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![3. Lymphoplasmacytic Lymphoma
• Two subtypes
IgM-LPL/ Waldenström Macroglobulinaemia (WM) type [most common]
Non-WM type LPL represents around 5% of LPL and includes:
-IgG or IgA monoclonal proteins
-Non-secretory LPL
-IgM LPL without BM involvement
• MYD88 mutation : hallmark driver mutation in the vast majority of LPL
(>90%) [To differentiate NMZL and ENMZL with plasmacytoid
differentiation and Multiple myeloma]
• Desirable to perform CXCR4 mutational analysis , esp. in patients planned
for Ibrutinib therapy](https://image.slidesharecdn.com/who5thhematolymphoidbcellneoplasm-230519003635-b1e4960f/75/who-5th-hematolymphoid-B-cell-neoplasm-pptx-17-2048.jpg)
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Similar to who 5th hematolymphoid B cell neoplasm.pptx
who 5th hematolymphoid B cell neoplasm.pptx
- 1. WHO 2022 updateon lymphoid malignancies, 5th Ed. Presenter: Dr. Shweta Moderator: Dr. Jasmita 11.08.2022
- 2. Evolution of classificationof B cell neoplasm
- 3. WHO-HAEM5 • Systemic evolutionof prior classifications • Hierarchical system: • Provisional entities not created - lack evidence • Non neoplastic mimickers of lymphoid neoplasms – added (to prevent over- diagnosis) • Germline tumour predisposition syndromes/ immunodeficiency syndromes • Recognizes increasing importance of genetic and molecular data Category Eg: Mature B cell Family/ class Eg: Large B cell lymphoma Entity/ type Eg: DLBCL, NOS Subtype Eg: DLBCL, NOS
- 4. Desirable Criteria Essential Criteria Aid inconfirmation and refinement of the diagnosis, and usually require the application of advanced techniques Minimal criteria to allow the diagnosis of an entity as universally as possible, although molecular criteria are inevitably included for some entities
- 5. Tumour-like lesions withB-cell predominance • IgG4-related disease • Progressive transformation of germinal centers • Infectious mononucleosis • Florid reactive lymphoid hyperplasia/lymphoma-like lesion of the female genital tract • Systemic lupus erythematosus
- 6. B-lymphoblastic leukaemias/lymphomas (B-ALL) • Classifiedaccording to ploidy changes, such as hyperdiploidy and hypodiploidy, as well as chromosomal rearrangements or the presence of other genetic drivers • Nomenclature focuses on molecular events rather than cytogenetic alterations • B-ALL, NOS is reserved for cases that cannot be classified even after comprehensive testing • TCF3::HLF fusion is distinct from B-ALL with TCF3::PBX1 fusion and associated with aggressive behaviour • B-ALL with BCR::ABL1-like features is now an entity • B-ALL with ETV6::RUNX1-like features – new entity
- 8. Mature B cellneoplasms • Comprises of 12 families: 1. Pre-neoplastic and neoplastic small lymphocytic proliferations Monoclonal B-cell Lymphocytosis(MBL) Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL/SLL) B-PLL is no longer recognized as an entity
- 9. Monoclonal B celllymphocytosis Low count MBL Clonal CLL/SLL - phenotype B-cell Count below 0.5 x 109/L No other features diagnostic of B- LPD CLL/SLL type MBL Monoclonal CLL/SLL- phenotype B-cell leukemia Count ≥0.5 x 109/L and total B-cell count less than 5 x 109/L No other features diagnostic of CLL/SLL Non-CLL/SLL type MBL ANY monoclonal non-CLL/SLL phenotype B-cell expansion with no symptoms or features diagnostic of another mature B- cell neoplasm All subtypes are recognized by immune impairment and increased risk of infections
- 10. CLL Essential markers CD5, CD19,CD20, CD23 and surface/cytoplasmic K/L light chains Additional markers CD10, CD43, CD79b, CD81, CD200 and ROR1 • del(11q), del(13q), del(17p) & Trisomy 12 • TP53 mutational status • IgHV region SHM analysis/ BCR subset analysis Prognostic evaluation • Karyotypic complexity, BTK, PLCG2 and BCl2 mutational status Desirable investigations
- 11. • Use ofRichter transformation preferred over Richter syndrome • B-prolymphocytic leukaemia (B-PLL) is no longer recognized Cases that have been labeled as B-PLL include: Prolymphocytic progression of CLL/SLL CD5-positive non-mantle B-cell neoplasm >15% prolymphocytes in the peripheral blood and/or bone marrow A variant of mantle cell lymphoma, characterized by presence of IGH:: CCND1 Other cases, now classified as “splenic B-cell lymphoma/leukaemia with prominent nucleoli”
- 12. 2. Splenic Bcell lymphoma/ leukemias New Entity : Splenic B-cell lymphoma/leukaemia with prominent nucleoli
- 13. Hairy Cell Leukaemia •Mature B-cell neoplasm with distinctive clinicopathologic features • BRAF p.V600E (NP_004324.2) somatic mutation in >95% of cases • Other splenic small B-cell lymphomas usually lack BRAF mutations
- 14. Splenic B-cell lymphoma/leukaemiawith prominent nucleoli (SBLPN) • Replaces the term Hairy cell leukaemia variant • Rare and comprises 0.4% of chronic lymphoid malignancies • Includes all cases of CD5 –ve B-PLL • Affects elderly patients • Neoplastic cells have prominent nucleoli and –ve for HCL markers (CD25, annexinA1, TRAP, and CD123) • Clinically more aggressive and resistant to cladribine as single- agent treatment
- 15. Splenic diffuse redpulp small B-cell lymphoma (SDRPL) • Features overlapping with HCL and SBLPN • Can be distinguished on careful evaluation of morphology and immunophenotypic characteristics • CD200 mean fuorescence intensity (MFI)/CD180 MFI ratio <0.5 on flow cytometry favours a diagnosis of SDRPL over HCL, SMZL, and SBLPN • For HPE : Spleen >> BM • Intrasinusoidal pattern ▫ SMZL and SBLPN - More diverse growth pattern ▫ HCL - Diffuse pattern with Reticulin fibrosis
- 17. 3. Lymphoplasmacytic Lymphoma •Two subtypes IgM-LPL/ Waldenström Macroglobulinaemia (WM) type [most common] Non-WM type LPL represents around 5% of LPL and includes: -IgG or IgA monoclonal proteins -Non-secretory LPL -IgM LPL without BM involvement • MYD88 mutation : hallmark driver mutation in the vast majority of LPL (>90%) [To differentiate NMZL and ENMZL with plasmacytoid differentiation and Multiple myeloma] • Desirable to perform CXCR4 mutational analysis , esp. in patients planned for Ibrutinib therapy
- 18. 4. Marginal ZoneLymphomas All these entities share histological and immunophenotypic features Trisomy 3 & 18 : common to all; 2p and 6p gain / loss of 1p and 6q - more in NMZL t(11;18)(q21;q21) resulting BIRC3::MALT1 fusion >> recurrent in gastric / pulm. ENMZL
- 20. 5. Follicular Lymphoma •Neoplasia is replaced by neoplasm • NO MAJOR CHANGES
- 21. Classic FL (cFL) •Follicular growth pattern (85%) • Centrocyte/ centroblasts • t(14;18) associated with IGH::BCL2 fusion • Grading is optional & no longer mandatory • Two related subtypes/ groups: FLBL : largely equals WHO-HAEM4R FL grade 3B, and renaming was done for reasons of consistency throughout the classification FL with uncommon features (uFL) : 2 subsets- Blastoid / large centrocyte & diffuse growth pattern
- 22. 6. Mantle celllymphoma Biomarkers of high-risk MCL include cytomorphology (pleomorphic or blastoid appearance), high Ki67 proliferative index, p53 expression and TP53 mutation Identification of prognostic subgroups has become highly relevant due to improved therapies
- 23. 7. High-grade transformationsteps forth • High-grade transformation of indolent B- cell lymphomas
- 24. 8. Large B-celllymphomas: new names and new umbrellas
- 25. DLBCL, NOS • Representsthe most common entity • 2 main subtypes previously defined in WHO-HAEM4R continue to be recognized (i.e. GCB and ABC) • 17 specific entities as “large B-cell lymphomas” other than DLBCL, NOS • Names of some entities have been modified for reasons of consistency, from “DLBCL” to “large B-cell lymphoma“, because diffuse growth pattern is either not apparent/present or cannot be assessed
- 26. Diffuse large B-celllymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements • Renames the entity to encompass tumours defined by dual MYC and BCL2 rearrangements composed of large/intermediate/ blastoid cells • Homogeneous entity with an exclusive GC GEP, close pathogenetic relationship to FL and molecular GC-like DLBCL subsets and overlap with BL • Lymphoid neoplasms with dual MYC and BCL6 rearrangements represent a more diverse spectrum- hence excluded and now classified either as a subtype of DLBCL, NOS or HGBL, NOS according to their cytomorphological features
- 28. High-grade B-cell lymphomawith 11q aberration (HGBL11q) • Formerly known as Burkitt-like lymphoma with 11q aberration • Aggressive MYC rearrangement-negative mature B-cell lymphoma with a morphology similar to Burkitt lymphoma (BL) • GEP similar to BL • Intermediate/blastoid appearing cells- CD10+, BCL6+, BCL2- • 11q24qter loss are more specific to this entity than the centromeric gains
- 29. Large B-cell lymphomas(LBCL) of immune-privileged sites • Aggressive B-cell lymphomas • Primary tumours in the central nervous system (CNS), vitreoretinal compartment and testes of immunocompetent patient • Arise in immune sanctuaries created by their respective anatomical structures (e.g. blood-brain, blood-retinal and blood-testicular barriers) and immune regulation systems within their respective primary sites • Share immunophenotypic and molecular features
- 30. Distinctive features ofprimary large B-cell lymphomas of immune privileged sites
- 31. Fluid overload-associated largeB-cell lymphoma • “PEL-like lymphoma” or “HHV8-unrelated PEL-like lymphoma” • Distinct from primary effusion lymphoma (PEL) • Adults (elderly) without underlying immunodeficiency • Exclusive involvement of body cavities, most commonly pleural cavity • Underlying condition causing fluid overload such as chronic heart failure, renal failure, protein losing enteropathy or liver failure/cirrhosis • Mature B-cell phenotype • EBV is positive in 13–30% of cases • Prognosis -fairly favorable
- 32. Mediastinal gray zonelymphoma (MGZL) • Overlapping between primary mediastinal B-cell lymphoma (PMBL) and classic Hodgkin lymphoma (CHL), especially nodular sclerosis CHL (NSCHL) • Replaces the term “B-cell-lymphoma, unclassifiable with features intermediate between DLBCL and classic Hodgkin lymphoma
- 33. High grade B-celllymphoma, NOS • Aggressive mature B-cell lymphomas composed of medium-sized or blastoid cells that do not fit into other well-defined entities • Most frequent mutations are found in KMT2D (43%) and TP53 (30%) • 54% of HGBL, NOS harbour “double hit” signature (DHITsig) of LBCL/HGBL with MYC/BCL2 despite lacking rearrangements of these genes
- 34. Summary of therelationship between large B-cell lymphoma (LBCL) entities
- 35. 9. KSHV/HHV8-associated B-cell lymphoidproliferations and lymphomas • PEL/EC-PEL and KSHV/HHV8-DLBCL - HIV patients, immunodeficiency settings • KSHV/HHV8-GLPD- elderly patients without overt immunodeficiency • KSHV/HHV8-MCD seen in both HIV –ve and +ve patients
- 36. 10. Burkitt lymphoma:EBV matters • Remains unchanged • 3 subtypes: endemic, non-endemic or sporadic and immunodeficiency- associated • EBV-positive BL and EBV-negative BL form discrete biologic groups based on their molecular features and supersede the epidemiological subtyping • Dual mechanism of BL pathogenesis: virus-driven versus mutational • EBV-positive BL: ▫ Higher levels of somatic hypermutation ▫ Fewer driver mutations ▫ Lower frequency of mutations in genes encoding transcription factor TCF3 or its repressor ID3
- 37. 11. Lymphoid proliferationsand lymphomas associated with immune deficiency and dysregulation • New standardized nomenclature builds on an integrated approach to diagnosis that combines all relevant data into a reporting system as follows: 1) Histological diagnosis according to accepted criteria and terminology 2) Presence or absence of one or more oncogenic virus(es) 3) Clinical setting/immunodeficiency background
- 38. • Poly-chemotherapy fortreatment of solid tumours and haematologic neoplasms has been largely accepted as an underlying cause for immunodeficiency • Primary immunodeficiencies associated with germline mutations renamed as “inborn errors of immunity” (IEI)
- 39. 12. Hodgkin lymphoma •CHL clearly defined from its mimickers, NLPHL on the way to, but not yet NLPBCL
- 40. 13. Plasma cellneoplasms
- 41. Plasma cell neoplasmsand other diseases with paraproteins: new conditions from AESOP to TEMPI TEMPI • Telangiectasias • Elevated erythropoietin and erythrocytosis • Monoclonal gammopathy • Perinephric fluid collection • Intrapulmonary shunting AESOP syndrome • Adenopathy • Extensive skin patch overlying a plasmacytoma MGRS: plasma cell or B-cell proliferation that does not meet accepted criteria for malignancy but secretes a monoclonal immunoglobulin or immunoglobulin fragment resulting in kidney injury CAD: AIHA mediated by monoclonal cold agglutinins and driven by an underlying clonal B- cell lymphoid proliferation not fulfilling criteria for a B-cell lymphoma
- 42. • Risk stratificationmodel for IgM MGUS and non-IgM MGUS has been updated • Presence of all 3 risk factors consisting of : (1) an abnormal serum free light chain ratio, (2) IgA or IgM type MGUS, and (3) serum M-protein value >1.5 g/dL • High risk with approximately 50–60% risk of progression at 20 years whereas risk is only 5% when none of the risk factors are present • Diagnosis of TEMPI syndrome is primarily made on clinical and imaging investigations. Bone marrow is unremarkable in majority cases; few cases show erythroid hyperplasia and low-volume of light chain restricted plasma cells • Skin biopsies of patients with AESOP syndrome show diffuse hyperplasia of dermal vessels associated with surrounding dermal mucin and lymph nodes can show features mimicking Castleman disease
- 43. Summary • Tumour-like lesionswith B-cell predominance • B-ALL: B-ALL with ETV6::RUNX1-like features; B-ALL with TCF3::HLF fusion; B-ALL with BCR::ABL1-like features • B-PLL is no longer recognized as an entity • “splenic B-cell lymphoma/ leukaemia with prominent nucleoli” replaces “hairy cell leukaemia variant” and “CD5-negative B-cell prolymphocytic leukaemia” • LPL: IgM-LPL/Waldenström Macroglobulinaemia (WM) type; Non-WM type LPL • Marginal zone lymphomas: cytogenetic and mutational profiles differ by anatomic site, and cutaneous MZL achieves independence • Follicular lymphoma (FL): from classic grading to biological grouping; cFL; FLBL and uFL.
- 44. • Diffuse largeB-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements • High-grade B-cell lymphoma with 11q aberration (HGBL-11q) • Large B-cell lymphomas (LBCL) of immune-privileged sites • Fluid overload-associated large B-cell lymphoma • Mediastinal gray zone lymphoma (MGZL) • Burkitt lymphoma: EBV matters • Hodgkin lymphoma: NLPHL on the way to, but not yet NLPBCL • Plasma cell neoplasms and other diseases with paraproteins: new conditions from AESOP to TEMPI, MGRS, CAD
Editor's Notes
- #5 In circumstances where resources are not available to reach a definitive diagnosis of an entity (or when suboptimal quality or quantity of material is limiting), a diagnostic label based on the family name of that entity can be applied.
- #6 Castleman disease is not a single disease but rather three clinicopathologically distinct entities: - unicentric Castleman disease - idiopathic multicentric Castleman disease - KSHV/HHV8- associated multicentric Castleman disease
- #7 (iAMP21, BCR::ABL1 fusion, KMT2A rearrangements, ETV6::RUNX1 fusion, TCF3::PBX1 fusion or IGH::IL3 fusion) to allow for the application of differing techniques for their detection (previously a provisional entity) shows significant benefit from targeted therapies
- #11 Use of Richter transformation preferred over Richter syndrome
- #13 Biologically distinct from HCL, despite morphological resemblance Also absorbs all cases previously termed CD5 negative B-PLL