hodgkin lymphoma and differential diagnosis - pathcme.com · classic hodgkin lymphoma •...
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Hodgkin Lymphoma and Differential Diagnosis
Lawrence M. Weiss, M.D.NeoGenomics
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Hodgkin Lymphoma: Historical Classifications
Jackson-Parker Lukes Rye
Paragranuloma Lymphocytic and histiocytic Lymphocyte predominancenodular or diffuse
Nodular sclerosis Nodular sclerosis
Granuloma Mixed cellularity Mixed cellularityDiffuse fibrosis
Sarcoma Reticular Lymphocyte depletion
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Hodgkin Lymphoma: Modern Classification
• Nodular lymphocyte predominance• Classic(al)
– Nodular sclerosis– Mixed cellularity– Lymphocyte-depleted– Lymphocyte-rich
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Classic Hodgkin Lymphoma• Monoclonal neoplasm of B-cells of the germinal
center that have ineffective immunoglobulin receptors but have somehow escaped the normal apoptotic process that culls these cells
• Unique histology influenced by cytokine-ligand interactions
• 95% of Hodgkin lymphoma• Male predominance with bimodal peak in young
adulthood and old age• 40% of cases associated with EBV in Western
countries; higher in developing countries
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Classic Hodgkin Lymphoma: Pathology
• Diagnosis established by the identification of Reed-Sternberg cells and variants in the appropriate milieu
• Reed-Sternberg cell: Multi-nucleate or multilobate large cell with each nucleus or lobe containing a prominent eosinophilic nucleolus with a modest rim of amphiphilic cytoplasm
• Hodgkin cell: Mononucleate cell with features similar to R-S cell
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Phenotype of Classic Hodgkin Cells in Paraffin Sections: Primary Panel
• CD45 (<5% +)
• CD30 (99% +)
• CD15 (65-85% +)
• CD20 (20% +, variable)
• PAX-5 (95% +, moderate)
• CD3 (<5% +)
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CD45CD45 CHL CD45 NHLPHL
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CD20 CHL CD20 NLPHL
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CD30/CHL
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PAX5PAX5PAX5 CHL
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Phenotype of Classic Hodgkin Cells : Additional Antibodies
• BOB.1/OCT-2/CD79a (15% +)• MUM-1 (98% +)• Fascin (90% +)• EBV LMP-1 (30-40% +)• BCL-6 (40% +)• CD138 (30% +)• EMA (<5% +)• Cytotoxic markers (<5% +)• ALK (0%)• CD43 and other T-cell markers (?1%)
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MUM1 CHL
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EBV-LMP CHL
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? Classic Hodgkin Lymphoma: Expanded Panel
• T-cell and cytotoxic markers, ALK (HL vs. ALCL)
• BOB-1, OCT-2, CD79a, MUM-1 (CHL vs. T/HRBCL or NLPHL)
• LMP-1 (CHL vs. other, particularly in children and elderly)
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Prognostic Significance of Immunohistochemical Markers in cHL
• Worse prognosis– CD68+ host cells
– CD20+ H/RS cells
– CD15- H/RS cells
– BCL2+ H/RS cells
– Low FOXP3 expression in H/RS cells
– EBV+ in patients older than 60
– EBV- in patients younger than 15
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Survival & EBV in Classic HL*Older Adults – Ages 45 to 96 Years
*J Clin Oncol 2005;23:7604-7613
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*J Clin Oncol 2013;31:692-700
GEP Predictor of Survival in Paraffin-Embedded Tissue in Advanced cHL
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Nodular Sclerosis Classic Hodgkin Lymphoma: BLNI Grading
• Grade II if:– >25% nodules show reticular or
pleomorphic lymphocyte depletion– >80% of the nodules show fibrohistiocytic
lymphocyte depletion– >25% nodules contain bizarre and highly
anaplastic Hodgkin cells with lymphocyte depletion
• Grade I: All other cases
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Survival of NS: Grade I vs. II*
*Cancer 1994;74:708-714
211 patients43 patients
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NS: Grading (GHSG)Pathologic Risk Criteria
• Eosinophilia• ~ >5% of All Cells or• Clusters in 5 HPF
• Lymphocyte Depletion• <33% of All Cells In Whole Section
• Atypia• >25% Bizarre & Anaplastic H/RS Cells
High Risk = 1 or More Risk Factors
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Survival of NS: Low vs. High Risk*
*Blood 2003;101:4063-4069
(Eosinophilia, LD, Atypia)
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Survival of NS: Low vs. High Risk*
*Blood 2003;101:4063-4069
(Eosinophilia, LD, Atypia)
Prognostically Relevant Only in Intermediate & Advanced Stage
Disease
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Nodular Sclerosis Classic Hodgkin Lymphoma: Differential Diagnosis
• Carcinoma (keratin)• Melanoma (S-100)• Germ cell tumor (OCT4, SALL4)• Non-Hodgkin lymphoma (CD45, CD20, CD3,
PAX-5, CD30, CD15)• Necrotizing granulomatous lymphadenitis
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Keratin
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OCT 4OCT-4
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Cat Scratch
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CD15PMBCL
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Gene Expression: HL & PMBL*
*Blood 2012;120:4609-4620
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B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between DLBCL
and Classic Hodgkin Lymphoma• Lymphoma with morphologic, phenotypic, and molecular
features overlapping DLBCL, particularly PMBCL and HL• Rare; usually young adults 20-40 years, with a male
predominance• Mediastinal mass most common, often with
supraclavicular LNs; may involve only lymph nodes• May occur sequentially, usually CHL followed by DLBCL• Usually EBV –• Poor outcome, worse than either CHL or PMBL; usually
treated as DLBCL, but still does not respond well
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B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between DLBCL
and Classic HD: Histopathology• Usually see confluent, sheet-like growth, often in
a diffusely fibrotic stroma; may see fibrous bands• Cells are large and pleomorphic; may resemble
RS/H cells; may resemble DLBCL cells• May see variation from field to field• May see a cohesive or sinusoidal growth pattern
focally• Inflammatory infiltrate is often sparse
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B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between DLBCL
and Classic HL: Immunophenotype
• CD30+, CD15 +/-• CD45 +/-, CD20 +/-• CD79a, PAX5, OCT-2 and BOB.1 +/-• Bcl-6, CD10 -/+• CD43, ALK, cytotoxic markers –• Clonal gene rearrangements in the few cases
studied
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Gene Expression: NS & MC*
*Br J Cancer 2009:101:1393-1401
GenesMC: Regulated by Interferon –Inflammation
NS: Extracellular Matrix Remodeling –Deposition of Fibroblasts
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Mixed Cellularity Classic Hodgkin Lymphoma: Differential Diagnosis
• T-cell/histiocyte-rich B cell lymphoma• Peripheral T-cell lymphoma, nos
– With R-S like cells• ALK+ anaplastic large cell lymphoma
– With lymphohistiocytic features• Reactive paracortical hyperplasia
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THRBCL
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Mixed Cellularity Hodgkin Lymphoma vs. T-cell/Histiocyte-Rich B-Cell Lymphoma
MCHL (%) T/HRBCL (%)CD30 100 5CD15 65-85 1CD45 <5 98CD20 20-50 99EBV-LMP 30-40 1PAX-5 90 (weak) 98 (strong)BOB1/OCT-2CD79a
15/15/15 95/95/95
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CD45/THRBCL
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CD20/THCRBCL
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PAX-5/THRBCL
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PTCL
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PTCL
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PTCL, Lennert Variant
PTCL, lymphoepithelioid
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Lennert Lymphoma:Review of 98 Epithelioid Cell-Rich Lymphomas From Kiel Registry*
• B-Cell (DLBCL, T/HRBCL) 25 26%• Hodgkin (Classic, NLP) 21 22• AITL 16 16• PTCL, NOS (TFH) 9 9• Lennert 8 8• AITL/NOS (Borderline) 7 7• Reactive 2 2• ALCL, ALK– 1 1
*Histopathology 2011;58:1173-1182
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Mixed Cellularity Hodgkin Lymphoma vs. Peripheral T-Cell Lymphoma
MCHL (%) PTCL (%)CD30 100 Variable
CD15 85 <5
CD45 <5 98
CD3, other T <5 98
PAX-5 90 <5
EBV-LMP 30-40 1
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CD3/PTCL
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CD30
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ALK/ALCL
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Infect Mono
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RPH CD30
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Lymphocyte Depletion Classic Hodgkin Lymphoma
• L & C: Diffuse fibrosis and reticular types
• Elderly, HIV +, and third world countries
• Presents with abdominal nodes, spleen, liver, and bone marrow involvement
• Response to treatment typical for HL
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CD68
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Lymphocyte Depletion Hodgkin Lymphoma:
Differential Diagnosis• Non-Hodgkin Lymphoma
– Diffuse large B-cell lymphoma, NOS• CD45, CD20, CD79a, OCT-2, BOB.1, CD30,
CD15, CD138– Anaplastic Large Cell Lymphoma
• CD45, PAX-5, CD3, CD43, CD30, CD15, EBV-LMP, EMA, cytotoxic markers, ALK
• Sarcoma (pleomorphic)• CD15, CD30
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Classic Hodgkin Lymphoma vs. Anaplastic Large Cell Lymphoma
CHL (%) ALCL (%)CD30 100 100CD15 85 5-10CD45/CD43 <5 66CD20 20-50 <1EBV-LMP 30-40 <1PAX-5 90 (weak) <5Cytotoxic <5 95ALK 0 40
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Lymphocyte-Rich Classic Hodgkin Lymphoma
• Diffuse or nodular
• Diffuse histologically similar to MC with few Hodgkin cells; may be few eosinophils and plasma cells
• Nodular often histologically similar to nodular LP type
• immunohistochemistry similar to MC, but may have higher incidence of CD79a, OCT-2, and BOB.1 expression
• Associated with EBV
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CD30 LRHL
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Lymphocyte Rich Hodgkin Lymphoma: Differential Diagnosis
• Nodular L & H lymphocyte predominance
– CD45, CD20, CD30, CD15, CD57/PD1, MUM-1
• SLL/CLL
– CD20, CD43, CD45, CD5, CD23, CD15, CD30, EBV-LMP-1
• Reactive paracortical hyperplasia
– CD20, CD43, CD15, CD30, EBV-LMP-1
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HL Arising in CLL* • “Richter-Type” Transformation
• Rare! [18/4121 Cases of CLL – 0.4% MDA][26/3887 Cases of CLL – 0.7% Mayo]
• Discrete or Intermixed• Phenotype of Classic HL
• CD20 +/–• EBV+ ~90%• Clonal Identity ~50% (Microdissection)• Fludarabine Related• Poor Prognosis – Median OS 0.8 Years (MDA)
Median OS 3.9 Years (Mayo)*Cancer 2006:107:1294-1302; Am J Hematol 2015;90:334-338
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CLLRS
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CD20
CD5
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CD15 Fascin
EBVCD30
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Synchronous HL & NHL• Composite or Discordant
• CLL/SLL• Follicular Lymphoma• Mantle Cell Lymphoma• Marginal Zone Lymphoma• Large B Cell Lymphoma
• Discrete or Intermixed• EBV+ (~50% in MZL & LBCL)
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HL – Post XRT
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HL – Post XRT
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NS + Foamy Macrophages
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Histology of Relapse• Untreated Site*
• Histologic Persistence 46/52 (89%)• Histologic Alteration 6/52 (11%)
• NS/MC MC/NS• NSCP/MC NSCP/LD
• Treated Site+
• Histologic Persistence 25/46 (54%)• Histologic Alteration 21/46 (46%)
• Unclassifiable 9/46 (20%)*Cancer 1980;45:289-292+Cancer 1981;48:1124-1126
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HL – Recurrence in Rx Site
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CD30HL – Recurrence in Rx Site
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HL – Post Rx NHL
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Extranodal Hodgkin Lymphoma? • Primary classic Hodgkin lymphoma
essentially does not occur in tonsil, appendix, or extranodal sites (or mesenteric lymph nodes)
• Be extremely skeptical of case– More likely to be non-Hodgkin lymphoma (e.g.,
ALCL)
– Or an EBV-positive lymphoproliferation (e.g. EBV+ mucocutaneous ulcer)
• Extranodal involvement may occur with contiguous or retrograde spread (e.g., lung)
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Nodular Lymphocyte Predominance Hodgkin Lymphoma: Clinical
• All ages, including children; M:F = 2.5:1
• Mostly Stage I; cervical, axillary, inguinal
• Lymph nodes most often involved
• Higher stages have spleen and liver
• Can arise in PTGC
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Needs to be flipped
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NLPHL: Architecture
• Complete or partial effacement common• Uneffaced areas may show normal
appearance, reactive follicular hyperplasia or PTGC
• Large nodules; diffuse areas may be present• Nodules may be highlighted by epithelioid
histiocytes• Vague nodularity even in diffuse cases
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NP
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Am J Surg Pathol 2003;27:1346-1356
CD20CD20
NLP – Variant Patterns
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Am J Surg Pathol 2003;27:1346-1356
CD20CD20
NLP – Variant Patterns
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Am J Surg Pathol 2003;27:1346-1356
CD20CD20
NLP – Variant Patterns
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NLPHL: LP/L & H cells
• Large cells with large nuclei
• Multilobated nuclear outlines
• Vesicular chromatin
• Medium-sized nucleoli
• Scanty nondescript cytoplasm
• No truly diagnostic R-S cells; mimics
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NLPHL: Host Cells
• Small lymphocytes
• Epithelioid histiocytes
• Plasma cells (between nodules)
• No eosinophils, typically
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Phenotype of LP/L&H Cells• CD45 + (95%)• CD30 - (10% weak +)• CD15 - (10% +)• CD20, PAX-5 + (95%)• CD79a, OCT-2, BOB.1 + (95%)• Bcl-6, bcl-2 + (95%)• EMA +/- (70%)• CD3, CD43, CD10, MUM-1 - (0%)
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CD20 NLPHL
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EMA/NLPHL
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Phenotype of Host Cells
• Nodules + for B-lineage antigens• Numerous CD57/PD-1/bcl-6 + T cells, with
ringing around L&H cells• May see CD4 +/CD8+ population by flow
cytometry• Numbers of T-cells increase with
recurrences
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CD57 NLPHLCD57 NLPHL
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PD1 NLPHL
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LP/L & H CELLS:Immunoglobulin Expression
• IHC: Polytypic, monotypic (k>>l), or absent Ig proteins
• ISH: Absent or monotypic (k>>l), mRNA• SBH: Nonclonally rearranged Ig
genes• PCR tissue: Nonclonally rearranged Ig genes• PCR cells: Clonal or nonclonally rearranged
Ig genes• IgD expression identifies subset of younger patients with
male predominance, in Stage I, with preferential involvement of cervical lymph nodes
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? NLPHL
• CD45• CD20• CD15• CD30• CD57/PD1• MUM-1
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Nodular Lymphocyte Predominance Hodgkin Lymphoma: Differential
Diagnosis
• Progressive transformation of germinal centers– No effacement of architecture– No L&H cells; OCT-2 can be helpful
• Classic Hodgkin lymphoma– Character of Hodgkin cells– Phenotype (CD30, CD15, CD45, MUM-1, CD79a,
BOB.1, OCT-2)• T-cell/histiocyte rich large B-cell lymphoma
– Clinical history– No nodularity– No nodules of B-cells– No ringing of CD57/PD-1/bcl-6 + cells (ringing of
PD-1 cells may be seen in T/histiocyte-rich B-cell lymphoma on occasion
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Classic Hodgkin Lymphoma vs. Nodular Lymphocyte Predominance
MCHL (%) NLPHL (%)CD30 100 5CD15 85 1CD45 <5 98CD20 20-50 99EBV-LMP 30-40 1PAX-5 95 (moderate) 98 (strong)BOB1/OCT-2/CD79a
15/15/15 95/95/95
MUM-1 90 <5
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NLPHL: Treatment and Prognosis
• Treatment:– Low stage disease: Surgical/RT/Chemo– High stage disease: Chemotherapy
• Prognosis:– Relapses common, independent of treatment– Excellent survival, independent of relapses, unless in
high stage• Complications
– B cell diffuse large cell lymphoma seen in 2-10% of cases
– PTGC may coexist or follow– Rare: progression to classic HL
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B-Cell Lymphoma Arising in Association with NLPHL
• Complicates about 2-10% cases of NLPHL
• Histopath: Sheets of large B cells, particularlyin internodular areas
• Immuno: B cell; rare T cell
• Molecular: Monoclonal Ig sometimescorresponding to clone in previousNLPHL
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*J Clin Oncol 2010;28:793-799
NLP Transforming to DLBCL* PFS & Survival
62% @ 10 Years
52% @ 10Years
Actuarial Risk of Transformation: 7% & 30% @ 10 & 20 Years
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“LP Cell-Rich”(Syncytial)
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Conclusions
• The most recent classifications of Hodgkin lymphoma distinguish between classic and lymphocyte predominance types
• There is a wide differential diagnosis of Hodgkin lymphoma
• A battery of immunohistochemical studies is most useful in distinguishing Hodgkin lymphoma from other entities
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