diffuse aggressive b-cell lymphomas - lasop.com jonathan... · diffuse aggressive b-cell lymphomas...
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Diffuse Aggressive B-cell Lymphomas
Jonathan Said MDDavid Geffen School of
Medicine UCLA
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Diffuse Aggressive B-cell Lymphomas
• Diffuse Large B-cell lymphoma– Nucleus equal or
exceeding a normal macrophage nucleus or more than 2X the size of a small lymphocyte
• Burkitt Lymphoma- Nucleus slightly smaller than a histiocyte nucleus
37%
WHO2008
BL1%PMLB3%
DLBCL 37%
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Diffuse Large B-cell Lymphoma
• Most common histologic subtype (30% adult NHL in the west and higher in developing countries)
• Occur at any age including childhood, median 64 years
• Slightly more common in males• Marked histologic and biologic diversity• Spontaneously aggressive and even with
improved therapy 40% not cured
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DLBCL
• De Novo (primary)• Progression or transformation from:
– CLL/SLL (Richter’s syndrome)– Follicular lymphoma– NLPHL to TCRBCL or DLBCL– Marginal Zone Lymphoma
• Immunodeficiency is a risk factor and about 10% DLBCL are EBV+
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Progression of FL to DLBCL
• FL grade 3 with diffuse areas containing >15 Centroblasts/HPF warrants separate diagnosis of DLBCL
• Staining for dendritic cells (CD23/CD21+) may be essential to distinguish large or confluent follicles from DLBCL
CD23
CD23
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DLBCL Clinical Features
• Extranodal (>40%) (Stage I or II) or nodal rapidly enlarging mass.
• Stomach, ileocecal region, bone, testis, spleen, Waldeyer’s ring, salivary gland, thyroid, liver, kidney, adrenal
• Long term remission rate 50-60% improved with rituximab. Overall 5-yr survival 46%, failure free survival 41%
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Unfavorable Variables in DLBCL
• Age >60 years• Poor performance status (ECOG>2)• Advanced stage (III-IV)• Extranodal involvement >2 sites• High serum LDH
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Diffuse Aggressive B-cell Lymphomas Clinical Features
DLBCL (30%) Burkitt (3%) and B-Lymphoblastic (<1%)
Age Usually older but any age
Children, Young Adults
Growth rate Fast Very fast
Stage Even distribution (50% Stage 1 or 2)
Usually high stage
Blood or Marrow Involvement
Uncommon, Often Terminal
Common
CNS involvement Unusual- New WHO category DLBCL of the CNS
Common
Response to treatment
60-80% response Up to 85-95% response
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DLBCL Diagnosis Usually Easy:
• Sheets of large cells• B-cell phenotype • Small T-lymphocytes/histiocytes usually
present (but do not confuse with TCRBCL)
• Sclerosis may be prominent• Mitotic figures easily identified.
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But diagnosis may be Difficult When:
– Mimics other neoplasms, may be cohesive or involve sinusoids, mimicking carcinoma, melanoma
– Lacks CD20 (Plasmablastic, ALK+ DLBCL)– Shares aspects with other lymphomas, probably
due to common pathogenic pathways (Burkitt-like, Hodgkin-like, Grey zone lymphomas)
– Don’t look like DLBCL (T-cell/Histiocyte rich lymphomas or presence of RS cells especially EBV+ cases)
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Differential diagnosis
• Carcinoma• Germ cell tumor• Burkitt lymphoma variants• Blastoid mantle cell lymphoma• Granulocytic sarcoma
– Myeloperoxidase, lysozyme, CD43+
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Nasopharyngeal carcinoma resembling DLBCL
Keratin
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Neuroendocrine Carcinoma Mimicking DLBCL
Chromogranin
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Germ Cell Tumor Mimicking DLBCL
OCT3/4
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Bone marrow biopsy DLBCL?
Keratin
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DLBCL Immunophenotype• Pan B-cell markers CD19, D20, CD22, CD79a, PAX5• Surface/cytoplasmic Ig (IgM>IgG>IgA) in 50-75% of cases• CD30 variable, positive in anaplastic variant• Complete B-cell program including expression of OCT-2 and
BOB.1• Other markers
– CD10 40%– bcl-6 60%– BCL2 50% – CD43 20%– CD5 <10% – CD30+ 10%– MUM1 40%– P53 30%– Ki67 40-90%
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Aberrant phenotypes in DLBCL• Often lack one or more B-cell markers CD19, CD20, CD22,
CD79a• Co-expression of MUM1 and BCL6 (unlike normal germinal
centers)• BCL6+ without t(14;18)• CD3+ DLBCL• CD5+ DLBCL• Cyclin D1+ DLBCL
– Ehringer Am J Clin Pathol 2008 129-630: 231 cases of de novo DLBCL 4% cyclin D1+, CD5-
– Extra copies of cyclin D1 may be due to trisomy of CCND1/chromosome 11
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DLBCL Genetics• Clonal rearrangements of
immunoglobulin heavy and light chain genes
• Somatic hypermutations in the variable regions
• Most common genetic findings– 30% abnormalities in 3q27 involving BCL6– BCL2 t(14;18) 20%– MYC rearrangement 10%
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Common Molecular EventsBCL6 (3q27)ABC>GC
35-40% 3q27
BCL2 (18q21)GC
40% 14;18
C-MYC (8q24)GC
10% t(8;14)t(8;2)t(8;22)t(8;?)
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma
Subtypes• Other Lymphomas of Large B-cells• Borderline cases
– B-cell lymphomas unclassifiable
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DLBCL Not otherwise Specified (NOS) WHO 2008
• Common Morphologic variants– Centroblastic– Immunoblastic– Anaplastic
• Rare Morphologic variants– Spindle cell, signet ring cell, microvillous projections etc.
• Molecular subgroups– Germinal centre B-cell like (GCB)– Non-germinal centre B-cell like (non-GCB)
• Immunohistochemical subtypes– CD5+ DLBCL
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DLBCL NOS Centroblastic Variant
• Most common variant• Cells intermediate to large with round or oval
nuclei, vesicular chromatin, 2-4 nucleoli often at the nuclear membrane
• Moderate amphophilic to basophilic cytoplasm• May be monomorphic centroblasts or admixed
with immunoblasts• Nuclei may be multilobated especially
extranodal such as primary bone DLBCL
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CentroblasticMULTILOBATED
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DLBCL NOS Immunoblastic Variant
• >90% cells immunoblastic
• Centrally located nucleolus
• Basophilic or amphophilic cytoplasm
• May have plasmacytoid cytoplasm
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DLBCL NOS Anaplastic Variant
• Large round oval or polygonal cells with bizarre pleomorphic nuclei
• May resemble Hodgkin or RS cells• May resemble ALCL• May show sinusoidal and/or cohesive
growth pattern• May mimic undifferentiated carcinoma• No related to T/NK cell ALCL or ALK-
positive LBCL
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DLBCL NOS Anaplastic Variant
CD20
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Rare Variants Signet Ring Cell DLBCL
CD20 CD10
Cancer52:16131983
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DLBCL Marrow Involvement• Marrow involvement 16%
– Concordant (Large cell lymphoma) associated with poor outcome (5 year survival 10%)
– Low grade lymphoma (discordant histology more common, similar outcome to negative marrow, but more frequent relapse, 5 year survival 62%)
– 30% of patients with BM disease have circulating cells
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DLBCL Concordant Marrow Involvement
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DLBCL BM Aspirate
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CD20
BM Infiltration by Single Cells
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DLBCL Not otherwise Specified (NOS) WHO 2008
• Common Morphologic variants– Centroblastic– Immunoblastic– Anaplastic
• Rare Morphologic variants– Spindle cell, signet ring cell, microvillous projections etc.
• Molecular subgroups– Germinal centre B-cell like (GCB)– Non-germinal centre B-cell like (non-GCB)
• Immunohistochemical subtypes– CD5+ DLBCL– Germinal centre B-cell like– Non-germinal centre B-cell like
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Gene Expression Profiling in DLBCL (Alizadeh et al, Nature 2000)
• Germinal Center B-cell (GCB) with signature of germinal center B-cells (50% cases)
• Activated B-cell (ABC)
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BCL2
Bcl-6 CD10
DLBCL GCB Signature
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DLBCL Activated signature (ABC)
• DLBCL with ‘activated’ gene profiles similar to those induced by in-vitro activation of peripheral blood B-cells by gene expression profiling have adverse prognosis
• Immunohistochemical markers include Mum-1 (IRF4), CD138
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DLBCL ‘Activated Signature’
MUM-1
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Sub grouping DLBCL NOS by Immunophenotype (Hans Classifier)
CD10
MUM1
BCL6
GCB CD10+>30% cells
GCB CD10-, BCL6+, MUM1-
NON-GC MUM1+
NON-GCB
-
+
- +
+
-
Blood, 103:275-82, 2004
FOXP1
LMO2
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DLBCL Not otherwise Specified (NOS) WHO 2008
• Common Morphologic variants– Centroblastic– Immunoblastic– Anaplastic
• Rare Morphologic variants– Spindle cell, signet ring cell, microvillous projections etc.
• Molecular subgroups– Germinal centre B-cell like (GCB)– Non-germinal centre B-cell like (non-GCB)
• Immunohistochemical subtypes– CD5+ DLBC
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CD5+ DLBCL• Higher age distribution (mean 66 yrs)• Female predominance• Advanced disease• B symptoms• Aggressive clinical course• Likely arise from the same progenitor cell as the
mutated variant of CD5+ SLL/CLL cell (Am J Clin Pathol 101:699-702, 2003)
• Arise de novo without prior history of CLL or MCL• Distinguish from blastoid MCL by absent cyclin D1• Blood 99:815-821, 2002
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CD5+ DLBCL
CD5
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Summary : DLBCL- Role of Immunohistochemistry
• Follicular signature characterized by CD10+, BCL6+/-• Activated B-cell signature CD10-, BCL6-/+, BCL2+/-
MUM1 (IRF4)+• Expression of BCL2 protein by DLBCL implies a worse
prognosis even in the rituximab era• Activated phenotype MUM1+ correlates with worse
prognosis and ABC signature• Identify unique variants
– plasmablastic lymphoma (lack Pax5, express CD138)– ALK+– CD5+ DLBCL
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes
– T-cell/histiocyte rich DLBCL– Primary DLBCL of the CNS– Primary cutaneous DLBCL Leg type– EBV positive DLBCL of the elderly
• Other Lymphomas of Large B-cells– Primary mediastinal (thymic) LBCL– Intravascular LBCL– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK-positive LBCL– Plasmablastic Lymphoma– Large B-cell lymphoma arising in HHV8+ MCD– Primary Effusion Lymphoma
• Borderline cases– B-cell lymphomas unclassifiable
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T-cell rich B-cell lymphoma
• Morphologic variant of DLBCL with minor component of large malignant B-cells in a T-cell/histiocyte rich background
• Large cells may be RS-like, centroblast/immunoblast like, or resemble L&H cells. May be confused with Hodgkin lymphoma particularly LPHL or lymphocyte rich Classical Hodgkin lymphoma
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T-cell Rich B-cell Lymphoma Clinical
• <10% DLBCL • Age range 12-61 years• Predominantly males (3-4 to 1)• Mainly high stage III or IV• Involves lymph nodes• Bone marrow, liver, spleen involved at
diagnosis in up to 60% of cases• Refractory to therapy
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T-cell Rich B-cell Lymphoma-Histology
• Diffuse effacement of nodal architecture• Tumor cells evenly dispersed within clusters
of bland histiocytes and small T-cells• Eosinophils or plasma cells not present• Large cells positive for B-cell markers, BCL6,
negative for CD15, CD30, EBV• Clonally rearranged IG genes carrying somatic
mutations, resemble germinal center B-cells
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TCRBCL Spleen
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CD2
Bcl-6 Ki67
T-cell Rich B-cell Lymphoma
CD20
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes
– T-cell/histiocyte rich DLBCL– Primary DLBCL of the CNS– Primary cutaneous DLBCL Leg type– EBV positive DLBCL of the elderly
• Other Lymphomas of Large B-cells– Primary mediastinal (thymic) LBCL– Intravascular LBCL– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK-positive LBCL– Plasmablastic Lymphoma– Large B-cell lymphoma arising in HHV8+ MCD– Primary Effusion Lymphoma
• Borderline cases– B-cell lymphomas unclassifiable
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Primary DLBCL of the CNS• Primary intracerebral or intraocular lymphoma• Lymphomas of the dura, intravascular
lymphoma, secondary lymphomas, immunodeficiency lymphomas excluded
• <1% of NHL• Most common in older males >60• Multiple lesions in about 30%• 25 year survival 40-75% (Blood 113:7, 2009)
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Primary DLBCL of the CNS
• Tumor cells in perivascular space• Mostly resemble centroblasts• May be intermixed with reactive small
lymphocytes, macrophages, active microglial cells, reactive astrocytes
• Necrosis frequent• Positive for pan B-cell markers, BCL6,
MUM1, negative for CD10, CD138
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Primary DLBCL of the CNS
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Primary DLBCL of the CNS: Just DLBCL or not?
• Poor prognosis compared with extracerebral DLBCL
• Histogenesis of the tumor cells?• Transforming event?• Role of the microenvironment?• Blood 113:7-10, 2008
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes
– T-cell/histiocyte rich DLBCL– Primary DLBCL of the CNS– Primary cutaneous DLBCL Leg type– EBV positive DLBCL of the elderly
• Other Lymphomas of Large B-cells– Primary mediastinal (thymic) LBCL– Intravascular LBCL– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK-positive LBCL– Plasmablastic Lymphoma– Large B-cell lymphoma arising in HHV8+ MCD– Primary Effusion Lymphoma
• Borderline cases– B-cell lymphomas unclassifiable
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Diffuse large B-cell lymphoma ‘leg type’
• Mostly in elderly females, mostly but not always on the lower legs
• Sheets of centroblasts and immunoblasts with round cell morphology and frequent mitoses
• BCL-2+ (unlike cutaneous follicular lymphoma), BCL6+, Mum1/IRF4+, CD10-
• 50% five year survival
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DLBCL Leg Type
MUM1
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes
– T-cell/histiocyte rich DLBCL– Primary DLBCL of the CNS– Primary cutaneous DLBCL Leg type– EBV positive DLBCL of the elderly
• Other Lymphomas of Large B-cells– Primary mediastinal (thymic) LBCL– Intravascular LBCL– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK-positive LBCL– Plasmablastic Lymphoma– Large B-cell lymphoma arising in HHV8+ MCD– Primary Effusion Lymphoma
• Borderline cases– B-cell lymphomas unclassifiable
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EBV+ DLBCL of the Elderly• Previously called senile associated• Defined as a clonal EBV+ large cell lymphoma• WHO definition of elderly is >50, median age 70. • No known cause for immunodeficiency or prior
lymphoma. Related to senescence of the immune system.
• Rare cases in young patients but need to rule out an undiagnosed immunodeficiency
• Must exclude other EBV related LPD (lyg, mono, PEL etc).
• EBV in malignant cells, not bystanders. EBER+, LMP1+, EBNA2+
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EBV+ DLBCL of the Elderly Clinical Features:
• 70% extranodal including skin, lung, tonsil, stomach, 30% nodal alone
• 50% have high IPI and prognosis is inferior to EBV- DLBCL even if adjusted for age
• More refractory to initial therapy (CR 66%) and poor overall survival (2 years or less)
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EBV+ DLBCL of the Elderly
• Histology varies from polymorphous to monomorphous• Polymorphous cases similar to PTLD• Geographical necrosis and RS-like cells common• Variable component of reactive
lymphocytes/histiocytes• Most cases CD20+, CD79a+, MUM1+, CD10-, BCL6-,
monoclonal• H-RS cells EBV+ (LMP1 and EBNA2), CD20+, CD30+
75%, CD15-• Clonal by molecular genetics – may help distinguish
from infectious mononucleosis of the elderly
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EBV+ DLBCL of the Elderly
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EBV+ DLBCL of the Elderly
EBER
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes
– T-cell/histiocyte rich DLBCL– Primary DLBCL of the CNS– Primary cutaneous DLBCL Leg type– EBV positive DLBCL of the elderly
• Other Lymphomas of Large B-cells– Primary mediastinal (thymic) LBCL– Intravascular LBCL– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK-positive LBCL– Plasmablastic Lymphoma– Large B-cell lymphoma arising in HHV8+ MCD– Primary Effusion Lymphoma
• Borderline cases– B-cell lymphomas unclassifiable
PMLB3%
DLBCL 37%
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Primary Mediastinal (Thymic) LBCL
• DLBCL arising in the mediastinum from thymic B-cell• 2-4% NHL• Young adults (median 35 years), female predominance• May present with SVC obstruction, dyspnea• Often bulky disease >10cm• Most have stage I/II disease• Marrow involvement rare (3%)• Aggressive, but more favorable prognosis than
previously thought with intensive chemo +/- radiation therapy (CR rate 80%, plateau beyond 2 yrs.)
• Relapse in unusual sites (GIT, kidney, adrenal, CNS)
DLBCL 37%
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Primary Mediastinal DLBCL -Pathology
• Common histologic features but not required for diagnosis– Sheets of large B-cell with clear cytoplasm– Usually round or oval, can be multilobated– Prominent sclerosis (broad bands,
compartmentalizing, interstitial)• Distinct immunophenotype
– Immunoglobulin negative,– CD30+ in 80%, usually weak, heterogeneous – CD23+ in 70% of cases– MAL+ in 70%
• Immunoglobulins rearranged with somatic hypermutations.
• Lack BCL2, BCL6, or MYC rearrangement
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Primary Mediastinal DLBCL
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CD20CD20
Primary Mediastinal DLBCL
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes
– T-cell/histiocyte rich DLBCL– Primary DLBCL of the CNS– Primary cutaneous DLBCL Leg type– EBV positive DLBCL of the elderly
• Other Lymphomas of Large B-cells– Primary mediastinal (thymic) LBCL– Intravascular LBCL– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK-positive LBCL– Plasmablastic Lymphoma– Large B-cell lymphoma arising in HHV8+ MCD– Primary Effusion Lymphoma
• Borderline cases– B-cell lymphomas unclassifiable
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Intravascular LBCL
• Synonymous terms: Angiotropic Large Cell lymphoma
• Multifocal, selective growth within lumina of capillaries
• Any organ affected, usually disseminated including marrow
• Lymph nodes usually uninvolved
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Clinical features• Average age 65 (range 34-85), slight male
predominance.• Present with weight loss, FUO, malaise and signs and
symptoms related to occlusion of small vessels in various organs, most often the CNS and skin.
• Isolated cutaneous variant more in females• Skin lesions include tender erythematous nodules,
tumors, telangiectasia, cellulitis, lymphedema.• Neurologic conditions include infarcts, dementia,
polyneuropathy, myalgia.
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Intravascular LBCL Phenotype
• 85-91% B-cells• Rare T-cell and NK cell variants• Bcl-2+, CD43+• Variable CD5, CD10, MUM1.• 20-25% express bcl-6• Asian variant can be CD5+
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CD20
Intravascular LBCLLarge cells with prominent nucleoliMay have fibrin thrombi, hemorrhage and necrosis
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CD20 CD20
Bone marrow Intravascular LBCL
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes
– T-cell/histiocyte rich DLBCL– Primary DLBCL of the CNS– Primary cutaneous DLBCL Leg type– EBV positive DLBCL of the elderly
• Other Lymphomas of Large B-cells– Primary mediastinal (thymic) LBCL– Intravascular LBCL– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK-positive LBCL– Plasmablastic Lymphoma– Large B-cell lymphoma arising in HHV8+ MCD– Primary Effusion Lymphoma
• Borderline cases– B-cell lymphomas unclassifiable
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Plasmablastic Lymphoma• Diffuse proliferation of large cells which resemble B-
immunoblasts or plasmablasts, and have the phenotype of plasma cells.
• First described in the oral cavity but may occur in other, predominantly extranodal sites including nasal sinuses, skin, soft tissue, GIT
• Usually males, median age 40 • Aggressive clinical course. • Highest association with HIV but can occur with
other immunodeficiencies including PTLD and the elderly. Some cases no history of immunodeficiency.
• Cases not associated with HIV more common in lymph nodes. Most are stage IV at diagnosis.
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Plasmablastic lymphoma Phenotype
• Majority are EBV+, KSHV-/+.• Frequent MYC/IgH rearrangements • Immunophenotype
– Weak CD45+, CD20-/+, Pax 5-/+ – CD79a+ in 50-85% cases.– CD38+, CD138+, MUM1+, EMA+
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Plasmablastic lymphoma
MUM1EMA
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Plasmablastic Lymphoma Subtypes
• Oral mucosa type– Minimal plasmacytic Differentiation– Often associated with HIV– Usually extranodal, may involve lymph nodes
• PBL with plasmacytic Differentiation– Plasmablastic appearance– May be indistinguishable from plasmacytoma/myeloma,
clinical history important• Differential includes HHV-8 Associated lymphomas
(PEL, extracavitary PEL, Multicentric Castleman’s) and plasmablastic myeloma). If HHV-8+ considered form of PEL not plasmablastic lymphoma.
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Plasmablastic Lymphoma Oral Cavity Type
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Plasmablastic lymphoma Plasmacytic
Differential from extramedullary plasmablastic myeloma requires clinical historyEBV+ in most PBL, only occasionally in myelomaMyeloma more often CD56+, cyclinD1+
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes• Other Lymphomas of Large B-cells
– Primary mediastinal (thymic) large B-cell lymphoma– Intravascular large B-cell lymphoma– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK positive LBCL– Plasmablastic lymphoma– Large B-cell lymphoma arising in HHV8-associated
multicentric Castleman disease– Primary effusion lymphoma
• Borderline cases
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ALK+ Diffuse Large B-cell Lymphoma
• ALK-positive DLBCL often have immunoblastic or plasmablastic morphology and involve subcapsular sinuses of lymph nodes.
• M:F 3:1, occurs at all ages median 36yrs
• Immunocompetent EBV-, KSHV-• CD30-, CD57+, EMA+, CD138+,
CD79a+/-, CD20-, cIgA+ • Present with generalized
lymphadenopathy and advanced stage. Often extranodal: skin, bone, brain
• 3 year survival 30%
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CD79aALK
ALK+ DLBCL
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ALK+ DLBCL• Most cases show
t(2;17)(p23;q23) with fusion of ALK and clathrin gene leading to cytoplasmic granular staining for ALK
• Rare cases show t(2;5) with NPM/ALK nuclear and cytoplasmic staining
• Must distinguish from systemic ALCL which are T/NK cell neoplasms
• ?ALK activation in B-cells turns on the plasma cell differentiation program
CD
3
CD7
CD
2
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes
– T-cell/histiocyte rich DLBCL– Primary DLBCL of the CNS– Primary cutaneous DLBCL Leg type– EBV positive DLBCL of the elderly
• Other Lymphomas of Large B-cells– Primary mediastinal (thymic) LBCL– Intravascular LBCL– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK-positive LBCL– Plasmablastic Lymphoma– Large B-cell lymphoma arising in HHV8+ MCD– Primary Effusion Lymphoma
• Borderline cases– B-cell lymphomas unclassifiable
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Lymphomatoid granulomatosis• Angiocentric angiodestructive lymphoproliferative
disease involving extranodal sites, composed of EBV+ B-cells admixed with reactive T-cells which usually predominate
• More common in adult males• Prototype: Pulmonary involvement (bilateral peripheral
lung nodules, solitary mass, or diffuse infiltrate)• Other sites: skin, CNS, kidney, liver• Importance of recognition: Early lesions Grade 1 or 2
may wax and wane respond to interferon alpha. Grade 3 aggressive regimens with rituximab
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Lymphomatoid Granulomatosis• Pulmonary nodules vary in size, often bilateral• Histologic triad:
– Atypical polymorphous lymphoid infiltrate often with a granuloma-like appearance
– Angiocentric and angiodestructive– Prominent geographic necrosis
• Confirmation of diagnosis:– CD20+ large cells, CD3+ reactive small cells– ISH for EBER and immunostain for EBV LMP1– Most Grade 2/3 cases have Ig gene
rearrangements
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Lymphomatoid Granulomatosis Grading
Grade I
PolymorphousNo atypia
Sparse EBV+ cells
Grade 2
Polymorphous
Scattered large EBV+ cells 5-20
Grade 3
Large cells form aggregates
>50 EBV+ cells/HPF
Worsening prognosis with increased large EBV+ cells, increasing necrosis, clusters of large cells
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CD20
EBV EBER EBV LMP
Lymphomatoid GranulomatosisImmunohistochemistry
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DLBCL Variants, Subgroups, and Subtypes /Entities (WHO 2008)
• Diffuse Large B-cell Lymphoma NOS• Diffuse Large B-cell Lymphoma Subtypes• Other Lymphomas of Large B-cells
– Primary mediastinal (thymic) large B-cell lymphoma– Intravascular large B-cell lymphoma– DLBCL associated with chronic inflammation– Lymphomatoid granulomatosis– ALK positive LBCL– Plasmablastic lymphoma– Large B-cell lymphoma arising in HHV8-associated
multicentric Castleman disease– Primary effusion lymphoma
• Borderline cases
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Primary Effusion Lymphoma• Serous effusion in the absence of a tumor
mass• Rarely present with or develop solid tumors• Express CD45, negative for B-cell markers
despite immunoglobulin gene rearrangements.• Express activation antigens CD30, CD38,
CD138• EBER+, EBV LMP-, HHV8 demonstrated by
LANA stain.
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Primary Effusion Lymphoma (PEL)
HHV8 LANA
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Summary DLBCL• Becoming more complicated – many
subcategories in WHO-2008• Heterogeneous in morphology and response to
therapy• Still limited treatment options (R-CHOP) but
worth identifying subtypes with more aggressive clinical course
• New therapeutic options, EPOCH-R, BMT, CNS prophylaxis for aggressive subtypes.
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Burkitt LymphomaBL1%
PMLB3%
DLBCL 37%
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Burkitt lymphoma• Monomorphic medium sized transformed B-
cells with round nuclei, clumped chromatin, basophilic cytoplasm, squared off cell borders, cytoplasmic vacuoles, medium sized paracentral nucleoli, starry sky pattern
• Translocation involving MYC characteristic but not specific or always identified
• No single parameter is gold standard; morphology, genetic immunophenotype, expression profiles
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Burkitt Lymphoma Clinical Features
• 1-2% in USA• 30-50% childhood lymphomas• Median age adult 30 yrs• Majority present as abdominal mass with
ileocecal and other organ involvement. May present as acute leukemia
• Bone marrow involvement at presentation uncommon with exception of HIV
• Usually treated with aggressive therapy (Hyper CVAD or related regimen plus CNS prophylaxis)
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BURKITT LYMPHOMA – Clinical Variants
• Endemic– Equatorial Africa– Strong association with EBV 95%– Commonly in children, affects jaws, gonads, kidneys
• Sporadic– EBV in about 40%– Children and young adults– Involves terminal ileum and Waldeyer’s ring– Marrow involvement more common than in the endemic form
• AIDS-associated– Associated with HIV with relatively high CD4 counts– More frequent nodal and BM localization
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Burkitt Lymphoma Morphology
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BL Marrow/Peripheral blood
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Burkitt lymphoma phenotype/genotype
• Germinal centre phenotype expressing IgM+, CD10+, BCL2-, TdT-, BCL6+, Ki67 100%
• Few reactive CD3+ T-cells• IgM+, Immunoglobulin genes hypermutated
but no class switch• Documentation of MYC translocation highly
desirable but no essential for diagnosis• 30% p53 positive
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CD20CD20
KiKi--6767
IGH/MYC
Phenotype Burkitt Lymphoma
TCL1
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Diagnosis of Burkitt lymphoma usually easy but sometimes difficult because:
• Rarely BL may be negative for BCL-6; BCL6 gets down regulated by EBV
• About 20% BL may be BCL2 weakly positive• Aberrant phenotypes occur including CD4+ BL• BL may be positive for MUM1 (up to 50%)• May get pleomorphism following therapy• May have overlapping features with DLBCL
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MYC translocations in Burkitt Lymphoma
• t(8;14) in 90%• t(8;2) or t(8;22) in 10-15%• Occasionally other translocation
partners may be missed with break apart probes so appear MYC negative in about 10% of cases.
• Helpful clue: Karyotype simple in BL, few additional abnormalities other than MYC (cf. MYC+ DLBCL)
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MYC break apart Probe for Interphase FISH
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Atypical BL (WHO 2001)
• WHO 2001 defined atypical BL cells with large central single nucleoli and more pronounced variation in size and shape
• Category eliminated for WHO 2008
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AIDS-Associated Burkitt Lymphoma
• EBV association 40%• 30% of NHL in AIDS• Young adults with relatively high CD4+
counts• Lymph nodes as well as extranodal sites,
marrow, GIT• Often has an ‘atypical’ or plasmacytoid
appearance
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Overlapping features BL vs DLBCL
• DBCL proliferation rate can approach 100% with frequent apoptotic bodies and/or starry sky macrophages.
• BL may have admixed larger cells, and DLBCL may have medium-sized cells
• C-MYC translocation is hallmark of BL but may occur in DLBCL.
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Burkitt vs DLBCL• Using gene expression profiling as the ‘gold standard’ expert
pathologists misdiagnosed BL as DLBCL or High Grade B-cell lymphoma unclassifiable.
Hummel M. et al. N Engl J Med 354:2419,2006
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Aggressive B-cell lymphomas take home messages:
• Usually an easy diagnosis, if it looks like DLBCL or BL it probably is.
• Atypical BL or Burkitt-like lymphoma no longer used by WHO 2008
• Remember to exclude “look alikes” including carcinoma, granulocytic sarcoma
• Don’t be confused by phenotypic heterogeneity• Use molecular studies as adjuncts to diagnosis but
trust the microscope• Work with your oncologists, clinical information is
important• You can help clinicians and patients by pointing the
way to appropriate therapy for aggressive subtypes
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