From www.bloodjournal.org by guest on March 17, 2016. For personal use only.

Prepublished online March 15, 2016; doi:10.1182/blood-2016-01-643569

The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms Steven H. Swerdlow, Elias Campo, Stefano A. Pileri, Nancy Lee Harris, Harald Stein, Reiner Siebert, Ranjana Advani, Michele Ghielmini, Gilles A. Salles, Andrew D. Zelenetz and Elaine S. Jaffe

Dr CK Das, MD

2008 WHO Lymphoma classificationFollicular lymphoma

        Pediatric follicular lymphoma*

    Primary cutaneous follicle centre lymphoma

    Mantle cell lymphoma

    Diffuse large B-cell lymphoma (DLBCL), NOS

        T-cell/histiocyte rich large B-cell lymphoma

        Primary DLBCL of the CNS

        Primary cutaneous DLBCL, leg type

        EBV-positive DLBCL of the elderly*

    DLBCL associated with chronic inflammation

    Lymphomatoid granulomatosis

    Primary mediastinal (thymic) large B-cell lymphoma

    Intravascular large B-cell lymphoma

    ALK-positive large B-cell lymphoma

    Plasmablastic lymphoma

    Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease

    Primary effusion lymphoma

    Burkitt lymphoma

    B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

    B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma

• Mature B-cell neoplasms •    

Mature T-cell and NK-cell neoplasms    T-cell prolymphocytic leukemia    T-cell large granular lymphocytic leukemia    Chronic lymphoproliferative disorder of NK cells*

    Aggressive NK-cell leukemia    Systemic EBV-positive T-cell lymphoproliferative disease of childhood    Hydroa vacciniforme-like lymphoma    Adult T-cell leukemia/lymphoma    Extranodal NK/T-cell lymphoma, nasal type    Enteropathy-associated T-cell lymphoma    Hepatosplenic T-cell lymphoma    Subcutaneous panniculitis-like T-cell lymphoma    Mycosis fungoides    Sézary syndrome    Primary cutaneous CD30+ T-cell lymphoproliferative disorders        Lymphomatoid papulosis        Primary cutaneous anaplastic large cell lymphoma    Primary cutaneous γδ T-cell lymphoma    Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma*

    Primary cutaneous CD4+ small/medium T-cell lymphoma*

    Peripheral T-cell lymphoma, NOS    Angioimmunoblastic T-cell lymphoma    Anaplastic large cell lymphoma, ALK-positive    Anaplastic large cell lymphoma, ALK-negative*

Hodgkin lymphoma    Nodular lymphocyte predominant Hodgkin lymphoma    Classical Hodgkin lymphoma    Nodular sclerosis classical Hodgkin lymphoma    Lymphocyte-rich classical Hodgkin lymphoma    Mixed cellularity classical Hodgkin lymphoma    Lymphocyte-depleted classical Hodgkin lymphomaHistiocytic and dendritic cell neoplasms    Histiocytic sarcoma    Langerhans cell histiocytosis

Mature B-cell neoplasms    Chronic lymphocytic leukemia/small lymphocytic lymphoma    B-cell prolymphocytic leukemia    Splenic marginal zone lymphoma    Hairy cell leukemia    Splenic lymphoma/leukemia, unclassifiable*

        Splenic diffuse red pulp small B-cell lymphoma*

        Hairy cell leukemia variant*

    Lymphoplasmacytic lymphoma        Waldenström macroglobulinemia    Heavy chain diseases        α Heavy chain disease        γ Heavy chain disease        μ Heavy chain disease    Plasma cell myeloma    Solitary plasmacytoma of bone    Extraosseous plasmacytoma    Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)    Nodal marginal zone lymphoma        Pediatric nodal marginal zone lymphoma*

What prompted the change ……….• NGS• New clinical, pathological and genetic/molecular data concerning the

“small B-cell” lymphomas.• Cooperative Multicentric trials

2016 WHO classification of Lymphoma• MATURE B-CELL NEOPLASMS • Chronic lymphocytic leukemia /small lymphocytic lymphoma • Monoclonal B-cell lymphocytosis* • B-cell prolymphocytic leukemia • Splenic marginal zone lymphoma • Hairy cell leukemia • Splenic B-cell lymphoma/leukemia, unclassifiable • Splenic diffuse red pulp small B-cell lymphoma • Hairy cell leukemia-variant • Lymphoplasmacytic lymphoma • Waldenström macroglobulinemia • Monoclonal gammopathy of undetermined significance (MGUS),

IgM* • Mu heavy chain disease • Gamma heavy chain disease • Alpha heavy chain disease • Monoclonal gammopathy of undetermined significance (MGUS),

IgG/A* • Plasma cell myeloma • Solitary plasmacytoma of bone • Extraosseous plasmacytoma • Monoclonal immunoglobulin deposition diseases* • Extranodal marginal zone lymphoma of mucosa-associated

lymphoid tissue (MALT lymphoma)• Nodal marginal zone lymphoma • Pediatric nodal marginal zone lymphoma • Follicular lymphoma • In situ follicular neoplasia* • Duodenal-type follicular lymphoma*

• Pediatric-type follicular lymphoma* • Large B-cell lymphoma with IRF4 rearrangement* • Primary cutaneous follicle center lymphoma • Mantle cell lymphoma • In situ mantle cell neoplasia* • Diffuse large B-cell lymphoma (DLBCL), NOS • Germinal center B-cell type* • Activated B-cell type* • T cell/histiocyte-rich large B-cell lymphoma • Primary DLBCL of the CNS • Primary cutaneous DLBCL, leg type • EBV positive DLBCL, NOS* • EBV+ Mucocutaneous ulcer* • DLBCL associated with chronic inflammation • Lymphomatoid granulomatosis • Primary mediastinal (thymic) large B-cell lymphoma • Intravascular large B-cell lymphoma • ALK positive large B-cell lymphoma • Plasmablastic lymphoma • Primary effusion lymphoma • HHV8 positive DLBCL, NOS* • Burkitt lymphoma • Burkitt-like lymphoma with 11q aberration* • High grade B-cell lymphoma, with MYC and BCL2 and/or BCL6

rearrangements* • High grade B-cell lymphoma, NOS* • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL

and classical Hodgkin lymphoma

• MATURE T-AND NK-NEOPLASMS • T-cell prolymphocytic leukemia • T-cell large granular lymphocytic leukemia • Chronic lymphoproliferative disorder of NK cells • Aggressive NK cell leukemia • Systemic EBV+ T-cell Lymphoma of childhood* • Hydroa vacciniforme-like lymphoproliferative disorder* • Adult T-cell leukemia/lymphoma • Extranodal NK/T-cell lymphoma, nasal type • Enteropathy-associated T-cell lymphoma • Monomorphic epitheliotropic intestinal T-cell

lymphoma* • Indolent T-cell lymphoproliferative disorder of the GI

tract * • Hepatosplenic T-cell lymphoma • Subcutaneous panniculitis- like T-cell lymphoma • Mycosis fungoides • Sézary syndrome • Primary cutaneous CD30 positive T-cell

lymphoproliferative disorders • Lymphomatoid papulosis • Primary cutaneous anaplastic large cell lymphoma • Primary cutaneous gamma-delta T-cell lymphoma • Primary cutaneous CD8 positive aggressive

epidermotropic cytotoxic T-cell lymphoma • Primary cutaneous acral CD8+ T-cell lymphoma*

Primary cutaneous CD4 positive small/medium T-cell lymphoproliferative disorder* Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Follicular T-cell lymphoma* Nodal peripheral T-cell lymphoma with TFH phenotype* Anaplastic large cell lymphoma, ALK positive Anaplastic large cell lymphoma, ALK negative * Breast implant-associated anaplastic large cell lymphomaHODGKIN LYMPHOMA Nodular lymphocyte predominant Hodgkin lymphoma Classical Hodgkin lymphoma

Nodular sclerosis classical Hodgkin lymphoma Lymphocyte-rich classical Hodgkin lymphoma Mixed cellularity classical Hodgkin lymphoma Lymphocyte-depleted classical Hodgkin lymphoma POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS (PTLD) Plasmacytic hyperplasia PTLD Infectious mononucleosis PTLD Florid follicular hyperplasia PTLD* Polymorphic PTLD Monomorphic PTLD (B- and T/NK-cell types) Classical Hodgkin lymphoma PTLD HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS Histiocytic sarcoma Langerhans cell histiocytosis Langerhans cell sarcoma Indeterminate dendritic cell tumour Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma Fibroblastic reticular cell tumour Disseminated juvenile xanthogranuloma Erdheim/Chester disease

In situ Follicular Neoplasm(ISFN)• Preserved tissue architecture and confined to the germinal centers,

without evidence of disseminated disease• low rate of progression, but are more often associated with prior or

synchronous overt lymphomas• D/D:partial involvement by FL• ISFN does have fewer chromosomal copy number abnormalities than

focal and especially overt FL• higher levels of circulating t(14;18)-positive lymphocytes (>10-4 of

total cells) indicate a higher risk for FL

Pediatric FL • large expansile highly proliferative follicles with prominent blastoid

follicular center cells • BCL2 rearrangements must not be present, but there may be some

BCL2 protein expression. • lack BCL6 and MYC rearrangements• D/D FL G3

Large B-cell lymphoma with IRF4 rearrangement• Around Waldeyer ring and/or cervical lymph nodes and low stage. • follicular, follicular and diffuse or pure diffuse growth pattern

resembling FL grade 3B or a DLBCL. • Strong IRF4/MUM1 expression with BCL6 and a high proliferative

fraction. • Germinal center type:on gene expression profiling • More aggressive than other pediatric-type FL but patients,• Good response to chemotherapy

Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults-German High-Grade Lymphoma Study Group, and the Berlin-Frankfurt-Münster-NHL trial grou July 7, 2011; Blood: 118 (1)

Duodenal-type FL• localized overt low grade FL, is distinct from other GI tract FL• Overlap with ISFN and extranodal marginal zone lymphoma • excellent outcome• watch and wait strategy

Monoclonal B-cell lymphocytosis (MBL) • The 2008 :monoclonal B-cell populations in the peripheral blood (PB) of

up to 5x109/l either with the phenotype of CLL, atypical CLL or non-CLL (CD5-) B-cells in the absence of other lymphomatous features.

• 12% of healthy individuals• MBL precedes virtually all cases of CLL• “low count” MBL , defined as a PB CLL count of <0.5 x109/l• “high count” MBL 0.5-5 x109 because low count MBL • NO CLL with <5x109/l PB CLL cells in the absence of extramedullary

disease even if there are cytopenias or disease-related symptoms

Landgren O, Albitar M, Ma W, et al. B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 2009;360(7):659-667.

CLL/SLL-LN variant of MBL• lymph node involvement by “SLL” • No significant rate of progression• proliferation centers were not observed • Adenopathy was <1.5cm based on CT scans

• Non-CLL type MBL: Early stage of splenic marginal zone lymphoma

Leukemic non-nodal mantle cell lymphoma and in situ mantle cell neoplasia (ISMCN)

• IGHV mutated /SOX11 negative /CYCD11+B-cells,Ki67<30%

• peripheral blood, bone marrow and often spleen.

• clinically indolent• Observation • ISMCN: cyclin D1+ cells in the

inner mantle zones of follicles, preserved architecture

IgM MGUS IgG/IgA MGUS• Related to LPL/B NHL• MYD88+ve• CCXR4 mutation+

• Related to myeloma• MYD 88-ve• CCXR4mutation-ve

Advances in the Diagnosis, Classification, Risk Stratification, and Management of Monoclonal Gammopathy of Undetermined Significance: Implications for Recategorizing Disease Entities in the Presence of Evolving Scientific Evidence S. Vincent Rajkumar, MD, Robert A. Kyle, Mayo Clin Proc. 2010 Oct; 85(10): 945–948

Monoclonal immunoglobulin deposition diseases(MIDD)• Renal involvement is almost always present• Renal insufficiency and proteinuria,nephrotic syndrome.• light chain deposition disease (LCDD)

light and heavy chain deposition disease (LHCDD)

heavy chain deposition disease (HCDD)

MC 92% k Y

light chain deposition disease (LCDD) light and heavy chain deposition disease (LHCDD)

heavy chain deposition disease (HCDD)

MC 92% k k/y y

DLBCL NOS

Hans algorithm :CD10, BCL6 and IRF4/MUM1

Germinal center B-cell type Activated B-cell type

High grade B-cell lymphoma [HGBL], with rearrangements of MYC and BCL2 and/or BCL6 • 5-15% of DLBCL, NOS• “starry sky” appearance with a high MiB-1 (which is consistent with

BL), but with larger cells with irregular nuclei and more prominent nucleoli (which is consistent with DLBCL).

• Aggressive clinical course:extranodal sites:bone marrow and CNS• The median survival time is reported to be about 5 months

BCL-2, BCL-6, c-MYC gene rearrangements as a break-apart FISH

Double Expressed Lymphoma• MYC protein expression (30-50%) and BCL2 in 20-35%• cut-off of 40% MYC , >50% for BCL2.• Most of these tumors do not carry MYC/BCL2 chromosomal alteration

• worse outcome than DLBCL, NOS but they are not as aggressive as Double hit/Tripple hit

A prognostic indicator in DLBCL, NOS but not a separate category.

High grade B cell Lymphoma NOS• intermediate between DLBCL and

BL • lack a MYC and BCL2 and/or BCL6

rearrangement

•

Indication of MYC, BCL2 and BCL6 rearrangements study

GCB phenotype and/or high grade morphology

cases with >40% MYC+ cells.

Epstein-Barr virus positive (EBV+) DLBCL NOS• >50 years old • worse prognosis than EBV-negative tumors• in younger patients, with a broader morphological spectrum and better

survival.

EBV+ mucocutaneous ulcer• self-limited growth potential and • response to conservative management• advanced age or with iatrogenic immunosuppression

Burkitt-like lymphoma with 11q aberration• phenotypically and by GEP like BL but which lack MYC

rearrangements. • chromosome 11q alteration characterized by proximal gains and

telomeric losses.• More complex karyotypes, lower levels of MYC expression, a certain

degree of cytological pleomorphism• frequently nodal presentation.• The clinical course similar to BL

Follicular T-cell related Lymphoma• Angioimmunoblastic T-cell lymphoma • Follicular T-cell lymphoma • Nodal peripheral T-cell lymphoma with TFH phenotype

• express at least two or three TFH-related antigens, including CD279/PD1, CD10, BCL6, CXCL13, ICOS, SAP, and CCR5

• contain EBV+B-cell blasts, simulate Hodgkin-Reed Sternberg (HRS) cells

• Progression to EBV positive B-cell neoplasms may occur

ALCL

CD30+LymphomaAlk+ALCL>Alk-ve ALCL>CD30+VE PTCL

JAK-STAT Mutation

Breast implant associated ALCL• Both saline and silicone filled

implants • Median interval from implant to the

lymphoma 10 yr• Trt: removal of the implant and

capsule. • If invasion through the

capsule:systemic chemotherapy

Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract andPrimary cutaneous acral CD8+ T-cell lymphoma

• CD8positive T cells• indolent clinical course• Localized to a single site:Ear • Managed conservatively

EBV-positive T-cell lymphomas

chronic active EBV-infection (CAEBV)• Asians, and in indigenous

populations from Central and South America and Mexico.

• indolent, localized forms like hydroa vacciniforme-like lymphoproliferative disorder

Systemic EBV+ T-cell lymphoma of childhood • fever, hepatosplenomegaly and

lymphadenopathy with or without cutaneous manifestations

• usually associated with a hemophagocytic syndrome

Enteropathy-associated T-cell lymphoma (EATL)Type I• closely linked to celiac disease • northern European origin• TCR αβ.

Type IIMonomorphic epitheliotropic intestinal T-cell lymphoma (MEITL

• no association with celiac disease• Asians, and Hispanic • monomorphic, and usually

positive for CD8, CD56, and MAPK• Gains in chromosome 8q24

involving MYC From γδ T-cells,