2017 Updates on WHO

Classification of
Hematopoietic and
Lymphoid Neoplasms

1/5/2018

Revised 4th Edition 2017

Objectives:

•Briefly review the updates in WHO classification of myeloid

neoplasms
•Briefly review the updates in WHO classification of lymphoid
neoplasms
•Describe the changes in hematopoietic neoplasms commonly
seen in pediatric population
 The WHO Classification for Tumors

One system shared by all the pathologists in the world.

The “Bible” for hematopathologists

2001 - 3rd edition released

2008 - 4th edition released
2017- Revised 4th edition, not a new 5th edition

Arber DA, Orazi A, Hasserjian, R, et al. The 2016 revision to the World Health Organization classification of
myeloid neoplasms and acute leukemia. Blood. 2016; 127(20): 2391-2405
Swerdlow S. Elias Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of
lymphoid neoplasms. Blood. 2016; 127(20):2375-2390

Hematopathologic Diagnosis=
Clinical+ Morphology+ Immunophenotype+ Cytogenetics/Molecular Genetics

Hematopathologic Diagnosis in the 21st Centrury: Data Integration!

Updates:

• Some entities have new names (name changes)

• New provisional entities
• Some diagnostic criteria have been updated
• Cytogenetic/Molecular findings added or
emphasized
• Some entity been placed in new category
• Some provisional entities from 2008 become real
entities
• Further “splitting” of some entities
• New diagnostic /prognostic markers
Myeloid Neoplasms
Clonal Proliferation with
complete maturation
Myeloproliferative neoplasms (MPN)

Clonal Proliferation with

abnormal maturation
Myelodysplastic syndrome (MDS)

Clonal Proliferation with

blocked maturation
Acute myeloid leukemia (AML)

Histiocytic and Dendritic Cell

Neoplasm
 Myeloid Neoplasms
2008 (6)
• Myeloproliferative neoplasms (MPN)
• Myeloid and lymphoid neoplasms
with eosinophilia and abnormalities
of PDGFRA, PDGFRB or FGFR1
• Myelodysplastic/myeloproliferative
neoplasms (MDS/MPN)
• Myelodysplastic syndromes (MDS)
• Acute myeloid leukemia and related
precursor neoplasms (AML)
• Acute leukemias of ambiguous
lineage
2017 (9)
• Myeloproliferative neoplasms
• Mastocytosis
• Myeloid and lymphoid neoplasms with
eosinophilia and abnormalities of
PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2
• Myelodysplastic/myeloproliferative
neoplasms
• Myelodysplastic syndromes
• Myeloid neoplasms with germline
predisposition
• Acute myeloid leukemia and related
precursor neoplasms
• Blastic plasmacytoid dendritic cell
neoplasm
• Acute leukemias of ambiguous lineage
2008 Myeloid 2017

CSF3R gene mutation

 Myeloid neoplasm with FGFR1 abnormality

Li W and Cooley L. Unusual infant eosinophilia: myeloid neoplasm with FGFR1 abnormality. Blood. 2016; 128 (10):
1440
2008
Myeloid 2017

SETBP1 and/or ETNK1 mutations

SF3B1 mutation

Myeloid neoplasms with germline predisposition

Juvenile Myelomonocytic Leukemia (JMML)

A clonal haematopoietic disorder of childhood characterized by

excess proliferation of the granulocytic and monocytic
lineages.
Pathogenesis: deregulation of RAS/MAPK pathway.

Germline CBL mutations

10-15%

Cytogenetics: monosomy 7 in 25% of patients, a normal karyotype in 65%

Clinical and Pathologic Features are not changed
Diagnostic criteria have been updated

WHO 2008
 Myeloid Neoplasms with Germline Predisposition

• Recognition that some myeloid neoplasms run in families

and are associated with germline mutations
• May have a preexisting disorders before onset of myeloid
neoplasm
• Thrombocytopenia
• BM failure
• May be associated with a systemic disorder
• Abnormalities of other organ systems
• Propensity for solid tumors
 Myeloid Neoplasms with Germline Predisposition

Specific predisposing mutation should be noted in diagnosis

• Behavior of the neoplasm may differ from true de novo
cases
• Implications for family members- need for screen
• May require additional screening of other organ systems
• BM transplant
• May need to choose a different regimen
• Family members may not be a good donors if they
have the same mutation
Individuals in whom the possibility of a myeloid neoplasm with germline
predisposition should be considered. From: Churpek JE, et al.Leuk
Lymphoma 2013 (54): 28-35

Any patients with MDS or acute leukemia, with any of the following:
• A personal history of multiple cancers
• Thrombocytopenia, bleeding propensity, or macrocytosis preceding the diagnosis
of MDS/AML by several years
• A first- or second-degree relative with a hematologic malignancy
• A 1st or 2nd –degree relative with a solid tumor c/w germline predisposition; i.e.
sarcoma, early-onset breast cancer (<50yo), or brain tumors
• Abnormal nails or skin pigmentation, oral leukoplakia, IPF, unexplained live dis,
lymphedema, atypical infection, immune def, congenital limb anomalies, or short
stature (in pt or a 1st or 2nd degree relative

Any healthy potential HSC donor planning to donate for a family member with a
hematological malignancy with any of the conditions listed above or who fails to
mobilize stem cells well using standard protocols
Acute Myeloid Leukemia and Related Neoplasms
 2008 Myeloid 2017
(6)
(11)
(7)
(9)

(BPDCN)

Blastic plasmacytoid dendritic cell neoplasm

AML with BCR-ABL1
AML with mutated RUNX1

Sood R, et al. Blood 2017 129:2070-2082

AML with mutated RUNX1
AML, NOS: New Acute Erythroid Leukemia Criteria

Acute Erythroid Leukemia, Erythroid/ Myeloid

Type (FAB-M6a)
AML, NOS: New Acute Erythroid Leukemia Criteria

• >80% immature erythroid precursors with

>30% proerythroblasts
 Myeloid
2008 2017 No big changes

Mixed-phenotype acute leukaemia, not otherwise specified, rare types

Acute leukaemias of ambiguous lineage, not otherwise specified
Lymphoid Neoplasms
Precursor Lymphoid Neoplasms
B-cell
T-cell
NK-cell

Mature Lymphoid neoplasms:

• Mature B-cell Neoplasms

• Mature T- and NK-cell Neoplasms
• Hodgkin Lymphomas
• Immunodeficiency- Associated
Lymphoproliferative Disorders
Precursor Lymphoid Neoplasms
2008 ALL 2017

(9)
(7)
 Case 1
• 16 yo male with history of ADD, eczema, partial
blindness of left eye came for chest pain
• Chest CT: b/l axillary and hilar LAD
• CBC: WBC (K/uL) 32.92 H, Hgb (g/DL) 13.7, Platelet (K/uL) 78 L; %
Blasts 65%
Precursor B- ALL, high risk, treated per AALL1131

End of induction: 0.47% MRD

 Cytogenetic: 47,XY,dup(5)(q14q32),+21[12]; 48,sl,+10[2]; 46,XY[6]

Microarray analysis shows

1. Gain of the 5q14.1q32 region with breaks at the SSBP2 and CSF1R genes. This interstitial
duplication likely results in SSBP2/CSF1R fusion. The SSBP2/CSF1R fusion has been shown to be
sensitive to the ABL-class inhibitors imatinib and dasatinib (1).
2. IKZF1 deletion exons 1-6 (NM_006060).
3. EBF1 deletion exons 2-16.
4. Gain of whole chromosome 21.
5. Biallelic deletions of TCRd and IGH regions consistent with gene rearrangement
CRLF2 gene rearrangement and overexpression

Harvey RC, et al. Blood 2010 115:5312-5321

B-ALL with iAMP21
Early T-precursor (ETP) -ALL
Mature Lymphoid Neoplasms
2008 Lymphoid: Mature B 2017
2008 Lymphoid: Mature B 2017
 Lymphoid: Mature B
2008 2017
Burkitt lymphoma Burkitt lymphoma
–Endemic –Endemic
–Sporadic –Sporadic 70% with TCF3 or ID3 mutations
–Immunodeficiency –Immunodeficiency
associated associated
Pediatric type follicular lymphoma
 Pediatric Follicular Lymphoma is a provisional entity in WHO 2008
 A real entity in new WHO classification (WHO 2017)
 Name changed to pediatric type FL since it can occur in adults
 Very rare, <3% of pediatric NHL
 Usually localized (stage I), nodal (cervical, etc) or extranodal sites (testis,
etc)
 Mostly curable with excision
 Large expansile follicles, highly proliferative, prominent blastoid follicular
center cells, commonly grade 3/3
 Positive for GC B cell markers: CD19+, CD20+, CD10+, BCL6+, light chain
restriction, high Ki67
 BCL2 expression uncommon
 No BCL2, BCL6, IRF4 or MYC rearragement

Oschlies I et al., Haematologica 2009

 Pediatric Follicular Lymphoma

CD20

MIB1
Large B-cell lymphoma with IRF4 rearrangement

• Most commonly in children/young adults

• GC B-cell lymphomas composing FL grade 3 or
(centroblastic) DLBCL characterized by coexpression of
MUM1 and BCL6 in the absence of PRDM1/BLIMP1
• t(6;14)(p25;q32), IGH/IRF4
–May have BCL6 R but not BCL2.
• Some otherwise similar cases lack a demonstrable IRF4
translocation (but may have IGH rearrangements)
• Involve Waldeyer ring &/or cervical lymph nodes, low stage
• Considered to be more aggressive than other pediatric FL
but do well when treated
Case 2
• 9 year old girl presented with a right posterior neck
mass for a few weeks.
• Possible history of cat scratch.
• Increasing in size.
• No fever, weigh loss or night sweating.
• An excisional biopsy was performed.
 CD3 CD20 TdT

BCL6 BCL2 Ki67

 FISH: Negative for MYC rearrangement

Cytogenetic results:
46,XX,t(6;17)(p25;q24),inv(14)(q31q32),der(22)t(11;22)(q12.3;p11.2)[19]
46,XX[1]
ABNORMAL
Abnormal female karyotype shows gain of 11q as seen by chromosome analysis
[der(22)t(11;22)] and FISH [gain of CCND1 & ATM]. Additionally, a reciprocal t(6p;17q)
translocation and an inversion within 14q are noted. Microarray analysis confirms gains at
11q, but not the t(6;17) or inv(14). One cell shows a normal diploid karyotype.
FISH analysis confirms IGH is rearranged by the inversion; the partner gene is not
identified. FISH shows 3 & 4 copies of ATM at 11q22.3 and three copies of CCND1 at
11q13. Analysis is negative for BCL6, MYC and IGH/BCL2 gene rearrangements.
COMMENTS (by Dr. Cooley)
• These cytogenetic results are consistent with the diagnosis of "high grade B-cell
lymphoma with features of Burkitt lymphoma, MYC negative, with 11q gain/loss
pattern" (1). As described by Salaverria, et al. this is a rare subgroup of
lymphomas with favorable outcome. See microarray report for additional
information (CA-15-017).
Diagnosis (WHO 2017):
Burkitt-like Lymphoma with 11q aberration
Burkitt-like lymphoma with 11q aberration
 Diffuse large B-cell lymphoma

• 10-15% of pediatric NHL

• More common in adolescents and older children
• Often localized or lower stage disease

Germinal center (GC) vs Activated B-cell (ABC)

 Gene Expression Profile

Rosenwald, A, et al. The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma. N Engl J
Med. 2002 Jun 20;346(25):1937-47.
Proposed IHC strategies for DLBCL classifying for cell of origin
Chronic lymphoproliferative disorder of NK cells; Aggressive NK-
cell leukaemia; EBV–positive NK-cell LPD; Extranodal NK/T-cell
lymphoma, nasal type; Hepatosplenic T-cell lymphoma; Monomorphic
epitheliotropic intestinal T-cell lymphoma
Primary cutaneous gamma delta T-cell lymphoma

Treg Adult T-cell leukaemia/lymphoma

Chronic active EBV infection of T

cells; Mycosis fungoides; Sézary
syndrome; Primary cutaneous anaplastic
large cell lymphoma; Lymphomatoid
papulosis; Primary cutaneous CD4+
small/medium T-cell LPD; Peripheral T-
cell lymphoma, NOS

Angioimmunoblastic T-cell lymphoma

and other nodal lymphomas of T
follicular helper (TFH) cell origin

Systemic EBV+ T-cell lymphoma of

childhood; Subcutaneous panniculitis-
like T-cell lymphoma; Primary cutaneous
CD8-positive aggressive epidermotropic
cytotoxic T-cell lymphoma; Primary
cutaneous acral CD8-positive T-cell
lymphoma; Anaplastic large cell
lymphoma, ALK-positive; Anaplastic large
cell lymphoma, ALK-negative.
 Lymphoid: Mature T/NK
2008 2017

Sézary syndrome
 Lymphoid: Mature T/NK
2008 2017

Type D, E
(3)

(4)
Case 3

12 yo female with recurrent infections and multiple

lymphadenopathy presented with abdominal pain.
Imaging study showed multiple GI tract wall
thickening and enlarged lymph nodes.

An axillary LN excisional biopsy and multiple GI

biopsies were performed.
Axillary LN

CD3 CD20 CD4

CD8 CD30 EBER

Appendix

Colon Rectum
EBER: Appendix Colon Rectum

PB and BM: not involved

TCR gene rearrangement: negative

Diagnosis: Chronic active EBV infection of T cells.

Case 4
• 3 yo previously healthy boy presented with high
fever, hepatomegaly, skin rash.
• CBC showed pancytopenia (Hg 8g/dL, WBC
1.8K/ul, plt 21 K/ul).
• Labs: increased LDH, ferritin, triglyceride, liver
enzyme, soluble CD25.
• PCR test was positive for EBV and influenza.
• Clinical diagnosis of HLH.
• Bone marrow was examined.
 CD3 CD4 CD8

CD5 CD7 CD56

ALK1 CD30 CD20

Flow Cytometry
Diagnosis: Systemic EBV+ T cell lymphoma of
Childhood (WHO 2017)
EBV–positive T-cell and NK-cell lymphoproliferative
diseases of childhood

• Systemic CAEBV, T-cell or NK-cell

• Cutaneous CAEBV
• Hydroa Vacciniforme (HV)-like LPD (T/NK)
• Severe Mosquito Bite Allergy (NK)

• Systemic EBV+ T-cell lymphoma of childhood

 Systemic CAEBV, T-cell or
NK-cell
• Systemic EBV+ polyclonal or oligoclonal T-
or NK-cell LPD .
• ​ High viral load in peripheral blood and
tissues and intermittent or chronic IM–like
features such as fever, lymphadenopathy,
and hepatosplenomegaly at least 3
months after primary virus infection in
patients with no known
immunodeficiency
• Prognosis: Variable
• Indolent to rapidly progressing
• 5-year survival: 59% for T, 87% for NK
• Risk factor: >8yo, liver dysfunction
 Cutaneous CAEBV:
• Hydroa Vacciniforme (HV)-like LPD (T/NK)
• Primary cutaneous disorder of polyclonal or (most often) monoclonal T or NK cells
• Microscopy: epidermal reticular degeneration-intraepidermal spongiotic vesiculation,
dermal lymphoid infiltrate, small to medium size w/o siginificant atypia. EBER+
• Broad spectrum of clinical course
• Long clinical course with risk to develop systemic lymphoma

• Severe Mosquito Bite Allergy (NK)

• EBV+ NK cell LPD
• Clinical: high fever, focal skin erythema, bullae, ulcers, necrosis and deep scarring
following mosquito bits
• PB: NK lymphocytosis
• Long clinical course with risk of HLH and aggressive NK-cell leukemia
 Systemic EBV+ T cell lymphoma of Childhood

• A fulminant illness characterized by a clonal proliferation of

EBV-infected T cells with an activated cytotoxic phenotype.
• Mostly in Asians or Native Americans.
• Children or young adults.
• It can occur shortly after primary acute EBV infection or
develop in the clinical setting of CAEBV-T/NK.
• A hemophagocytic syndrome is nearly always present.
• It is usually characterized by a rapid clinical progression, with
multiple organ failure, sepsis, and death within few weeks.
 Lymphoid
2008 2017
Thank you!