9/18/2017. Overview reasons an update was necessary. Myeloproliferative neoplasms
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1 2016 WHO updates to the classification of hematologic neoplasms Darshan Roy, MD Assistant Professor Department of Pathology Director of Hematopathology Rowan School of Osteopathic Medicine Outline Myeloid neoplasms and acute leukemias Myeloproliferative neoplasms (MPN) Myelodysplastic syndromes (MDS) MDS/MPN Acute myeloid leukemia (AML) Acute lymphoblastic leukemia (ALL) Lymphoid Mature B cell lymphomas Mature T and NK cell lymphomas Hodgkin Lymphomas 1
2 Overview reasons an update was necessary 1. Discovery of molecular features affecting diagnosis and prognosis 2. Improved characterization and standardization of morphological features aiding in the differentiation of disease groups 3. Evidence validating a clinicopathologic approach for classification Myeloproliferative neoplasms Chronic myeloid leukemia (CML) Polycythemia vera (PV) Essential thrombocythemia (ET) Primary myelofibroisis (PMF) Chronic neutrophilic leukemia (CML) Mastocytosis has been removed from this category 2
3 Chronic myeloid leukemia (CML) Single relevant change in diagnosis of Accelerated Phase (AP) persistent or increasing WBC (>10x10 9 /L) and/or persistent or increasing splenomegaly unresponsive to therapy Persistent thrombocytosis (>1000x10 9 /L) uncontrolled by therapy Persistent thrombocytopenia (<100x10 9 /L) unrelated to therapy clonal cytogenetic evolution occurring after the initial diagnostic karyotype 20% or more basophils in the peripheral blood 10 19% myeloblasts in the blood or BM Provisional additions: Evidence of Tyrosine kinase inhibitor (TKI) resistance Hematologic resistance to first TKI Evidence of resistance to 2 sequential TKI 2 or more mutations in BCR ABL during TKI therapy Presence of fibrosis may indicate AP Presence of definitive lymphoblasts of any count should warrant concern for BP MPN Polycythemia vera (PV) PV (all 2 major criteria or first two 2 major + 1 minor) Major criteria: HGB (16.5 m, 16.0 f) or HCT (49% m, 48% f) Bone marrow biopsy findings JAK2 mutation Minor criteria Decreased serum EPO Criteria 2 not needed if sufficiently elevated HGB (>18.0 m, 16.5 f) however, the importance of bone marrow biopsy evaluate fibrosis DR2 DR3 DR4 Barbui, Tiziano T. American Journal of Hematology: Masked Polycythemia Vera (mpv): Results of an International Study. 89 Vol. John Wiley & Sons Inc, 01/2014. Web. 10 Sep
4 Slide 9 DR2 DR3 DR4 Darshan Roy, 9/15/2017 Darshan Roy, 9/15/2017 Darshan Roy, 9/15/2017
5 MPN Essential thrombocythemia (ET) and Primary myelofibroisis (PMF) Essentially unchanged. Discovery of recurrent CALR (calreticulin) mutation as diagnostic criteria of clonality in both ET and PMF (in addition to JAK2 and MPL) 20 25% of ET and PMF PMF if major clonal marker not identified, search for additional mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) Nangalia, Jyoti J. Hematology: The Evolving Genomic Landscape of Myeloproliferative Neoplasms Vol. American Society of Hematology, 12/2014. Web. 10 Sep MPNs the rest Chronic neutrophilic leukemia now has identifiable recurrent mutation, CSF3R mutations can be seen in 50 80% of patients Mastocytosis no longer considered MPN. Myelodysplastic syndromes Terminology Refractory anemia/cytopenias removed, now: Myelodysplastic syndrome with MDS with single lineage dysplasia MDS with ring sideroblasts (MDS RS) MDS RS and single lineage dysplasia MDS RS and multilineage dysplasia MDS with multilineage dysplasia MDS with excess blasts MDS with isolated del(5q) MDS, unclassifiable Provisional entity: Refractory cytoplenia of childhood 4
6 Myeloid myelodysplastic syndromes Myeloid neoplasms with erythroid predominance (>50% erythroid cells) Now blast % of all nucleated cells (Previously counted blast % out of nonerythroid cells) Many cases of acute erythroid leukemia would now be classified as MDS EB MDS defining genetic abnormalities must be identified by conventional karyotype (not by FISH alone) MDS with del(5q) may include 1 additional cytogenetic abnormality As long as it isn t monosomy 7 or del(7q) Clonal hematopoiesis of indeterminate potential (CHIP) Somatic gene mutations can occur in low levels in normal patient populations not solely sufficient for a diagnosis of MDS, however testing should be done in all new diagnosis to determine prognosis Heuser, Michael, Felicitas Thol, and Arnold Ganser. Clonal Hematopoiesis of Indeterminate Potential: A Risk Factor for Hematologic Neoplasms. Deutsches Ärzteblatt International (2016): PMC. Web. 12 Sept MDS Ringed sideroblasts SF3B1 gene identified and associated with ringed sideroblasts If found, sideroblasts only need to account for 5% of nucleated erythrocytes (otherwise previous standard of 15%) MDS with ringed sideroblasts may now include multilineage dysplasia 5
7 New group MDS with germline mutations Arber, Daniel A. DA. Blood: The 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemia. 127 Vol. American Society of Hematology, 05/2016. Web. 12 Sep MDS/MPN Chronic myelomonocytic leukemia (CMML) Atypical chronic myeloid leukemia (acml), BCR ABL1 Juvenile myelomonocytic leukemia (JMML) MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN RS T) MDS/MPN, unclassifiable MDS/MPN Chronic myelomonocytic leukemia (CMML) Differentiate proliferative (WBC >13) vs dysplastic type Now 3 categories based on blast percentage CMML 0 (<2% peripheral blood, <5% bone marrow) CMML 1 (2 4% peripheral blood, 5 9% bone marrow) CMML 2 (5 19% peripheral blood, 10 19% bone marrow) Juvenile myelomonocytic leukemia (JMML) >90% contain somatic or germline mutation in PTPN11,KRAS, NRAS, CBL, or NF1. Refractory anemia with ring sideroblasts and thrombocytosis (RARS T) is now MDS/MPN with ringed sideroblasts and thrombocytosis (MDS/MPN RS T) 6
8 Schuler, E. E. Leukemia Research: Refined Medullary Blast and White Blood Cell Count Based Classification of Chronic Myelomonocytic Leukemias. 38 Vol. Elsevier, 12/2014. Web. 10 Sep Acute myeloid leukemia AML with recurrent genetic abnormalities AML with myelodysplasia related changes Therapy related myeloid neoplasms AML, NOS Myeloid sarcoma Myeloid proliferations related to Down syndrome AML New provisional categories (both with worse prognosis) AML with BCR ABL1 AML with mutated RUNX1 CEBPA requires biallelic mutations Acute erythroid leukemia (erythroid/myeloid type) removed 7
9 Nacheva, Ellie P. EP. British Journal of Haematology: Does BCR/ABL1 Positive Acute Myeloid Leukaemia Exist?. 161 Vol. Blackwell Publishing, 05/2013. Web. 10 Sep B lymphoblastic leukemia/lymphoma (B ALL) Two new provisional categories: B ALL with intrachromosomal amplification of chromosome 21 Occurs in 2% of pediatric ALL (usually older with lower WBC counts) >5 copies of RUNX1 (or >3 copies on a single chromosome) Poorer prognosis (partially overcome by aggressive therapy) B ALL, BCR ABL1 like Involve other tyrosine kinases (over 30 different genes) Cytokine receptor like factor 2 (CRLF2) Often associated with JAK2 Children with Down syndrome Moorman, Anthony V. AV. Haematologica (Roma): New and Emerging Prognostic and Predictive Genetic Biomarkers in B-Cell Precursor Acute Lymphoblastic Leukemia. 101 Vol. Il Pensiero Scientifico, 04/2016. Web. 10 Sep
10 T cell lymphoblastic leukemia/lymphoma (T ALL) New provisional entity Early T precursor (ETP) ALL Retention of some myeloid and stem cell characteristics CD1a CD8 CD7+ Positive for one or more of the following: CD34, CD117, HLA DR, CD13, CD33, CD11b, or CD65 Often have myeloid associated gene mutations (FLT3, NRAS/KRAS, etc) and lack T ALL mutations (NOTCH1, etc). Very poor prognosis You, M. James MJ. American Journal of Clinical Pathology: T-Lymphoblastic leukemia/lymphoma. 144 Vol. American Society for Clinical Pathology, 09/2015. Web. 11 Sep Kaplan-Meier plots of overall survival (A, D), event-free survival (B, E), and the cumulative incidence of remission failure or haematological relapse (C, F) in patients with typical T- lymphoblastic leukaemia (T- ALL; red) versus early T-cell precursor (ETP)-ALL (blue) treated on either St Jude (A C) or AIEOP protocols (D F) Coustan-Smith, Elaine E. The Lancet Oncology: Early T-Cell Precursor Leukaemia: A Subtype of very High-Risk Acute Lymphoblastic Leukaemia. 10 Vol. Lancet Pub. Group, 02/2009. Web. 10 Sep
11 Lymphoid neoplasms Mature B cell neoplasms Mature T and NK neoplasms Hodgkin lymphoma Posttransplant lymphoproliferative disorders (PTLD) Histiocytic and dendritic cell neoplasms Mature B cell neoplasms Monoclonal B cell lymphocytosis Should be defined as low count (PB CLL count of <0.5 x 10 9 /L) vs high count Low count rarely progresses to CLL Non CLL phenotype now recognized Chronic lymphocytic leukemia (CLL) Now requires 5 x 10 9 PB CLL cells regardless of extramedullary disease Mature B cell neoplasms Follicular lymphoma (FL) Follicular lymphoma In situ follicular lymphoma renamed in situ follicular neoplasia (ISFN) Pediatric FL renamed pediatric type FL No BCL2 (or BCL6 or MYC) rearrangements Nodal disease with blastoid follicular centers Localized (resection only) Caution to avoid underdiagnosing Conventional grade 3 FL. Excluded by focal diffuse areas (DLBCL) 10
12 Follicular Lymphoma continued New provisional entity Large B cell lymphoma with IRF4 rearrangement Young adults and children Waldeyer ring/cervical lymph nodes Low stage Resemble FL grade 3B or DLBCL MUM1 strongly expressed (usually with BCL6 and often with BCL2 and CD10) High proliferative index Lack BCL2 rearrangement Must be distinguished from MUM1+ CD10 FL (older patients and associated with DLBCL) Figure 1. New provisional B-cell lymphoma entities. (A-D) LBCL with IRF4 rearrangement. (A) Note the very large abnormal-appearing follicles in the central portion of this tonsil. (B) The neoplastic follicles have numerous transformed cells that are (C) IRF4/MUM-11 and (D) BCL61. Swerdlow, Steven H. SH. Blood: The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms. 127 Vol. American Society of Hematology, 05/2016. Web. 12 Sep Mature B cell neoplasms FL continued Follicular lymphoma continued Duodenal type FL Distinct from other GI FL Resembles ISFN May resemble MZL of MALT Excellent outcome (some watch and wait) Diffuse appearing FL Inguinal masses Lack BCL2 rearrangements 1p36 deletion (not specific) 11
13 Mantle cell lymphoma (MCL) In situ MCL now in situ mantle cell neoplasia (ISMCN) Two indolent variants Unmutated IGHV SOX11+ MCL Nodal and may progress to classic MCL Mutated IGHV SOX11 MCL Frequently indolent leukemic variant Half of CCND1 MCL have CCND2 translocations Usually IGK or IGL partner Swerdlow, Steven H. SH. Blood: The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms. 127 Vol. American Society of Hematology, 05/2016. Web. 12 Sep Diffuse large B cell lymphoma (DLBCL) Separation of germinal center (GC) and non GC subgroups of DLBCL recommended MYC and BCL2(/BCL6) expressor IHC Expression vs rearrangement ( double/triple hit lymphoma now new category High Grade B cell lymphoma) >40% MYC, >50% BCL2 IHC positivity in tumor cells Prognosis worse than NOS, better than double/triple hit 12
14 High Grade B cell lymphoma (HGBL) HGBL, NOS Includes previously described entity B cell lymphoma, unclassifiable with features intermediate between DLBCL and BL HGBL with MYC and BCL2 (or BCL6) rearrangements double/triple hit lymphomas Swerdlow, Steven H. SH. Blood: The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms. 127 Vol. American Society of Hematology, 05/2016. Web. 12 Sep Swerdlow, Steven H. SH. Blood: The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms. 127 Vol. American Society of Hematology, 05/2016. Web. 12 Sep
15 EBV+ DLBCL and EBV+ mucocutaneous ulcer EBV+ DLBCL, NOS Previously included of the elderly Worse prognosis than DLBCL, NOS EBV+ mucocutaneous ulcer, provisional entity Self limited disease, conservative management Large Hodgkin like cells Patients with history of advanced age or iatrogenic immunosuppression (A) Panoramic view of the rectal ulcer (hematoxilin eosin, X40); (B) Polymorphous infiltrate of plasma cells, small lymphocytes, eosinophils and scattered Reed Sternberglike cells (hematoxilin eosin, X400); (C) Reed Sternberg like cells are CD30 positive (CD30, X400) and Epstein Barr virus (EBER, X400). Juan, Alba A. Digestive and Liver Disease: Epstein-Barr Virus-Positive Mucocutaneous Ulcer in Crohn's Disease. A Condition to Consider in Immunosuppressed IBD Patients. 49 Vol. Elsevier, 08/2017. Web. 12 Sep Burkitt lymphoma Provisional entity Burkitt like lymphoma with 11q aberration Similar to BL morphology and by gene expression profiling Lack MYC rearrangement 14
16 (E-H) Burkitt-like lymphoma with 11q aberration. (E) The touch imprint demonstrates a monotonous population of transformed cells with basophilic cytoplasm that are (F) CD201, (G) have a very high MIB1/Ki-67 proliferation fraction, and are (H) BCL61. Swerdlow, Steven H. SH. Blood: The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms. 127 Vol. American Society of Hematology, 05/2016. Web. 12 Sep Impact of molecular pathology on mature B cell lymphomas Hairy Cell leukemia Near 100% assocations with BRAF V600E (not seen in HCL v) Lymphoplasmcytic lymphoma 90% have MYD88 L265P mutation Not specific, seen in (IgM MGUS, DLBCL) Not seen in myeloma Mature T cell and NK cell neoplasms Follicular T cell lymphoma PTCL with follicular T helper cell (TFH) phenotype (CD10+, PD1+, BCL6+) in a follicular pattern May contain large EBV+ B cells Lack of high endothelial venules and expanded dendritic meshworks (of AITL) Nodal PTCL with TFH phenotype Diffuse pattern but with follicular T helper cell phenotype 15
17 ALK Anaplastic large cell lymphoma No longer provisional entity Require strong and diffuse CD30 positivity Cohesive growth pattern with hallmark type cells DUSP22 rearrangements have better prognosis (similar to ALK+) TP63 rearrangements do much worse Breast implant associated ALK ALCL Provisional entity 10 years after implant, associated with capsule seroma Conservative management including excision Representative cases of genetic subtypes of ALCL. (A) ALK-negative ALCL with DUSP22 rearrangement. The tumor cells are positive for CD30 and are negative for ALK, TIA-1, and p63. (B) ALK-negative ALCL with TP63 rearrangement. The tumor cells are positive for CD30, TIA-1, and p63 and are negative for ALK. Parrilla Castellar, Edgardo R. ER. Blood: ALK-Negative Anaplastic Large Cell Lymphoma is a Genetically Heterogeneous Disease with Widely Disparate Clinical Outcomes. 124 Vol. American Society of Hematology, 08/2014 Web 13 Sep 2017 Lechner, Melissa G. MG. Cancer: Breast Implant- Associated, ALK-Negative, T-Cell, Anaplastic, Large-Cell Lymphoma: Establishment and Characterization of a Model Cell Line (TLBR-1) for this Newly Emerging Clinical Entity. 117 Vol. John Wiley & Sons Inc, 04/2011. Web. 12 Sep
18 Enteropathy associated T cell lymphoma (EATL) EATL only includes type 1 Type 2 now defined as monomorphic epitheliotropic intestinal TCL (MEITL) shows no association with celiac disease increased in incidence in Asians and Hispanic populations Low magnification (a, x20, H&E) and high magnification (b, x 400, H&E) images of enteropathy-associated T- cell lymphoma with villous blunting and a transmural infiltrate composed of atypical, intermediate-sized lymphocytes and a mixed inflammatory background. c Low magnification (x 2 H&E) of MEITL with a monotonous infiltrate of neoplastic lymphocytes extending through the entire bowel wall and demonstrating epitheliotropism. d High magnification (x 400, H&E) emphasizes the monomorphism of the lymphoma cells. The tumor cells are positive for CD3 (e), CD56 (f), and TIA-1 (g) Ondrejka, Sarah S. Current Hematologic Malignancy Reports: Enteropathy- Associated T-Cell Lymphoma. 11 Vol. Current Science, Inc., 12/2016. Web. 14 Sep Hodgkin Lymphomas Nodular lymphocyte predominant Hodgkin lymphoma (NLP HL) may evolve into T cell histiocyte rich large B cell lymphoma (THRLBCL) THRLBCL like transformation of NLP HL 17
19 Conclusion Numerous recent advancements in genetic data (NGS) along with new treatment options drive the modifications to the WHO classification of hematopoietic neoplasms END 18
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