAK-STAT activated b B-ALL, BCR::ABL1–like, not otherwise specified b B-ALL with iAMP21 b B-ALL with MYC rearrangement b B-ALL with DUX4 rearrangement b B-ALL with MEF2D rearrangement b B-ALL with ZNF384(362) rearrangement b B-ALL with NUTM1 rearrangement b B-ALL with HLF rearrangement b B-ALL with UBTF::ATXN7L3/PAN3,CDX2 (“CDX2/UBTF”) b B-ALL with mutated IKZF1 N159 Y b B-ALL with mutated PAX5 P80 R b (Provisional) B-ALL, ETV6::RUNX1-like b (Provisional) B-ALL, with PAX5 alteration b (Provisional) B-ALL, with mutated ZEB2 (p.H1038R)/IGH::CEBPE b (Provisional) B-ALL, ZNF384 rearranged-like b (Provisional) B-ALL, KMT2A rearranged-like b B-ALL, not otherwise specified T-acute lymphoblastic leukemia/lymphoma (T-ALL) Early T-cell precursor ALL with BCL11B rearrangement b Early T-cell precursor ALL, not otherwise specified b T-ALL, not otherwise specified Other provisional entities a given in reference [37] (Provisional) Natural killer (NK) cell ALL c |
4.3. Specific Genetic Types of B-ALL and T-ALL Described in the Fifth-Edition WHO Classification
4.3.1. B-ALL with High Hyperdiploidy and B-ALL with ETV6::RUNX1 Fusion
B-ALL with ETV6::RUNX1 Fusion
B-ALL with High Hyperdiploidy
4.3.2. B-ALL with Hypodiploidy
4.3.3. B-ALL with Intrachromosomal Amplification of Chromosome 21
4.3.4. B-ALL with BCR::ABL1 Fusion or Ph-Positive B-ALL
4.3.5. B-ALL with BCR::ABL1-like Features (or Ph-like B-ALL)
4.3.6. B-ALL with TCF3::PBX1 Fusion and B-ALL with TCF3::HLF Fusion
B-ALL with TCF3::PBX1 Fusion
B-ALL with TCF3::HLF Fusion
4.3.7. B-ALL with KMT2A Rearrangement
4.3.8. New Subtypes of B-ALL Introduced in WHO-HAEM5
B-ALL with DUX4 Rearrangement
B-ALL with ZNF384 Rearrangement
B-ALL with MEF2D Rearrangement
B-ALL with PAX5alt and B-ALL with PAX5 p.P80R
B-ALL with MYC Rearrangement
B-ALL with NUTM1 Rearrangement
B-ALL with ETV::RUNX1-like Features
4.3.9. Molecular Genetic Subtypes of B-ALL Defined by Standard Genetic Techniques and Whole-Genome Sequencing
4.3.10. T-ALL, Not Otherwise Specified
Early T Precursor Lymphoblastic Leukemia/Lymphoma
4.3.11. Summary of Specific Flow Cytometric Immunophenotypic Features in the Genetic Types of B-ALL and T-ALL
4.3.12. Clinical Significance of the Newer Subtypes of ALL
5. Inherited Genetic Predisposition to ALL
6. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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B-ALL Genetic Subtypes | Primary Genetic Aberrations | Prognostic Significance | FISH Probes | Fusion Genes | Detectable by Which Methods? | ||
---|---|---|---|---|---|---|---|
CBA and FISH | Molecular Assay | WGS | |||||
High hyperdiploidy | 51–65 chromosomes | Favorable risk | Centromeric probes | Not applicable | Yes | CMA; not by RT-PCR | Yes |
ETV6::RUNX1 fusion | t(12;21)(p13.2;q22.1)/ETV6::RUNX1 a | Favorable risk | Dual-color fusion | ETV6::RUNX1 | Yes a,b | Yes RT-PCR | Yes |
Hypodiploidy | 43 or fewer chromosomes: Near-haploid: 24–31 chromosomes; alterations in NF1, NRAS, KRAS, MAPK1, FLT3, or PTPN11; and IKZF3; Low-hypodiploid: 32–39 chromosomes; TP53, IKZF2, and RB1 mutations; 50% of TP53 mutations are germline; High-hypodiploid: 40–43 chromosomes | High risk | Screening probes may show a typical pattern of chromosomal gains and losses to suggest the diagnosis | Not applicable | Yes | Yes CMA; not by RT-PCR | Yes |
Intrachromsomal amplification of chromosome 21 | ≥3 or more copies of RUNX1 on a single abnormal chromosome 21 with frequent deletion of subtelomeric 21q sequences | Higher risk improved with intense treatment | ETV6::RUNX1 probe [153] | Not applicable | Yes c | Yes CMA | Yes |
BCR::ABL1 fusion | t(9;22)(q34.1;q11.2) | High risk improved with TKI therapies | Dual color or tricolor dual fusion | BCR::ABL1 | Yes | Yes RT-PCR | Yes |
BCR::ABL1-like features | CRLF2 rearrangements, including P2RY8::CRLF2; JAK mutations; ABL1, ABL2, PDGFRB, and CSF1R fusions; and NTRK3, FLT3, PTK2B, and TYK2 alterations | High risk | CRLF2 BA | P2RY8::CRLF2 | CBA: No FISH: Yes | Yes; MLPA | Yes |
TCF3::PBX1 fusion | t(1;19)(q23.3;p13.3) | Favorable to intermediate | Dual color fusion | TCF3::PBX1 | Yes | Yes RT-PCR | Yes |
TCF3::HLF fusion | t(17;19)(q22;p13) | High risk | TCF3 BA d | TCF3::HLF | Yes | Yes RT-PCR | Yes |
KMT2A-rearranged | KMT2A (11q23) rearrangements | High risk | KMT2A BA | 11q23 translocations | Yes a | Yes RT-PCR | Yes |
DUX4-rearranged | DUX4 fusions; DUX overexpression | Favorable, despite high MRD | Not applicable | IGH::DUX4 or ERG::DUX4 | No | Not by PCR e | Yes |
ZNF384 rearrangement | ZNF384 rearrangements; EP300::ZNF384; and TCF3::ZNF384 | Favorable [157]; intermediate; depends on partner gene | ZNF384 BA | EP300::ZNF384; TCF3::ZNF384 | CBA: No | Not by PCR e | Yes |
MEF2D rearrangement | MEF2D rearrangements; MEF2D::BCL9 or MEF2D::HNRNPUL1 | High risk | MEF2D BA | MEF2D::BCL9 or MEF2D::HNRNPUL1 | CBA: No | RT-PCR [17] | Yes |
PAX5alt | PAX5 abnormalities other than PAX5 p.P80R: gene rearrangements, non-p.P80R sequence mutations, or focal intragenic amplifications, with the exception of PAX5::JAK2 (Ph-like B-ALL) and PAX5::ZCCH7, which occurs in cases with other class-defining alterations [34,36] | Intermediate in children; high risk in adults | PAX5 BA for rearrangements | Not applicable | CBA: No; FISH only for PAX5 BA | Not by PCR e | Yes |
PAX5 p. P80R | PAX5 p. P80R | Intermediate in children; high risk in adults | Not applicable | Not applicable | No | Not by PCR e | Yes |
MYC rearrangement | MYC rearrangement; IGH::MYC, IGK::MYC, or IGL::MYC | High risk in adults; better in children | MYC BA | IGH::MYC, IGK::MYC, or IGL::MYC | Yes | Not by PCR e | Yes |
NUTM1 rearrangement | NUTM1 (15q14) rearrangement | Favorable | NUTM1 BA | CBA: yes f (subset) | Not by PCR e | Yes | |
ETV6::RUNX1-like features | ETV6 fusions excluding PAX5::ETV6, ETV6::ABL1, and ETV6::JAK2; IKZF1 fusion and/or deletion; ETV6 biallelic inactivation if lacking other defining features [156] | Unfavorable [157] Favorable g [131,156] | Not applicable | Not applicable | No | Not by PCR e | Yes |
T-ALL Genetic Subgroups | Primary Genetic Aberrations | FISH Probes | Fusion Genes | Detectable by Which Methods? | ||
---|---|---|---|---|---|---|
Both CBA and FISH | Molecular Assay | WGS | ||||
TLX1 | t(10;14)(q24;q11); TRAD::TLX1 | TLX1 BA | Yes | No | Yes | |
t(7;10)(q34;q24); TRB::TLX1 | TLX1 BA | Yes | No | Yes | ||
TLX3 | t(5:14)(q35;q32);BCL11B::TLX3 | BCL11B::TLX3, TLX3 BA | FISH: yes; CBA: no | No | Yes | |
TAL1 | t(1:14)(p32:q11); TRAD::TAL1 | TRAD BA | Yes b | No | Yes | |
del(1)(p32p32) a | STIL::TAL1 | CBA: no c | Yes | Yes | ||
HOXA9/10 | inv(7)(p15q34); HOXA::TRB | HOXA BA | yes | No | Yes | |
SET::NUP214 | del(9)(q34q34) a | SET::NUP214 | No | Yes | Yes | |
MLLT10 | t(10;11)(p12;q14) | PICALM::MLLT10 | CBA: yes c | Yes | Yes | |
t(X;10)(p11;p12) | DDX3X::MLLT10 | CBA: yes c | Yes c | Yes | ||
NUP98 | t(4;11)(q23;p15) | NUP98 BA | NUP98::RAP1GDS1 | Yes | Yes c | Yes |
MYB | t(6;7)q23;q34); TRB::MYB | TRB BA | Yes b | No | Yes | |
BCL11B | t(8;14)(q24;q32); BCL11B::CCDC26 a | CBA: no c | No | Yes | ||
t(6;14)(q25;q32); BCL11B::ARID1B a | CBA: no c | No | Yes | |||
t(3;14)(p24;q32); BCL11B::SATB1 | CBA: yes c | No | Yes | |||
BCL11B enhancer amplification | No | No | Yes | |||
Rare | t(4;14)(q25;q11); TRAD::LEF1 | TRAD BA | Yes b | No | Yes | |
t(11;14)(p13;q11); TRAD::LMO2 | TRAD BA | Yes b | No | Yes | ||
t(7;10)(q34;q24); TRB::NKX2 | TRB BA | Yes b | No | Yes | ||
t(7;9)(q34;q34); TRB::NOTCH1 | TRB BA | Yes b | No | Yes | ||
t(11;14)(p13;q32); LMO2 | CBA: yes c | No | Yes | |||
Mutation in MYB enhancer | No | Yes c | Yes |
B-ALL Genetic Subtypes | Total N in [136] | Distribution of Pro-B, Common, and Pre-B Cases for Each Genetic Type of B-ALL [136] | Percentages of B-ALL Cases Showing >20% Positivity for a Few Specific Antigens in [136] | Specific Features, if Any, of the Leukemic Cells by FCI Based on Referenced Publications | |||||
---|---|---|---|---|---|---|---|---|---|
CD10− cyt IgM− Pro-B | CD10+ | cyt IgM+ Pre-B | CD10 % CD34 % | CD33 % CD13 % | CD66 % | CD27 % CD44 % | |||
High hyperdiploidy | 179 | 0 | 85.5% | 14.5% | CD10: 100% CD34: 87.7% | CD33: 9.5% CD13: 3.4% | CD66c: 73.7% | CD27: 10.1% CD44: 100% | Higher-intensity CD9, CD20, CD22, CD58, CD66c, CD86, and CD123, and lower-intensity CD45 compared with B-ALL with other ploidy status [53]; Strong CD123+ [170,171] |
ETV6::RUNX1 fusion | 164 | 0 | 86.1% | 13.9% | CD10: 99.4% CD34: 72.6% | CD33: 42.4% CD13: 24.4% | CD66c: 0% | CD27: 70.6% CD44: 45.3% | Absent or partial positivity for CD9, CD20, and CD66c; frequent CD13+ and CD33+ [20,36,49,136]; CD27 + CD44(−)/low+ [31,50,136]; Uniformly low CD123+ [170,172] a |
Hypodiploidy | 6 | 0 | 66.7% | 33.3% | CD10: 100% CD34: 85.7% | CD33: 42.9% CD13: 14.3% | CD66c: 85.7% | CD27: 20.0% CD44: 100% | DNA index by flow cytometry may suggest the diagnosis if both hypodiploid and near-triploid clones are present [36] |
iAMP21 | NA | NA | NA | NA | NA | NA | NA | NA | None |
BCR::ABL1 fusion | 46 | 0 | 84.4% | 15.6% | CD10: 97.8% CD34: 97.8% | CD33: 34.5% CD13: 15.2% | CD66c: 91.3% | CD27: 41.9% CD44: 97.7% | Coexpressed CD66c+ and CD25+ [173]; higher intensity of CD13, CD33, CD66c, CD10, CD34, and CD25 than BCR::ABL1-negative [174,175]; CD123 higher-intensity expression [171] |
BCR::ABL1-like features, kinase fusion-positive | 11 | 0 | 63.6% | 36.4% | CD10: 100% CD34: 100% | CD33: 36.4% CD13: 9.1% | CD66c: 36.4% | CD27: 44.4% CD44: 100% | Immunophenotype similar to BCR::ABL1; high CD20 and CD45RA expression; CD99+ (91%) TdT+ (100%), and cyt IgM+ (36.4%) [136] |
BCR::ABL1-like features, CRLF2-rearranged | 15 | 0 | 86.7% | 13.3% | CD10: 100% CD34: 93.3% | CD33: 46.7% CD13: 0% | CD66c: 80.4% | CD27: 57.1% CD44: 100% | CRLF2 overexpressed [96,136]; all other features described here were similar to BCR::ABL1 and BCR::ABL1-like kinase+ [136] |
TCF3::PBX1 fusion | 68 | 0 | 26.5% | 73.5% | CD10: 98.5% CD34: 4.4% | CD33: 0% CD13: 0% | CD66c: 0% | CD27: 4.2% CD44: 100% | Homogeneous CD19+, CD10+, and CD9+, with partial expression of CD20; absent CD34 [19] |
TCF3::HLF fusion | NA | NA | NA | NA | NA | NA | NA | NA | High expresssion of CD19 [36] |
KMT2A::AFFI-rearranged | 13 | 69.2 | 7.7% | 3.1% | CD10: 7.7% CD34: 76.9% | CD33: 7.7% CD13: 0% | CD66c: 0% | CD27: 0% CD44: 100% | CD10–, CD24–, CD15+, and CD19+ blasts in B-ALL with t(4;11)(q21;q23) [18]; NG2+ [136,176] |
KMT2A::MLLT3-rearranged | 10 MLLT3 | 33% | 11% | 55.5% | CD34: 0% | CD33 b CD13: 0% | CD66c: 0% | CD27: 0% CD44: 100% | Aberrant CD7+, CD2+, and CD5+, more frequent in CD10+ cases; NG2+, CD15+, CD65+, CD117+, CD56+, CD99+, CD45RA+, and CD20− in CD10– cases [136] |
DUX4-rearranged | 20 | 5.9% | 52.9% | 41.2% | CD10: 95.0% CD34: 90.0% | CD33: 10.0% CD13: 15.0% | CD66c: 30.0% | CD27: 0% CD44: 94.1% | CD66c and CD2 coexpression-specific [136]; CD2+ [131]; CD20− TdT+ CD99−/rare +; CD56+ in 15% cases [136]; CD371+ [135]; and monocytic CD14, gain of CD45 and CD33, may be present at diagnosis and post-induction [36] |
ZNF384 rearrangement | 29 | 44.4% | 51.9% | 3.7% | CD10: 51.7% CD34: 100% | CD33: 82.8% CD13: 27.6% | CD66c: 10.3% | CD27: 10.5% CD44: 95.7% | Negative or dim CD10 with aberrant CD13 and/or CD33 expression [30,177]; monocytic differentiation may be present at diagnosis and early after induction [36], note c |
MEF2D rearrangement | 13 | 15.4% | 23.1% | 61.5% | CD10: 76.9% CD34: 38.5% | CD33: 15.4% CD13: 0% | CD66c: 0% | CD27: 0% CD44: 84.6% | Negative or dim CD10 and high expression of CD38 [32] |
PAX5alt: PAX5 fusion in [136] | 11 | 0 | 72.7% | 27.3% | CD10: 100% CD34: 81.8% | CD33: 9.1% CD13: 0% | CD66c: 63.6% | CD27: 0% CD44: 100% | CD20+ (64%), TdT+ (100%), CD34+ (82%), CD99+ (73%), and CD21+ (20%) [136] |
B-other in Ohki et al. [136] | 335 | 3.8 | 76.5 | 19.7 | CD10: 95.5% CD34: 79.8% | CD33: 17.8% CD13: 4.7% | CD66c: 49.0% | CD27: 17.3% CD44: 91.9% | CD20+ (42%), TdT (16.7%), CD99 (65.7%), and CD45RA (51.3%) [136] |
PAX5 p. P80R | NA | NA | NA | NA | NA | NA | NA | NA | CD2+ CD10+ CD33+ CD15- CD65- blasts [131] |
MYC rearrangement | NA | NA | NA | NA | NA | NA | NA | NA | Precursor B-cell immunophenotype; no specific features reported by FCI |
NUTM1 rearrangement | NA | NA | NA | NA | NA | NA | NA | NA | CD10+ or CD10– blasts [151] |
ETV6::RUNX1-like features | NA | NA | NA | NA | NA | NA | NA | NA | CD24+ and CD44– or low+ blasts [31] |
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Kansal, R. Diagnosis and Molecular Pathology of Lymphoblastic Leukemias and Lymphomas in the Era of Genomics and Precision Medicine: Historical Evolution and Current Concepts—Part 2: B-/T-Cell Acute Lymphoblastic Leukemias. Lymphatics 2023, 1, 118-154. https://doi.org/10.3390/lymphatics1020011
Kansal R. Diagnosis and Molecular Pathology of Lymphoblastic Leukemias and Lymphomas in the Era of Genomics and Precision Medicine: Historical Evolution and Current Concepts—Part 2: B-/T-Cell Acute Lymphoblastic Leukemias. Lymphatics. 2023; 1(2):118-154. https://doi.org/10.3390/lymphatics1020011
Chicago/Turabian StyleKansal, Rina. 2023. "Diagnosis and Molecular Pathology of Lymphoblastic Leukemias and Lymphomas in the Era of Genomics and Precision Medicine: Historical Evolution and Current Concepts—Part 2: B-/T-Cell Acute Lymphoblastic Leukemias" Lymphatics 1, no. 2: 118-154. https://doi.org/10.3390/lymphatics1020011