malignant lymphomas. lymph nodes: germinal center (gc) and mantle b-cells paracortical t-cells and...
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Malignant lymphomasMalignant lymphomas
Lymph nodes:Lymph nodes: Germinal center (GC) Germinal center (GC) and mantle B-cellsand mantle B-cells
Paracortical T-cells Paracortical T-cells and high endothelial and high endothelial venulesvenules
capsulecapsule
sinussinus
GCGC
mantlemantle
Lymphoma - incidence and mortalityLymphoma - incidence and mortality 3-5% of deaths in developed world3-5% of deaths in developed world
– higher in other areashigher in other areas 3-7 cases per 100,000 in USA3-7 cases per 100,000 in USA
– males greater than females, white males highestmales greater than females, white males highest increases with ageincreases with age
– histology varies with age, low grade frequent in adultshistology varies with age, low grade frequent in adults– high grade most frequent in childrenhigh grade most frequent in children
Classification of lymphomaClassification of lymphoma Hodgkin’s Hodgkin’s
– mixed cellularitymixed cellularity
– nodular sclerosisnodular sclerosis
– lymphocyte depletedlymphocyte depleted
– lymphocyte lymphocyte predominantpredominant
Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma
– low grade B-celllow grade B-cell
» small lymphocyticsmall lymphocytic
» marginal zonemarginal zone
– mantle cell (B-cell)mantle cell (B-cell)
– follicular (B-cell)follicular (B-cell)
– large B-celllarge B-cell
– Burkitt’s (B-cell)Burkitt’s (B-cell)
– lymphoblastic (mostly T-cell)lymphoblastic (mostly T-cell)
– T/NK-cellT/NK-cell
– mycosis fungoides (cutaneous T-cell)mycosis fungoides (cutaneous T-cell)
ML types in POG 1998-2000ML types in POG 1998-2000
0
50
100
150
200
250
300L
MC
HD
NSH
D
LD
HD
LP
HD
HD
, NO
S
LB
SNC
DL
BC
AL
CL
cases reviewed
476 NHL
373 HD
Thomas HodgkinThomas Hodgkin
Hodgkin’s DiseaseHodgkin’s DiseaseMixed cellularity
Nodular sclerosis
Lymphocyte depleted
Lymphocyte predominant
Reed Sternberg CellReed Sternberg Cell
R-S cells:H&E
Wright stainCD30
Incidence of HDIncidence of HD 3-7 per 100,0003-7 per 100,000 BimodalBimodal
– 15-34 & > 5515-34 & > 55 NS increasing in NS increasing in
young patientsyoung patients– young womenyoung women
LD decreasing in LD decreasing in older patientsolder patients
57.7
23.4
6 3.89.1
0
10
20
30
40
50
60
NS
MC
LP
LD
uncl
ass
Medeiros, Cancer 75:357,1995
Hodgkin’s DiseaseHodgkin’s Disease Reed-Sternberg (RS) cell in immunoproliferative backgroundReed-Sternberg (RS) cell in immunoproliferative background
– RS cells minorityRS cells minority
– backgroundbackground
» lymphocytes, eosinophils, plasma cells, histiocyteslymphocytes, eosinophils, plasma cells, histiocytes
– RS cells B-cells (90%) or T-cells (10%)RS cells B-cells (90%) or T-cells (10%) cervical LN or mediastinum; spread to thoracic para-aortic LN, spleen, cervical LN or mediastinum; spread to thoracic para-aortic LN, spleen,
liver, abdominal Para-aortic nodesliver, abdominal Para-aortic nodes Association with EBV: 96% MC, 34% NS, 10% LPAssociation with EBV: 96% MC, 34% NS, 10% LP radiation for localized disease radiation for localized disease chemotherapy or chemo/RT for advanced diseasechemotherapy or chemo/RT for advanced disease
Mixed cellularity Hodgkin’s DiseaseMixed cellularity Hodgkin’s Disease
Diffuse infiltrate Diffuse infiltrate including relatively including relatively frequent RS cellsfrequent RS cells
CD15 and CD30 CD15 and CD30 antigen expressionantigen expression
classical HDclassical HD
Nodular Sclerosis Hodgkin’s DiseaseNodular Sclerosis Hodgkin’s Disease
RS cells and RS cells and “lacunar” cells in “lacunar” cells in clusters surrounded clusters surrounded by collagen fibrosisby collagen fibrosis
CD15 and CD30+CD15 and CD30+ Often mediastinal Often mediastinal
mass in young mass in young womenwomen
Lymphocyte depletion HDLymphocyte depletion HD Diffuse infiltrate Diffuse infiltrate
– numerous RS cells numerous RS cells and variants with and variants with relatively few relatively few lymphocyteslymphocytes
Often older men Often older men with advanced with advanced diseasedisease
Difficult to Difficult to distinguish from distinguish from large cell NHLlarge cell NHL
Lymphocyte predominant HDLymphocyte predominant HD Nodular or sometimes Nodular or sometimes
diffuse infiltrate diffuse infiltrate containing “L&H” containing “L&H” cells (for “lymphocytic cells (for “lymphocytic and histiocytic and histiocytic LPHD”)LPHD”)
label as polyclonal B-label as polyclonal B-cellscells
usually localized (often usually localized (often cervical LN)cervical LN)
indolent clinical courseindolent clinical course
Hodgkin’s diseaseHodgkin’s disease
Most cases derived from clonal B-cellsMost cases derived from clonal B-cells Heavy load of somatic mutationsHeavy load of somatic mutations Lack crippling mutations, but do not transcribe Lack crippling mutations, but do not transcribe
IgH due to functional regulatory defectsIgH due to functional regulatory defects HD and NHL have derived from same cloneHD and NHL have derived from same clone
Seitz, Blood. 2000 May 15;95(10):3020-4
Non-Hodgkin’s LymphomaNon-Hodgkin’s LymphomaSmall lymphocytic Mantle cell Burkitt Lymphoblastic
Follicular center cell Large B-cell Peripheral T-cell
Phenotype in diagnosis of NHLPhenotype in diagnosis of NHL
CD79a (B-cell)
CD45Ro (T-cell)
BCL-2
ALK-1
Incidence of NHL in US overallIncidence of NHL in US overall 7.4-17.1 per 100,0007.4-17.1 per 100,000 Males > femalesMales > females Racial differencesRacial differences
– whites more FLwhites more FL– blacks more PTCblacks more PTC
SL
FL
Dif B
HG
PTC
NOS
0
1
2
3
4
5
6
7
8
SL
Dif
B
PT
C
n per100K
Groves, JNCI, 92;1240-51, 2000
NHL in ChildrenNHL in Children 4.6-9.1 per million 4.6-9.1 per million
– white > blackwhite > black– male > femalemale > female
1/3-1/2 SNC, LB, LC1/3-1/2 SNC, LB, LC Geographic variationGeographic variation
– incidenceincidence– histologic typehistologic type– biology of Burkitt’sbiology of Burkitt’s
0
20
40
60
80
100
120
140
160
SNC
LB
DL
BC
AL
CL
n
Shad, Ped Clin NA 44:863-89, 1997
POG 1998-2000
Human B-cell lymphomasHuman B-cell lymphomas Sequencing of the variable region genes - Sequencing of the variable region genes -
somatically mutated in majority of non-somatically mutated in majority of non-Hodgkin’s and Hodgkin’s lymphomasHodgkin’s and Hodgkin’s lymphomas
this indicates germinal or post-germinal this indicates germinal or post-germinal center origincenter origin
unmutated variable region genes: mantle unmutated variable region genes: mantle lymphoma, some CLL’slymphoma, some CLL’s
Burkitt’s LymphomaBurkitt’s Lymphoma Medium size cellsMedium size cells
– nuclei same as histiocyte nucleinuclei same as histiocyte nuclei Oval nucleiOval nuclei
– 3-5 nucleoli, open chromatin3-5 nucleoli, open chromatin Basophilic (vacuolated) cytoplasm Basophilic (vacuolated) cytoplasm High mitotic rate, starry skyHigh mitotic rate, starry sky Mature B-cell, surface IG+, Mature B-cell, surface IG+,
analogous to L3 ALLanalogous to L3 ALL EBV in endemic areas and EBV in endemic areas and
immunosuppressionimmunosuppression
Large B-cell LymphomaLarge B-cell Lymphoma
Average nuclei larger than Average nuclei larger than histiocyte nucleihistiocyte nuclei
Mature B-lineage (CD20+)Mature B-lineage (CD20+) Morphologic heterogeneityMorphologic heterogeneity
– CentroblasticCentroblastic– Centroblastic/centrocyticCentroblastic/centrocytic– B-immunoblasticB-immunoblastic
BCL 6 or BCL2 BCL 6 or BCL2 overexpression in someoverexpression in some
Burkitt-Like LymphomaBurkitt-Like Lymphoma Mature B-cellMature B-cell Average cell medium size (like Average cell medium size (like
Burkitt)Burkitt) More variability than BurkittMore variability than Burkitt
– Nuclear sizeNuclear size
– Nuclear shapeNuclear shape
– Nucleolar prominenceNucleolar prominence
– Sometimes fine fibrosisSometimes fine fibrosis Interface between Burkitt & large Interface between Burkitt & large
B-cell lymphomaB-cell lymphoma
Small lymphocytic lymphoma/CLLSmall lymphocytic lymphoma/CLL slow growingslow growing diffuse infiltrate of diffuse infiltrate of
small lymphocytessmall lymphocytes admixed admixed
prolymphocytes; prolymphocytes; growth centersgrowth centers
often indolentoften indolent mature B-cell with mature B-cell with
CD5 expressionCD5 expression
SLL in childrenSLL in children Rare cases describedRare cases described t(2;14)(p13;q32) in severalt(2;14)(p13;q32) in several Citations:Citations:
– Fell, et al. Science 232:491-4, 1986Fell, et al. Science 232:491-4, 1986
– Yoffe, et al. J Pediatr 116:114-7, 1990Yoffe, et al. J Pediatr 116:114-7, 1990
– Ribeiro, et al. Leukemia 6:761-5, 1992Ribeiro, et al. Leukemia 6:761-5, 1992
Follicular lymphomasFollicular lymphomas One of the most One of the most
common NHLcommon NHL Mature B-cellMature B-cell Slow-growing, Slow-growing,
persistentpersistent t(14;18) with bcl-2 t(14;18) with bcl-2
overexpressionoverexpression graded by cell typegraded by cell type
Follicular Lymphoma in childrenFollicular Lymphoma in children 1% (17) of 1336 pediatric lymphomas1% (17) of 1336 pediatric lymphomas
– Ribeiro, et al. Leukemia 6:761-5, 1992Ribeiro, et al. Leukemia 6:761-5, 1992
usually mixed or large cell, usually mixed or large cell, lack bcl-2 or p52 abn; some testicularlack bcl-2 or p52 abn; some testicular generally good outcomegenerally good outcome
– those who fail progressed to DLBCLthose who fail progressed to DLBCL» Frizzera, Cancer 44:2218, 1979; Winberg, Cancer 48:2223, 1981Frizzera, Cancer 44:2218, 1979; Winberg, Cancer 48:2223, 1981» Pinto, Mod Pathol 3:308, 1990; Moertel, Cancer 75:182, 1995Pinto, Mod Pathol 3:308, 1990; Moertel, Cancer 75:182, 1995» Atra, Br J Haem 103:220, 1998; Finn, Cancer 85:1626, 1999Atra, Br J Haem 103:220, 1998; Finn, Cancer 85:1626, 1999
Marginal zone lymphomaMarginal zone lymphoma mature B-cellmature B-cell arises from splenic or arises from splenic or
mucosal mucosal (MALT)(MALT) marginal marginal zone cellszone cells– ““monocytoid” appearancemonocytoid” appearance
– Lymphoepithelial lesions Lymphoepithelial lesions in MALTin MALT
often indolentoften indolent– Gastric; H. pyloriGastric; H. pylori
Marginal Zone lymphoma in childrenMarginal Zone lymphoma in children Occasional (<1%) Occasional (<1%) GastricGastric
– associated with H. pyloriassociated with H. pylori– may resolve with tx of H. pylorimay resolve with tx of H. pylori
Many associated with HIVMany associated with HIV Salivary gland, lung, GISalivary gland, lung, GI
– Citations:Citations:» Teruya-Feldstein, AJSP 19:357, 1995; Blecker, Gastroent.109:973, 1995Teruya-Feldstein, AJSP 19:357, 1995; Blecker, Gastroent.109:973, 1995» Joshi, AJCP 107:592, 1997; Corr, J Ultrasound Med 16:615, 1997Joshi, AJCP 107:592, 1997; Corr, J Ultrasound Med 16:615, 1997» Berrebi, J Peds 133:290, 1998; Fukumoto Hihon Rinsho MGK 23:49, 2000Berrebi, J Peds 133:290, 1998; Fukumoto Hihon Rinsho MGK 23:49, 2000
Mantle cell lymphomaMantle cell lymphoma mature B-cellmature B-cell arises from follicular mantlearises from follicular mantle resembles SLL and MZLresembles SLL and MZL t(11;14) with cyclin-D1, CD5, t(11;14) with cyclin-D1, CD5,
(CD23-)(CD23-) expresses bcl-2 as do nl expresses bcl-2 as do nl
mantle cells; long-livedmantle cells; long-lived difficult to eradicate and difficult to eradicate and
aggressiveaggressiveResidual germinal center
Neoplastic mantle zone cells
T-cell lymphomasT-cell lymphomas Less common that B-cellLess common that B-cell Some associations with retrovirusesSome associations with retroviruses
– HTLV-1HTLV-1 Cytogenetic abnormalities variableCytogenetic abnormalities variable
– include chr. 14 abnormalitiesinclude chr. 14 abnormalities– t(2;5) and variants in ALCLt(2;5) and variants in ALCL
Generally difficult to eradicateGenerally difficult to eradicate
T-cell developmentT-cell development Maturation/selection in thymusMaturation/selection in thymus T-cell receptor gene rearrangementT-cell receptor gene rearrangement
– gamma/deltagamma/delta
– alpha/betaalpha/beta Tdt, CD7, CD5, CD2Tdt, CD7, CD5, CD2 CD1, CD4/CD8, CD3CD1, CD4/CD8, CD3 Mature cells CD4 or CD8 and CD3Mature cells CD4 or CD8 and CD3
Lymphoblastic LymphomaLymphoblastic Lymphoma Small cellsSmall cells
– nuclei smaller than histiocyte’snuclei smaller than histiocyte’s Diffuse chromatin, inconspicuous Diffuse chromatin, inconspicuous
nucleoli, often nuclear convolutionsnucleoli, often nuclear convolutions High mitotic rate, starry skyHigh mitotic rate, starry sky Precursor T-cellPrecursor T-cell
– T-zone distribution, infiltrativeT-zone distribution, infiltrative– Tdt, CD7, CD1, CD4/CD8Tdt, CD7, CD1, CD4/CD8
Rare precursor B-lineageRare precursor B-lineage
Anaplastic Large Cell LymphomaAnaplastic Large Cell Lymphoma Large cells with abundant Large cells with abundant
cytoplasmcytoplasm
– often indented or lobated often indented or lobated nucleinuclei
– LN sinus, paracortexLN sinus, paracortex CD30 expressionCD30 expression T or null phenotypeT or null phenotype t(2;5)t(2;5) ALK protein expressionALK protein expression
ALCL - CD30 and ALK expressionALCL - CD30 and ALK expression
CD30
ALK1
Most cases in children and young adults express ALK due to t(2;5) or variant translocation. Most cases over 35 are ALK negative
ALK-1 in recent LCLALK-1 in recent LCL
35
1
8
47
12
48
05
10
1520
2530
3540
4550
B-cell T/null CD30
ALK-ALK+
A majority of T or null LCL in children express CD30 and ALK
Non-anaplastic PTCLNon-anaplastic PTCL Diverse entitiesDiverse entities
– PTCL, NOS; angiocentric; nasal; T-PTCL, NOS; angiocentric; nasal; T-gamma; panniculitic; ATL; MF gamma; panniculitic; ATL; MF
Rare in childrenRare in children Likely worse than ALCLLikely worse than ALCL
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