1. Malignant lymphomas

2. Lymph nodes: Germinal center (GC) and mantle B-cells capsule
Paracortical T-cells and high endothelial venules
sinus
mantle GC

3. Lymphoma - incidence and mortality
3-5% of deaths in developed world
higher in other areas
3-7 cases per 100,000 in USA
males greater than females, white males highest
increases with age
histology varies with age, low grade frequent in adults
high grade most frequent in children

4. Classification of lymphoma
Hodgkin’s
mixed cellularity
nodular sclerosis
lymphocyte depleted
lymphocyte predominant
Non-Hodgkin’s lymphoma
low grade B-cell
small lymphocytic
marginal zone
mantle cell (B-cell)
follicular (B-cell)
large B-cell
Burkitt’s (B-cell)
lymphoblastic (mostly T-cell)
T/NK-cell
mycosis fungoides (cutaneous T-cell)

5. ML types in POG
476 NHL
373 HD

6. Thomas Hodgkin

7. Hodgkin’s Disease Mixed cellularity Lymphocyte depleted
Nodular sclerosis
Lymphocyte predominant

8. Reed Sternberg Cell
H&E
Wright stain
R-S cells:
CD30

9. Incidence of HD 3-7 per 100,000 Bimodal
15-34 & > 55
NS increasing in young patients
young women
LD decreasing in older patients
Medeiros, Cancer 75:357,1995

10. Hodgkin’s Disease
Reed-Sternberg (RS) cell in immunoproliferative background
RS cells minority
background
lymphocytes, eosinophils, plasma cells, histiocytes
RS cells B-cells (90%) or T-cells (10%)
cervical LN or mediastinum; spread to thoracic para-aortic LN, spleen, liver, abdominal Para-aortic nodes
Association with EBV: 96% MC, 34% NS, 10% LP
radiation for localized disease
chemotherapy or chemo/RT for advanced disease

11. Mixed cellularity Hodgkin’s Disease
Diffuse infiltrate including relatively frequent RS cells
CD15 and CD30 antigen expression
classical HD

12. Nodular Sclerosis Hodgkin’s Disease
RS cells and “lacunar” cells in clusters surrounded by collagen fibrosis
CD15 and CD30+
Often mediastinal mass in young women

13. Lymphocyte depletion HD
Diffuse infiltrate
numerous RS cells and variants with relatively few lymphocytes
Often older men with advanced disease
Difficult to distinguish from large cell NHL

14. Lymphocyte predominant HD
Nodular or sometimes diffuse infiltrate containing “L&H” cells (for “lymphocytic and histiocytic LPHD”)
label as polyclonal B-cells
usually localized (often cervical LN)
indolent clinical course

15. Hodgkin’s disease Most cases derived from clonal B-cells
Heavy load of somatic mutations
Lack crippling mutations, but do not transcribe IgH due to functional regulatory defects
HD and NHL have derived from same clone
Seitz, Blood May 15;95(10):3020-4

16. Non-Hodgkin’s Lymphoma
Small lymphocytic
Mantle cell
Burkitt
Lymphoblastic
Follicular center cell
Large B-cell
Peripheral T-cell

17. Phenotype in diagnosis of NHL
CD45Ro (T-cell)
ALK-1
CD79a (B-cell)
BCL-2

18. Incidence of NHL in US overall
per 100,000
Males > females
Racial differences
whites more FL
blacks more PTC
Groves, JNCI, 92; , 2000

19. NHL in Children 4.6-9.1 per million 1/3-1/2 SNC, LB, LC
white > black
male > female
1/3-1/2 SNC, LB, LC
Geographic variation
incidence
histologic type
biology of Burkitt’s
POG
Shad, Ped Clin NA 44:863-89, 1997

20. Human B-cell lymphomas
Sequencing of the variable region genes - somatically mutated in majority of non-Hodgkin’s and Hodgkin’s lymphomas
this indicates germinal or post-germinal center origin
unmutated variable region genes: mantle lymphoma, some CLL’s

21. Burkitt’s Lymphoma Medium size cells nuclei same as histiocyte nuclei
Oval nuclei
3-5 nucleoli, open chromatin
Basophilic (vacuolated) cytoplasm
High mitotic rate, starry sky
Mature B-cell, surface IG+, analogous to L3 ALL
EBV in endemic areas and immunosuppression

22. Large B-cell Lymphoma Average nuclei larger than histiocyte nuclei
Mature B-lineage (CD20+)
Morphologic heterogeneity
Centroblastic
Centroblastic/centrocytic
B-immunoblastic
BCL 6 or BCL2 overexpression in some

23. Burkitt-Like Lymphoma
Mature B-cell
Average cell medium size (like Burkitt)
More variability than Burkitt
Nuclear size
Nuclear shape
Nucleolar prominence
Sometimes fine fibrosis
Interface between Burkitt & large B-cell lymphoma

24. Small lymphocytic lymphoma/CLL
slow growing
diffuse infiltrate of small lymphocytes
admixed prolymphocytes; growth centers
often indolent
mature B-cell with CD5 expression

25. SLL in children Rare cases described t(2;14)(p13;q32) in several
Citations:
Fell, et al. Science 232:491-4, 1986
Yoffe, et al. J Pediatr 116:114-7, 1990
Ribeiro, et al. Leukemia 6:761-5, 1992

26. Follicular lymphomas One of the most common NHL Mature B-cell
Slow-growing, persistent
t(14;18) with bcl-2 overexpression
graded by cell type

27. Follicular Lymphoma in children
1% (17) of 1336 pediatric lymphomas
Ribeiro, et al. Leukemia 6:761-5, 1992
usually mixed or large cell,
lack bcl-2 or p52 abn; some testicular
generally good outcome
those who fail progressed to DLBCL
Frizzera, Cancer 44:2218, 1979; Winberg, Cancer 48:2223, 1981
Pinto, Mod Pathol 3:308, 1990; Moertel, Cancer 75:182, 1995
Atra, Br J Haem 103:220, 1998; Finn, Cancer 85:1626, 1999

28. Marginal zone lymphoma
mature B-cell
arises from splenic or mucosal (MALT) marginal zone cells
“monocytoid” appearance
Lymphoepithelial lesions in MALT
often indolent
Gastric; H. pylori

29. Marginal Zone lymphoma in children
Occasional (<1%)
Gastric
associated with H. pylori
may resolve with tx of H. pylori
Many associated with HIV
Salivary gland, lung, GI
Citations:
Teruya-Feldstein, AJSP 19:357, 1995; Blecker, Gastroent.109:973, 1995
Joshi, AJCP 107:592, 1997; Corr, J Ultrasound Med 16:615, 1997
Berrebi, J Peds 133:290, 1998; Fukumoto Hihon Rinsho MGK 23:49, 2000

30. Mantle cell lymphoma mature B-cell arises from follicular mantle
Neoplastic mantle zone cells
mature B-cell
arises from follicular mantle
resembles SLL and MZL
t(11;14) with cyclin-D1, CD5, (CD23-)
expresses bcl-2 as do nl mantle cells; long-lived
difficult to eradicate and aggressive
Residual germinal center

31. T-cell lymphomas Less common that B-cell
Some associations with retroviruses
HTLV-1
Cytogenetic abnormalities variable
include chr. 14 abnormalities
t(2;5) and variants in ALCL
Generally difficult to eradicate

32. T-cell development Maturation/selection in thymus
T-cell receptor gene rearrangement
gamma/delta
alpha/beta
Tdt, CD7, CD5, CD2
CD1, CD4/CD8, CD3
Mature cells CD4 or CD8 and CD3

33. Lymphoblastic Lymphoma
Small cells
nuclei smaller than histiocyte’s
Diffuse chromatin, inconspicuous nucleoli, often nuclear convolutions
High mitotic rate, starry sky
Precursor T-cell
T-zone distribution, infiltrative
Tdt, CD7, CD1, CD4/CD8
Rare precursor B-lineage

34. Anaplastic Large Cell Lymphoma
Large cells with abundant cytoplasm
often indented or lobated nuclei
LN sinus, paracortex
CD30 expression
T or null phenotype
t(2;5)
ALK protein expression

35. ALCL - CD30 and ALK expression
Most cases in children and young adults express ALK due to t(2;5) or variant translocation.
ALK1
Most cases over 35 are ALK negative

36. ALK-1 in recent LCL
A majority of T or null LCL in children express CD30 and ALK

37. Non-anaplastic PTCL Diverse entities Rare in children
PTCL, NOS; angiocentric; nasal; T-gamma; panniculitic; ATL; MF
Rare in children
Likely worse than ALCL