WHO lymphoma classification, Blood,mar 2015

1. 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

3. 2008 WHO Lymphoma classification
Follicular 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 lymphoma
Histiocytic 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*

4. What prompted the change ……….
• NGS
• New clinical, pathological and genetic/molecular data concerning the
“small B-cell” lymphomas.
• Cooperative Multicentric trials

5. 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

6. • 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 lymphoma
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 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

7. 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

8. 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

9. 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)

10. 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

11. 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.

12. 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

13. 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

14. 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

15. 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

16. DLBCL NOS
Hans algorithm :CD10,
BCL6 and IRF4/MUM1
Germinal center B-cell type
Activated B-cell type

17. 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

18. 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.

19. 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.

20. 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

21. 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

22. 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

23. ALCL
CD30+Lymphoma
Alk+ALCL>Alk-ve ALCL>CD30+VE PTCL
JAK-STAT Mutation

24. 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

25. Indolent T-cell lymphoproliferative disorder (LPD)
of the GI tract and
Primary cutaneous acral CD8+ T-cell lymphoma
• CD8positive T cells
• indolent clinical course
• Localized to a single site:Ear
• Managed conservatively

26. 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

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