HEMATOPATHOLOGY

Pathobiology and Classification of Lymphoproliferative Disorders

Elaine Jaffe

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

Diagnosis and classification of lymphoproliferative disorders

Delineate new disease entities and identify new parameters important in disease classification. Identify meaningful clinical correlates that translate into different therapeutic approaches. Technical approaches: Immunohistochemistry for basic and novel 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)

Follicular Lymphoma In Situ (FLIS)

Cong et al Blood 2002

Bcl-2

BCL2 + cells are clonal by IGH PCR & are positive for BCL2/IGH R

 FL in situ B-cells home to the

germinal center environment FL-like PB B-cells & FL in situ are different phases of the same incipient neoplasia

Lack of progression in most patients

suggests BCL2/IGH is necessary but not sufficient for neoplastic transformation
Secondary

hit(s) are required

Treatment recommendations: If there no other evidence of disease, no therapeutic intervention is indicated

Microdissection of RH, FLIS, PFL, iFL & FL

FLIS

PFL

iFL

Array CGH: Number of major alterations per sample

Mamessier E et al.

55 50

Nb of Alterations/ per sample

25 20 15 10 5 0

Co

FL

DF

PF L

1/ 2

FL

FL

3A

nt

IS

Cont.

FLIS

IFL
L

PFL

FL1/2

FL3A

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

Gain Loss 45 40
Number of alterations/sample

35

30
25 20 15 10 5

0
Cont BKDG Bkgd RFH FLIS FLIS iFL IFL PFL PFL FL I FL1/2 FL III FL3A All ALL

Conclusions
E. 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 Grade 1-2, 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

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 discovery Enhance 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

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 genomic technologies that are becoming increasingly essential to study biological and clinical questions

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