Linfomas intermedios entre Linfoma de

Hodgkin y Linfoma Mediastínico de

Célula Grande

Juan F. García

XXVI Congreso Nacional de la SEAP-IAP

CURSO DE PATOLOGÍA LINFOIDE

Linfomas de la zona gris

Classical HL : HRS cells + characteristic reactive microenvironment

cHL

Subtype

Neoplastic

cellularity Reactive background

Fibrosis

%

NS

• Variable number of

H&RS cells

• Lacunar cells

• T-lymphocytes,

numerous eosinophils

• Abundant

• Broad collagen

bands that

surround nodules

50-70%

MC

• Many H&RS cells

and variants

• Mummy cells

• Heterogeneous:

histiocytes,

eosinophils,

neutrophils, plasma

cells,…

• Absent or

interstitial

20-40%

LRCHL

• Low number of

classical H&RS

and mononuclear

variants

• Nodules of mature B-

lymphocytes

• Histiocytes

• Can exist

<5%

LD

• Abundant and

pleomorphic

• Poor

• Absent or diffuse

fibrosis <5%

Nodular Sclerosis HL

• Young females

• Mediastinum

• More frequent EBV-

H&RS + lacunar cells

CD30

CD30

> 90%

CD15

70-80%

CD20

CD79a

PAX5

BCL2

Diffuse Large B-cell Lymphoma

Morphology: diffuse, with centroblastic, immunoblastic,

plasmablastic, pleomorphic cytology

Immunophenotype: CD20+ CD79a+ OCT2+ Pax5+

Bcl6: 80%

Bcl2: 50-70%.

p53: 10%, poor response to chemotherapy

GC-type: CD10+

ABC: MUM1+

Genotype:

t(14;18) (bcl2-IgH): 20%

t(3q27) (bcl6): 30%

8q24 (c-myc): 10%

CD20 BCL2

Phenotype

CD20 CD79a OCT2 PAX5 MUM1 BCL2 BCL6 CD30 CD15 EBV

cHL -/+ - -/+ + + -/+ - + +/- 30-70%

LMP1+

DLBCL + + + + -/+ +/- + -/+ - 10-15%

LMP1-

Differential diagnosis: classical HL vs DLBCL

Primary Mediastinal DLBCL

• Young adults (W>M)

• Clinical symptoms, related with the

localization

• Sclerosis surrounding the tumor

cells

• Weak expression of Ig and other B-cell

markers

• HRS-like cells may be present

• Clinical course depending the stage at

diagnosis

• CD23+, CD30+, MAL1+

CD23 CD30

MAL1

Most PMBCL and 10% of cHL express

the MAL protein, linking them

histogenetically to the thymic asteroid

medullary B cells.

C. Copie-Bergman, A. Plonquet, M. A. Alonso et al.

Modern Pathology 2002, 15(11), 1172–1180

MAL Expression in Lymphoid Cells: Further Evidence

for MAL as a Distinct Molecular Marker of Primary

Mediastinal Large B-Cell Lymphomas

Double IF labeling of thymic tissue with anti-

MAL (red) and anti-CD79a (green) Abs.

Molecular diagnosis of primary mediastinal B cell

lymphoma identifies a clinically favorable subgroup

of diffuse large B cell lymphoma related to Hodgkin

lymphoma.

Rosenwald A, et al. J Exp Med 2003;198(6):851-62.

• 47-y old male

• Constitutional syndrome with fever and weight loss (january 2011)

• Mediastinal mass (bulky) and cava syndrome

• FNA: consistent with large-cell lymphoma

• Biopsy (trucut): consistent with Hodgkin lymphoma

• Open biopsy is performed by mediastinoscopy

Clinical case

Clinical case

Clinical case

Clinical case

Clinical case

CD15

CD30

EBV (LMP1)

Clinical case

Caso clínico

CD20 CD79a

Clinical case

B-Cell Lymphoma, Unclassifiable, with Features

Intermediate between Diffuse Large B-Cell

Lymphoma and Classical Hodgkin Lymphoma

(BCLu-DLBCL/cHL)

• The patient was treated with intensive chemotherapy:

R-CHOP-21 (x8) + Radiotherapy, with complete

remission

• Follow-up: alive without disease

Clinical case

• Most lymphomas can be accurately classified based on the current

WHO classification of lymphoid neoplasms (clinical information

morphology, immunophenotype, and genetic characteristics).

• Despite technical and scientific progress, some aggressive B-cell

lymphomas with features overlapping between two different types

of lymphomas remain difficult to classify.

• The updated 2008 WHO classification has addressed this problem

by creation of two new provisional categories of B-cell lymphomas,

unclassifiable; one with features intermediate between diffuse large

B-cell lymphoma and classical Hodgkin lymphoma and the second

with features intermediate between diffuse large B-cell lymphoma

and Burkitt lymphoma.

Grey Zone Lymphomas: Lymphomas with Intermediate Features

B-Cell lymphoma, unclassifiable, with features

intermediate between diffuse large B-cell lymphoma

and classical Hodgkin lymphoma (WHO 2008)

• Neoplasms with morphological and immunophenotypic features

intermediate between DLBCL and HL

• Usually young males with mediastinal involvement, diagnosed at

advanced stages

• Tumors with similar morphology and immunophenotype may also

present in extramediastinal locations.

Workshop report on Hodgkin's disease and related diseases

('grey zone' lymphoma).

Rudiger T, Jaffe ES, Delsol G, et al. Ann Oncol. 1998;9 Suppl 5:S31-38.

• Three cases showed features of both

diffuse large B-cell lymphoma and

classical Hodgkin's lymphoma within

the same specimen (composite

lymphomas).

• Additionally, five cases occurring in

the mediastinum showed both

morphological and

immunohistochemical transition

between cHL and DLBCL.

• 9 cases with morphological and immunophenotypic

features intermediate between DLBCL and HL

• Usually young males with mediastinal involvement,

diagnosed at advanced stages

• Aggressive tumors

36 cases: 21 cases with

intermediate features, 6

composite or synchronous

(1), and 9 sequential cases

• MAL staining was found in 7 of 10 MGZL, and in at least

one component of 6 of 7 evaluable composite or

sequential MLBCL/cHL cases.

• Two cases of sequential lymphoma showed

rearrangements of the IgH gene of identical size: one in

which MLBCL was the first diagnosis and one in which

MLBCL was diagnosed at relapse, indicating clonal

identity for the two components of cHL and MLBCL.

PMBCL cHL-NS BCLu-DLBCL/cHL

Age Young patients Young patients Young patients

Gender Female predominance Female predominance Male predominance

Localization Mediastinal mass eventually supraclavicular lymph nodes

Mediastinal mass eventually supraclavicular lymph nodes

Mediastinal mass eventually supraclavicular lymph nodes or more rarely other lymph nodes

Morphology Compartmentalizing fibrosis Fibrosis in thick bands Confluent, sheet like growth of pleomorphic tumor cells with diffuse fibrotic stroma Variability from area to area

Immunophenotype Lack of Ig-Expression Lack of HLA I expression Frequent CD30 expression Expression of MAL and CD23

Lack of Ig-expression Lack of HLA I expression CD30 / CD15 expression

Transitional features between PMBCL and cHL B-cell program often preserved

Genetic and molcular features

Expression of HLA-I REL (2p15) and JAK2 gains (9p24) CIITA breaks Activation: NF-kappaB, JAK-STAT, and P13K/AKT pathway High expression of extracellular matrix elements, overexpression of TNF family members

Expression of HLA-I REL (2p15) and JAK2 gains (9p24) CIITA breaks Activation: NF-kappaB, JAK-STAT, and P13K/AKT pathway High expression of extracellular matrix elements, overexpression of TNF family members

REL (2p15) and JAK2 gains (9p24) CIITA breaks

Common features of PMBCL, cHL-NS, and BCLu-DLBCL/cHL

PMBCL cHL-NS BCLu-DLBCL/cHL

Morphology Clear cells often homogenous (but Reed Sternberg cells may occur) Little or no inflammatory background

Hodgkin cells and Reed Sternberg cells Typical inflammatory background

Transitional features between PMBCL and cHL

Immunophenotype B-cell markers preserved (CD20, CD79a, PAX5) B-cell transcription factors present (BOB.1 and OCT-2) CD15 absent

Absence of EBV B-cell markers lacking or only weakly or heterogeneously expressed (especially PAX5) B-cell transcription factors usually negative CD15 may be present EBV may be present

Overlapping features between PMBCL and cHL B-cell program often preserved

Distinguishing features of PMBCL, cHL-NS, and

BCLu-DLBCL/cHL

Molecular diagnosis of primary mediastinal B cell

lymphoma identifies a clinically favorable subgroup

of diffuse large B cell lymphoma related to Hodgkin

lymphoma.

Rosenwald A, et al. J Exp Med 2003;198(6):851-62.

The molecular signature of mediastinal large B-cell lymphoma

differs from that of other diffuse large B-cell lymphomas and

shares features with classical Hodgkin lymphoma.

Savage KJ, et al. Blood 2003;102(12):3871-9.

• MLBCLs had low levels of

expression of components of the

BCR signaling, a profile resembling

that of RS cells of cHL.

• Like cHLs, MLBCLs also had high

levels of expression of IL-13R and

downstream effectors of IL-13

signaling (JAK2 and STAT1), TNF

family members, and TNF receptor-

associated factor-1 (TRAF1).

Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive

signature with elements shared by classical Hodgkin's lymphoma and primary

mediastinal large B-cell lymphoma.

Eberle et al. Haematologica 2011;96(4):558-66

Gray zone lymphoma: chromosomal aberrations with immunophenotypic

and clinical correlations

Eberle FC, et al. Mod Pathol 2011;24(12):1586-97

Gray zone lymphoma (n=27), mediastinal composite lymphoma

(n=3) and mediastinal synchronous/metachronous lymphoma (n=3)

• Gains including amplifications in 2p16.1 (REL/BCL11A locus)

were observed in 33% of all patients,

• Gains/amplifications affecting the JAK2/PDL2 locus in 9p24.1

were present in 55%.

• Rearrangement of the CIITA locus at 16p13.13 in 8/30 cases

(27%)

• 7/26 cases (27%) demonstrated gains of 8q24 (MYC).

70-90 % of PMBCL and 10% of cHL

express the MAL protein linking them

histogenetically to the thymic asteroid

medullary B cells.

C. Copie-Bergman, A. Plonquet, M. A. Alonso et al.

Modern Pathology 2002, 15(11), 1172–1180

MAL Expression in Lymphoid Cells: Further Evidence

for MAL as a Distinct Molecular Marker of Primary

Mediastinal Large B-Cell Lymphomas

Double IF labeling of thymic tissue with anti-

MAL (red) and anti-CD79a (green) Abs.

70-80% of BCLu-DLBCL/cHL also

express the MAL protein

B-Cell lymphoma, unclassifiable, with features

intermediate between diffuse large B-cell lymphoma

and classical Hodgkin lymphoma (WHO 2008)

• How to treat them?

Gray zone lymphoma: better treated like cHL or PMLBCL?

Dunleavy K, et al. Curr Hematol Malig Rep 2012;7(3):241-7

Grant C, et al. Curr Hematol Malig Rep. 2011;6(3):157-63

• There is a lack of prospective experience in treating GZL

because of the rarity of these tumors.

• Historical data indicate that they have done poorly with

traditional approaches developed for the treatment of

either cHL or diffuse large B-cell lymphoma.

• Preliminary results indicate that 4 of 4 patients treated

with R-CHOP regimen are in complete remission, with 1

patient requiring mediastinal radiation

Traverse-Glehen A, et al. Am J Surg Pathol 2005;29:1411–1421

BCLu-DLBCL/cHL: Diagnostic criteria

• Cases morphologically resembling PMBCL but

with strong expression of CD15, absence of

CD20 or presence of EBV.

• Cases rich in tumor cells resembling cHL, which

are strongly positive for CD20 and other B-cell

markers (CD79a).