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HEMATOPATHOLOGY

Pathobiology and Classification of

Lymphoproliferative Disorders

Elaine Jaffe

Confidential

(distribute only to Laboratory of Pathology Strategic Visioning Committee Members)

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Diagnosis and classification of

lymphoproliferative disorders

Delineate new disease entities and identify new parametersimportant in disease classification.

Identify meaningful clinical correlates that translate into

different therapeutic approaches.

Technical approaches: Immunohistochemistry for basic andnovel antigenic determinants

In collaboration with other groups, both within and outside of

LP:

DNA based methods including PCR, FISH, array CGH Laser capture microdissection

Gene expression profiling (Affymetrix; Nanostring)

DNA sequencing (future goal)

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Follicular Lymphoma In Situ (FLIS)

Cong et al Blood 2002

Bcl-2

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BCL2 + cells are clonal by IGH PCR

& are positive forBCL2/IGH R

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FL in situ B-cells home to thegerminal center environment

Lack of progression in most patientssuggests BCL2/IGHis necessary but

not sufficient for neoplastic

transformation

Secondary hit(s) are required

FL-like PB B-cells & FL in situ are

different phases of the same

incipient neoplasia

Treatment recommendations: If there no other evidence of

disease, no therapeutic intervention is indicated

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Microdissection of RH, FLIS, PFL, iFL & FL

FLIS

PFL

iFL

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ont

F

LIS

D

FLPFL

FL

1/2

FL3

A

0

5

10

15

20

25

50

55

N

bofAlteration

s/

persample

Array CGH: Number of major alterations per sampleMamessier E et al.

Cont. FLIS IFL PFL FL1/2 FL3A

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0

5

10

15

20

25

30

35

40

45

Gain

Loss

Number of gains and losses in early-FL and FLsamples (>700kb)

Numberof

alterations/samp

le

RFH BKDG FLIS IFL PFL FL1/2 FL3A ALL

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ConclusionsE. Mamessier, J. Song, S. Roulland, A. Chott, E. Jaffe, B. Nadel

Array CGH data show a stepwise increase in

chromosomal aberrations in FLIS, FL with

partial involvement, duodenal FL, FL Grade1-2, and FL Grade 3A

Most of the affected regions in FLIS are the

same as those altered in usual FL

The specific genetic alterations that lead to

progression are yet to be elucidated

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Research Implications

Starting with an observation made at the

microscope, we pursue it to delineate the

underlying biology and clinical significance

- Use the microscope as a tool for disease

discoveryEnhance the clinical and basic research in CCR,

NCI, through collaborations with clinical

investigators

Help fulfill the educational mission of LP

Provide service to community in resolving

challenging diagnostic problems

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Future Directions

Continued studies of lymphomas and novel

lymphoproliferative disorders

Integrate new technologies to better understand disease

pathogenesis

NGS approaches; Gene expression profiling

Challenges & Obstacles

To pursue these studies in LP we are largely dependent

on collaborations with outside groups

Within LP we have limited access to newer genomictechnologies that are becoming increasingly essential to

study biological and clinical questions

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Principal Collaborators

LP: M. Raffeld, L. Xi, S. Pack, M. Emmert-Buck,

S. Hewitt

W. Wilson, L. Staudt, T Waldmann; Lymphoid

Malignancy Branch (former Metabolism Branch),CCR

Jeffrey Cohen, NIAID, EBV related diseases

LLMPP consortium

Bertrand Nadel, Marseille, France

Reiner Siebert, Kiel, Germany

Elias Campo, Barcelona, Spain