Malignant lymphomas

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

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

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)

ML types in POG 1998-2000 476 NHL 373 HD

Thomas Hodgkin

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

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

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

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

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

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

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

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

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. 2000 May 15;95(10):3020-4

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

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

Incidence of NHL in US overall 7.4-17.1 per 100,000 Males > females Racial differences whites more FL blacks more PTC Groves, JNCI, 92;1240-51, 2000

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 1998-2000 Shad, Ped Clin NA 44:863-89, 1997

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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