Dr Priya Mary Jacob

Asst Professor Pathology

WHO UPDATE ON LYMPHOMAS

wwwtcsr

esin

3rd 4th 4th revised

2001 2008 2017 wwwtcsr

esin

bull The Change

bull The Significance of the Change-

Diagnostic Prognostic

bull The Rationale behind the change

wwwtcsr

esin

CHRONIC LYMPHOCYTIC LEUKAEMIA

2008

Monoclonal B cell lymphocyotosis ndash monoclonal B cells

with phenotype of CLL atypical CLL or non CLL (CD5) B

cells in peripheral blood upto a count of 5000 in the

absence of other lymphomatous features

gt5000 makes it CLL

Not known if it is a precursor of CLL wwwtcsr

esin

Whats Changed In 2017

Criteria for MBL remains the same

Acknowledged as precursor of CLL

low count (lt500) with extramedullarydisease

high count (gt500 amp lt5000)

Tissue based MBL ndash LN size lt 15cm no Proliferation

centres

wwwtcsr

esin

In CLL Proliferation centres- large confluent high MIB

are an independent adverse prognostic factor

Ciccone et al Leukaemia 2012

Giemsa x 40

Typical PC PC rich

Giemsa x400 wwwtcsr

esin

FOLLICULAR LYMPHOMA

Bit by the renaming bug

Victoria Terminus

Chattrapati Shivaji Terminus

Chattrapati Shivaji Maharaj Terminus

wwwtcsr

esin

Criteria same with a new name

ISFL is now ISFN ( In situ Follicular Neoplasia )

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

3rd 4th 4th revised

2001 2008 2017 wwwtcsr

esin

bull The Change

bull The Significance of the Change-

Diagnostic Prognostic

bull The Rationale behind the change

wwwtcsr

esin

CHRONIC LYMPHOCYTIC LEUKAEMIA

2008

Monoclonal B cell lymphocyotosis ndash monoclonal B cells

with phenotype of CLL atypical CLL or non CLL (CD5) B

cells in peripheral blood upto a count of 5000 in the

absence of other lymphomatous features

gt5000 makes it CLL

Not known if it is a precursor of CLL wwwtcsr

esin

Whats Changed In 2017

Criteria for MBL remains the same

Acknowledged as precursor of CLL

low count (lt500) with extramedullarydisease

high count (gt500 amp lt5000)

Tissue based MBL ndash LN size lt 15cm no Proliferation

centres

wwwtcsr

esin

In CLL Proliferation centres- large confluent high MIB

are an independent adverse prognostic factor

Ciccone et al Leukaemia 2012

Giemsa x 40

Typical PC PC rich

Giemsa x400 wwwtcsr

esin

FOLLICULAR LYMPHOMA

Bit by the renaming bug

Victoria Terminus

Chattrapati Shivaji Terminus

Chattrapati Shivaji Maharaj Terminus

wwwtcsr

esin

Criteria same with a new name

ISFL is now ISFN ( In situ Follicular Neoplasia )

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

bull The Change

bull The Significance of the Change-

Diagnostic Prognostic

bull The Rationale behind the change

wwwtcsr

esin

CHRONIC LYMPHOCYTIC LEUKAEMIA

2008

Monoclonal B cell lymphocyotosis ndash monoclonal B cells

with phenotype of CLL atypical CLL or non CLL (CD5) B

cells in peripheral blood upto a count of 5000 in the

absence of other lymphomatous features

gt5000 makes it CLL

Not known if it is a precursor of CLL wwwtcsr

esin

Whats Changed In 2017

Criteria for MBL remains the same

Acknowledged as precursor of CLL

low count (lt500) with extramedullarydisease

high count (gt500 amp lt5000)

Tissue based MBL ndash LN size lt 15cm no Proliferation

centres

wwwtcsr

esin

In CLL Proliferation centres- large confluent high MIB

are an independent adverse prognostic factor

Ciccone et al Leukaemia 2012

Giemsa x 40

Typical PC PC rich

Giemsa x400 wwwtcsr

esin

FOLLICULAR LYMPHOMA

Bit by the renaming bug

Victoria Terminus

Chattrapati Shivaji Terminus

Chattrapati Shivaji Maharaj Terminus

wwwtcsr

esin

Criteria same with a new name

ISFL is now ISFN ( In situ Follicular Neoplasia )

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

CHRONIC LYMPHOCYTIC LEUKAEMIA

2008

Monoclonal B cell lymphocyotosis ndash monoclonal B cells

with phenotype of CLL atypical CLL or non CLL (CD5) B

cells in peripheral blood upto a count of 5000 in the

absence of other lymphomatous features

gt5000 makes it CLL

Not known if it is a precursor of CLL wwwtcsr

esin

Whats Changed In 2017

Criteria for MBL remains the same

Acknowledged as precursor of CLL

low count (lt500) with extramedullarydisease

high count (gt500 amp lt5000)

Tissue based MBL ndash LN size lt 15cm no Proliferation

centres

wwwtcsr

esin

In CLL Proliferation centres- large confluent high MIB

are an independent adverse prognostic factor

Ciccone et al Leukaemia 2012

Giemsa x 40

Typical PC PC rich

Giemsa x400 wwwtcsr

esin

FOLLICULAR LYMPHOMA

Bit by the renaming bug

Victoria Terminus

Chattrapati Shivaji Terminus

Chattrapati Shivaji Maharaj Terminus

wwwtcsr

esin

Criteria same with a new name

ISFL is now ISFN ( In situ Follicular Neoplasia )

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Whats Changed In 2017

Criteria for MBL remains the same

Acknowledged as precursor of CLL

low count (lt500) with extramedullarydisease

high count (gt500 amp lt5000)

Tissue based MBL ndash LN size lt 15cm no Proliferation

centres

wwwtcsr

esin

In CLL Proliferation centres- large confluent high MIB

are an independent adverse prognostic factor

Ciccone et al Leukaemia 2012

Giemsa x 40

Typical PC PC rich

Giemsa x400 wwwtcsr

esin

FOLLICULAR LYMPHOMA

Bit by the renaming bug

Victoria Terminus

Chattrapati Shivaji Terminus

Chattrapati Shivaji Maharaj Terminus

wwwtcsr

esin

Criteria same with a new name

ISFL is now ISFN ( In situ Follicular Neoplasia )

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

In CLL Proliferation centres- large confluent high MIB

are an independent adverse prognostic factor

Ciccone et al Leukaemia 2012

Giemsa x 40

Typical PC PC rich

Giemsa x400 wwwtcsr

esin

FOLLICULAR LYMPHOMA

Bit by the renaming bug

Victoria Terminus

Chattrapati Shivaji Terminus

Chattrapati Shivaji Maharaj Terminus

wwwtcsr

esin

Criteria same with a new name

ISFL is now ISFN ( In situ Follicular Neoplasia )

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

FOLLICULAR LYMPHOMA

Bit by the renaming bug

Victoria Terminus

Chattrapati Shivaji Terminus

Chattrapati Shivaji Maharaj Terminus

wwwtcsr

esin

Criteria same with a new name

ISFL is now ISFN ( In situ Follicular Neoplasia )

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Criteria same with a new name

ISFL is now ISFN ( In situ Follicular Neoplasia )

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Criteria same with a new name

Paediatric FL is now Paediatric type FL

Localized early stage

IHC- Bcl2 usually negative can be rarely +

Bcl2 rearrangements must not be present

Exclude cases with diffuse areas

No Rx other than excision

- Criteria strictly followed to avoid missing out FL grade 3

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

A new provisional entity in paediatric age group

Large B cell lymphoma with IRF4 rearrangement

wwwtc

sres

in

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Follicular follicular amp diffuse pure diffuse

Children amp young adults

Low stage - cervical nodes Waldeyer ring

IHC- Strong IRF4MUM1 expression is seen usually with

BCL6 Bcl2 + in 50 cases

FISH- most cases have IRF4 amp Bcl6 rearrangements but

uniformly lack Bcl2 rearrangements

More aggressive but responds well to Rx

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

IRF4 MUM1 Bcl6

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Duodenal-type Follicular Lymphoma

FL constitutes only 1 to 3 of primary GI lymphomas

When FL involves the GI tract the duodenum is most

often affected (89)

Always low grade (grade 1ndash2)

Wait amp watch policy

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

CD 23 CD 21

Takata K et al Modern Pathology 2009

Follicular dendritic cells are arranged at the periphery of

the neoplastic follicle lsquohollowing outrsquo pattern wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Predominantly Diffuse FL with 1p36 deletion

Accounts for some cases of diffuse FL

Lacks Bcl2 rearrangement

Presents as a localized mass often inguinal

Low grade

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

MANTLE CELL LYMPHOMA

Criteria same with a new name

ISMCL is now ISMCN (In situ Mantle cell Neoplasia)

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

2 different pathways SOX11 +

SOX11 ndash

Cyclin D1 t(1114)(q13q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL)

Negative CCND1t(1114) were there but still had a gene expression profile suggesting a diagnosis of MCL

SOX11 was found to be 100 positive in MCL with negative CCND1t(1114) wwwtc

sres

in

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Impact Of NGS Studies

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

bull 2008 no specific cytogenetic abnormality for HCL HCL-v LPL

bull 2017

Mutations in BRAF V600E for Hairy Cell leukemia

Mutations in MAP2K1 which encodes MEK1 for Hairy Cell Leukemia-variant

Mutations in MYD88 L265P for Lymphoplasmacytic Lymphoma

Mutations affecting different genes- CLL amp MCL

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

DIFFUSE LARGE B CELL LYMPHOMA

2008

Cell of origin classification

IHC markers CD 10 Bcl-6 MUM1

( gt30 positivity)

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

FAQ By The Medical Oncology Resident

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Q Unclassifiable Does it mean you canrsquot classify it

A No Thatrsquos the name of the diagnosis Itrsquos the

category it fits in as per the 2008 WHO

Q So is it going to behave like a DLBCL or Burkitt

A Neither Its going to behave like a

BCLUDLBCLBL

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

2008

B- Cell lymphoma unclassifiable with features

intermediate between Diffuse large B cell lymphoma and

Burkitt Lymphoma

BCLUDLBCLBL

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

2017

Prognostic impact of the cell of origin status is impacted

by MYC Bcl2 status

MYC amp Bcl2 by IHC for protein expression

(MYC gt40 Bcl2gt50)

MYC Bcl2 and Bcl6 by FISH for translocations

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

High Grade B-cell Lymphoma With And Without

MYC And Bcl2 Or Bcl6 Translocations

bull Double expressor

IHC MYC and Bcl2 +

FISH MYC and Bcl2 translocations ( - )

bull Double or Triple Hit

IHC MYC and Bcl2 +-

FISH MYC and Bcl2 and Bcl6 translocations +

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

So Do We Need To Do FISH For All Cases Of

DLBCL

bull All DLBCL

bull Limit them to

cases with a

GCB

phenotype

high grade

morphology

gt40 MYC+

cells wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Except for cases that fulfill criteria for FL and LBL

Orange arrow - single hit

Red arrow - double or triple hit

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

whether true BL without MYC translocations

really exist

Do true BL without MYC translocations exist

Burkitt ndash like lymphoma with 11q aberration

Lower levels of MYC expression on IHC

Cytological pleomorphism

Occasionally a follicular pattern

Chromosomal 11q aberration

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

EBV + DLBCL of elderly

Recognizes the fact that it can occur in younger patients

Better survival than previously thought

EBV+ DLBCL NOS

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

A New Provisional entity

EBV+ mucocutaneous ulcer

Self limited growth

Good response to

conservative

management

Advanced age or with

iatrogenic

immunosuppression

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

EBV+ Mucocutaneous Ulcer

Isolated well-circumscribed ulcers involving

oropharyngeal mucosa skin GI tract

Polymorphous infiltrate with T cellhistiocyte-rich

background immunoblasts and Hodgkin-like cells

Prominent rim of small T-cells at base of ulcer

CD30+ EBER+ CD20+- CD15+- CD10- BCL6- MUM1+

CD45+

Localized defect in immune surveillance

Dojcinov et al AJSP 2010 wwwtc

sres

in

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Angioimmunoblastic T Cell Lymphoma Follicular Tcell

lymphoma PTCL With TFH Phenotype now under the

same umbrella

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Nodal T- cell lymphomas with T-follicular helper (TFH)

phenotype

Lot of similarities in genetic changes

Neoplastic cells should express atleast 2 or 3 TFH related

antigens

CD279PD-1

CXCL13

CD10

ICOS

Bcl6

SAP

CCR5

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Lymphomatoid Papulosis

A B C

New subsets in 2017

D E and Lp with 6p25 rearrangement

New indolent provisional entities

Indolent T cell Lymphoproliferative disorder of the GIT

Primary cutaneous acral CD8+ T cell lymphoma

wwwtc

sres

in

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Breaking News ALK ndash ALCL is now a definite entity

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

In 2008 criteria for separating CD30+ PTCL from ALK-

ALCL were imperfect and ambiguous

GEP has facilitated this distinction with ALK- ALCL having

a superior prognosis over PTCL NOS

Application of quantitative RT-PCR in validated a 3-gene

model (TNFRSF8 BATF3 and TMOD1) able to

successfully separate ALKminus ALCL from peripheral T-cell

lymphoma not otherwise specified with overall accuracy

near 97

Agnelli et al Blood 2012 wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Breast Implant Associated ALCL

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

This is very very rare

In the scientific literature from January 1 1997 through May 21 2010 the FDA identified 34 definite cases

Number of breast imlplants during this time period in the USA

4 million wwwtc

sres

in

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

EATL Type II Is now Called MEITL

Monomorphic epitheliotropic intestinal TCL (MEITL)

Systemic EBV +T cell lymphoproliferative disorder of

childhood

Systemic EBV +T cell lymphoma of childhood

Hydroa vacciniforme ndash like lymphoma

Hydroa vacciniforme ndash like lymphoproliferative disorder

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

NLPHL THRLBCL-likehellip

THRLBCL-like transformation of NLPHL

Erdheim Chester disease ndash distinguished from other

members of juvenile xanthogranuloma family

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Diagnostic approach to Lymphomas

Good morphology Clear clinical picture IHC

FISH followed by NGS is the way to go

Walking towards a closer integration between morphology

and genetics

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

References

bull The 2016 revision of the World Health Organization classification of lymphoid

neoplasms Blood 2016 May 19127(20)2375-90 Swerdlow SH Campo E Pileri

SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz

AD1 Jaffe ES1

bull Follicular Lymphomas in children and young adults A comparison of the

pediatric variant with usual follicular lymphoma Am J Surg Pathol 2013 Mar

37(3) 333ndash343 Qingyan Liu Itziar SalaverriaStefania Pittaluga Armin G

Jegalian Liqiang Xi Reiner Siebert Mark Raffeld Stephen M Hewitt Elaine

S Jaffe

bull Identification of a 3-gene model as a powerful diagnostic tool for the

recognition of ALK-negative anaplastic largecell lymphoma Blood

2012120(6)1274-1281 Agnelli L Mereu E Pellegrino E et al European T-Cell

Lymphoma Study Group

wwwtcsr

esin

Thank you wwwtcsr

esin