WHO 2016 update of lymphoid

neoplasms

Medical Director,Hematopathology and Molecular Pathology Program Director,International Hematopathology/Molecular Pathology Fellowship,Florida HospitalProfessor of Pathology,University of Central Florida, College of Medicine

E-mail: c.jeff.chang.md@flhosp.org

Phone: 407-303-1879

• Updated diagnostic categories and criteria to

current entities (some with new names) and a

limited number of new provisional entities

• Expanding the genetic/molecular landscape

and the biologic and clinical correlates

• Development of targeted therapeutic

strategies

Monoclonal B-cell lymphocytosis

(MBL)

• Up to 12% healthy individuals (DO NOT

ORDER FLOW CYTOMETRY FOR FUN)

• Must distinguish low count (< 0.5 x109/l),

extremely limited chance of progression, no

follow-up needed, from high count (> 0.5

x109/l) MBL, need yearly follow-up (annual

progression rate: 1 to 2%).

• Non-CLL type MBL: related to splenic MZL

• A lymph node equivalent of MBL exists:

preserved nodal architecture, with cells of

MBL phenotype, <1.5 cm, no proliferation

center (be careful with FNA specimen)

CLL/SLL

• Cytopenias or disease-related symptoms are now

insufficient to make a diagnosis of CLL with < 5

x109/l PB CLL cells.

• Large/confluent (broader than a 20x field) and/or

highly proliferative proliferation centers (PC) (either

>2.4 mitoses or Ki-67 >40%/PC) are adverse

prognostic indicators.

• PC may express weak cyclin D1, increase MYC

protein expression

• Mutations of TP53, NOTCH1, SF3B1, ATM, and

BIRC3: adverse prognostic factors, targeted therapy

(del TP53 for Ibrutinib).

Follicular lymphoma (FL)

• Mutational landscape better understood but

clinical impact remains to be determined

• Mutations in chromatin regulator/modifier

genes [CREBBP, KMT2D (MLL2)] and

EZH2: early event and potential treatment

targets

In situ follicular neoplasia

• New name for in situ follicular lymphoma (FL)

reflecting low risk of progression to lymphoma

• May associated with prior or synchronous overt

lymphoma, requiring clinical assessment

• Strong BCL2 expression, CD10+/BCL6+ cells

predominantly restricted inside follicle (no

spilling out)

• Flow cytometry showing clonal B-cells with FL

phenotype: be careful with FNA specimen

• Must be distinguished from partial involvement

by FL

Pediatric-type FL

• A localized (most stage 1) clonal proliferation with

excellent prognosis; excision alone may be sufficient

• Occurs in children and young adults, rarely in older

individuals

• Blastoid cells more frequent than centroblasts/or

centrocytes

• “Starry sky” follicles, no diffuse areas (foci of DLBCL)

• BCL2 protein -/+, CD10+, BCL6+, MUM1-/+ (+ in

Waldeyer’s ring cases), MIB1 high (> 30%)

• IGH clonal rearrangement

• BCL2, BCL6, MYC rearrangement: absent, IRF4

rearrangement: some Waldeyer’s ring cases (overlapping

with LBL-IRF4)

Am J Surg Pathol. 2013 Mar; 37(3): 333–343.

Large B-cell lymphoma with IRF4

rearrangement

• New provisional entity to distinguish from

pediatric-type FL and other DLBCL

• Children and young adult

• Localized disease, often involves cervical lymph

nodes or Waldeyer ring

• Low stage, treatment usually required

• Follicular (Grade 3B, D/D CD10-, MUM1+ FL in

older patients; pediatric-type FL, may need FISH),

follicular and diffuse, or pure diffuse pattern

• Strong MUM1+, BCL6+, high MIB1, BCL2 +/-

(NO BCL-2 rearrangement), CD10+/-

IRF4/MUM1 BCL6

Duodenal-type FL

• Localized process with low risk for

dissemination, excellent outcome

• Overlap with ISFN

Predominantly diffuse FL with 1p36

deletion

• Grade 1 to 2

• Presents as localized mass, often inguinal

• Lacks BCL2 rearrangement

• CD10+, CD23+, BCL2+/-

• 1p36 deletion not specific, seen in other

lymphomas, including classical FL

• Appearing to have good prognosis (13%

recurred and 6% progressed after

chemo/radiotherapy in 29 cases reported)

Blood.

2009;113:1053-1061

Mantle cell lymphoma (MCL)

• Two MCL subtypes: different clinicopathological

manifestations and molecular pathogenetic pathways

• Classical: Largely with unmutated/minimally

mutated IGHV and mostly SOX11+, nodal and

extranodal site

• largely with mutated IGHV and mostly SOX11-

(indolent leukemic non-nodal MCL with PB, BM,

±splenic involvement, may become more aggressive

with additional mutations, such as p53).

• Mutations of potential clinical importance, such as TP53,

NOTCH 1/2, recognized in small proportion of cases.

• CCND2 rearrangements in approximately half of cyclin

D1 negative MCL.

In situ mantle cell neoplasia• New name for in situ MCL, reflecting low

clinical risk

• Cyclin D1+ cells in the inner mantle zone of

follicles with preserved nodal architecture

• D/D: overt MCL with a mantle zone growth

pattern

Scientific Figure on ResearchGate. Available from:

https://www.researchgate.net/figure/257780134_fig7_Fig-8-Session-

32-Mantle-cell-lymphoma-'-in-situ-'-Case-431-P-Browne-a-At-low

Lymphoplasmacytic lymphoma (LPL)

• MYD88 L265P mutation in vast majority (90%) of

LPL and significant portion of IGM MGUS (more

closed to LPL/B-cell lymphoma than PCM)

• CXCR4: 30% of LPL (higher extent of BM

infiltration and lower leucocyte counts, haemoglobin

and platelet counts, resistant to Ibrutinib)

• Not specific for LPL: small proportion of other small

cell lymphoma (MZL, CLL); 30% non-GC DLBCL;

50% primary cutaneous DLBCL, leg type; but not

PCM, even of IGM type

• Morphology: monotony of lymphoplasmacytic

proliferation (lack of monocytoid cells, large

transformed cells), sometimes follicular colonization

Hairy cell leukemia

• BRAF V600E mutations in vast majority of

cases

• MAP2K1 mutations in most cases that that

use IGHV4-34 and lack BRAF mutation

Diffuse large B-cell lymphoma, NOS

• Distinction of GCB versus ABC/non-GC type

required with use of immunohistochemical

algorithm acceptable, may affect therapy.

• Co-expression of MYC (> 40% cells) and BCL2

(> 50% of cells) considered new prognostic

marker (20 to 35% of DLBCL, double expressor

lymphoma, most do not have MYC/BCL2

rearrangement)

• Double expressor worse outcome than other

DLBCL, NOS but better than the DHLs

• CD30 expression may be tested for new

antibody-based (anti-CD30) treatment

• GCB-DLBCL: mutations in histone methyl

transferase EZH2, cell motility regulator

GNA13, BCL2 translocation

• ABC-DLBCL: BCR/TLR and NFkB pathway

(MYD88, CD79A, CARD11, TNFSIP3)

Diffuse large B-cell lymphoma, NOS

EBV+ DLBCL, NOS

• Replaceing EBV-positive DLBCL of the

elderly (worse prognosis) since it may occur

in younger patients (with better outcome)

• Not including EBV+ B-cell lymphomas that

can be given a more specific diagnosis (e.g.

LYG)

EBV+ mucocutaneous ulcer

• New provisional entity associated with iatrogenic

immunosuppression or age-related

immunosenescence.

• Self-limited growth potential

• Conservative management

• Isolated sharply circumscribed ulcers involving

oropharyngeal mucosa, skin, and gastrointestinal

tract

• Polymorphous infiltrate and atypical large B-cell

blasts often with Hodgkin/Reed-Sternberg (HRS)

cell-like morphology

• B cells showed strong CD30 and EBER positivity

• CD15 -/+, CD20+/-

Modern Pathology (2013) 26, S42–S56

Blood 2011;117(18):4726-4735

Burkitt lymphoma

• TCF3 or ID3 (negative regulator of TCF3)

mutations in up to approximately 70% of

sporadic and immunodeficiienty related cases

and 40% of endemic cases

• TCF3 activating BCR/PI3K pathway

promoting survival and proliferation of

lymphoid cells

Burkitt-like lymphoma with 11q

aberration

• New provisional entity that closely resembles

Burkitt lymphoma but lacks MYC

rearrangement

• Clinical course and gene expression profile

similar to BL

• Interstitial gains including 11q23.2-q23.3 and

telomeric losses of 11q24.1-qter

• More complex karyotypes, lower level of MYC

expression, certain degree of cytological

pleomorphism, sometimes a follicular patten,

frequently nodal presentation

CD20

BCL6MIB1

High grade B-cell lymphoma, with MYC

and BCL2 and/or BCL6 translocations

• New category for all ‘double/triple hit’

lymphomas other than FL or lymphoblastic

lymphomas.

High grade B-cell lymphoma, NOS

• Together with the new category for the

‘double/triple hit’ lymphomas, replacing the

2008 category of B-cell lymphoma,

unclassifiable, with features intermediate

between DLBCL and Burkitt lymphoma

(BCLU)

• Includes blastoid-appearing large B-cell

lymphomas and cases lacking MYC and

BCL2 or BCL6 translocations that would

formerly have been called BCLU

MYC R

Peripheral T-cell lymphoma (PTCL),

NOS• Subsets based on phenotype and molecular

abnormalities being recognized that may have clinical

implications but are mostly not a part of routine

practice at this time.

• GATA3 overexpression subtype: inferior prognosis,

high levels of Th2 cytokines

• Mutations of epigenetic mediators: KMT2D, TET2,

KDM6A, ARID1B, DNMT3A, CREBBP, MLL AND

ARID2.

• Mutations in signaling pathway: TNFAIP3, APC,

CHD8, ZAP70, NF1, TNFRSF14, TRAF3

• Mutations in tumor suppressors: TP53, FOXO1, ATM

Node-based EBV+ PTCL

• Considered a variant of PTCL, NOS

• EBV in the majority of neoplastic cells

• Monomorphic, lack of angioinvation and

necrosis

• Older pateints, post-transplant setting, other

immunodeficiency states

Nodal T-cell lymphomas with T

follicular helper (TFH) phenotype• A new umbrella category created to highlight the

spectrum of nodal lymphomas with a TFH

phenotype : angioimmunoblastic T-cell lymphoma,

follicular T-cell lymphoma and other nodal PTCL

with TFH phenotype (specific diagnoses to be used

due to clinicopathologic differences)

• TFH phenotype: at least 2 or 3 of TFH-related

antigens: CD279/PD1, CD10, BCL6, CXCL13,

ICOS, SAP, CCR5

• Overlapping recurrent molecular/cytogenetic

abnormalities: TET2, IDH2, DNMT3A, RHOA,

CD28 mutations; ITK-SYK OR CTLA4-CD28 fusion

• AITL and FTCL: EBV+ B-cell blasts,

progression to EBV+ (rarely EBV-) BCL

• FTCL: localized disease, fewer systemic

symptoms

Nodal T-cell lymphomas with T

follicular helper (TFH) phenotype

ALK-negative anaplastic large cell

lymphoma

• Now a definite entity

• Convergent mutations and kinase fusions

leading to activation of JAK/STAT3 pathway

• Including cytogenetic subsets with

prognostic implications:

• 6p25 rearrangements at IRF4/DUSP22

locus: relatively monomorphic, lack

cytotoxic granules, superior prognosis,

also occurring in LYP, primary

cutaneous ALCL

• TP63 rearrangement: very aggressive

Breast implant-associated anaplastic

large cell lymphoma

• New provisional entity distinguished from

other ALK-negative ALCL

• Seroma fluid between the implant and

surrounding fibrous capsule.

• Both saline and silicone implants

• Median time interval: 10 years

• If no invasion of the capsule, removal of

implant and capsule

• If invasion through the capsule, systemic

chemotherapy due to risk of LN involvement

and systemic spray

CD3CD45

CD30TIA1

GRAZYME BALK1

Primary cutaneous acral CD8+ T-cell

lymphoma

• New provisional entity

• Indolent, originally described as originating in the ear,

almost always localized to a single site

• Clonal CD8+ cytotoxic T-cells

• Dense, diffuse proliferation of monomorphous

medium-sized T cells throughout the dermis and

subcutis; no epidermotropism

• CD3+, CD8+, CD4−, TIA1+, granzyme B−

• Conservative management only

• D/D: primary cutaneous CD8+ aggressive

epidermotrophic cytotoxic T-cell lymphoma

CD8

haematologica | 2014; 99:1421

T-cell large granular lymphocyte

leukemia

• New subtypes recognized with clinicopathologic

associations.

• STAT3 mutations common (also in NK-LGL)

• STAT5B mutations in a subset, associated with

more clinically aggressive disease.

Systemic EBV+ T-cell Lymphoma of

childhood

• Name changed from lymphoproliferative

disorder to lymphoma due to its fulminant

clinical course and desire to clearly

distinguish it from chronic active EBV

infection (CAEBV).

• CAEBV: from indolent/localized forms

(hydroa vacciniforme-like LPD, severe

mosquito bite allrgy ) to a more systemic

form with fever, hepatosplenomegaly,

lymphadenopathy, w/wo skin manifestations.

• D/D: EBV associated HLH, may response to

HLH 94 protocol, not neoplastic

Hydroa vacciniforme-like

lymphoproliferative

disorder

• Name changed from lymphoma to

lymphoproliferative disorder.

• Relationship with CAEBV and a spectrum in

terms of its clinical course.

Enteropathy associated T-cell

lymphoma (EATL)

• Diagnosis only to be used for cases formerly

known as type I EATL

• Typically associated with celiac disease

• Predominantly occurring in patients of

northern European origin

Monomorphic epitheliotropic

intestinal T-cell lymphoma (MEITL)

• Formerly type II EATL

• Lack of association with celiac disease

• Asians and Hispanic population

• Monomorphic, expression of CD8, CD56

and MAPK, most are GD-T cells,

• STAT5B mutation

• Gains in 8q24 involving MYC

Indolent T-cell lymphoproliferative

disorder of the GI tract

• New provisional entity

• diffuse, band-like monoclonal intestinal T-

cell infiltration of the lamina propria, and,

focally, the submucosa by lymphoid infiltrate

• Clonal cytotoxic T-cells: CD8+ >> CD4

• Indolent clinical course, some cases show

progression

Blood 2013, 122:3599

TIA1

CD8CD4

Blood 2013, 122:3599

CD8CD4

Blood 2013, 122:3599

Phenotype/genotype: T-LPD

• CD3+, CD2+, CD5±, CD7±, CD56-, TCRβ+,

TCRγ-, EBER-, CD30-.

• Ki-67 up to 5-10%.

• CD8+ cases (majority): TIA1+, granz B-

• CD4+ cases: cytotoxic marker negative

• Clonal TCRγ rearrangements (1 oligoclonal)

D/D: Histologically/

immunophenotypically

Indolent T-LPD: nondestructive, involving the

lamina propria and muscularis mucosae, small

mature cells.

EATL : large and destructive infiltrate.

medium- to large-sized pleomorphic cells with

prominent nucleoli; the intestinal mucosa

adjacent to the main tumor mass frequently

shows evidence of enteropathy (Not indolent T-

LPD)

MEITL: destructive infiltrate, monotonous and

small to medium-sized cells, florid infiltration

of the intestinal crypt epithelium and adjacent

intestinal mucosa by lymphoma cells (Not

indolent T-LPD).

MEITL: CD3+, CD8+, CD56+, often TCR-

G+, CD4-.

CD56- in indolent T-LPD also aids in the

distinction from NK cell enteropathy.

Primary cutaneous CD4+ small

medium T-cell lymphoproliferative

disorder

• Remains a provisional entity.

• No longer to be diagnosed as an overt

lymphoma due to limited clinical risk,

localized disease, and similarity to clonal

drug reactions.

Nodular lymphocyte predominant

Hodgkin lymphoma

• Variant growth patterns, if present, should be noted in

diagnostic report: “classic” (B-cell-rich) nodular

(patter A), serpiginous/interconnected nodular (B),

nodular with prominent extranodular L&H cells (C),

T-cell-rich nodular (D), diffuse with a T-cell-rich

background (T-cell-rich B-cell lymphoma [TCRBCL]-

like) (E), and a (diffuse) B-cell-rich pattern (F)

• Presence of many extranodular L&H cells (pattern C)

predicts for progression to a diffuse pattern

• Histopathologic NLPHL variants (pattern C,

D, E, F) are associated with advanced disease

and a higher relapse/progress rate.

• Cases associated with synchronous or

subsequent sites indistinguishable from

THRLBCL without a nodular component

should be designated THRLBCL-like

transformation.

Erdheim-Chester disease

• Should be distinguished from other members

of the juvenile xanthogranuloma family

• Often associated with BRAF mutations

Other histiocytic/dendritic neoplasms

• Clonal relationship to lymphoid neoplasms

(FL, CLL, T/B lymphoblastic lymphoma,

PTCL) recognized in some cases.

• Indicating transdifferentiaiton.

• V600E in LCH, histiocytic sarcoma,

disseminatied JXG, ECD, FDCS