LYMPHOMA - Non-Hodgkin lymphoma - Hodgkin lymphoma (Hodgkin disease) Agnieszka Tomaszewska...

LYMPHOMALYMPHOMA- Non-Hodgkin - Non-Hodgkin lymphomalymphoma- Hodgkin lymphoma - Hodgkin lymphoma (Hodgkin disease)(Hodgkin disease)

Agnieszka TomaszewskaAgnieszka Tomaszewska Department of Hematology, Department of Hematology, Oncology and Internal Medicine, Oncology and Internal Medicine, Medical University of Warsaw, 12 Medical University of Warsaw, 12 JAN 2006JAN 2006

Lymphoma - definitionLymphoma - definition

Lymphoma (or malignant lymphoma) – Lymphoma (or malignant lymphoma) – a neoplasm of cells derived from a neoplasm of cells derived from lymphocytes or lymphocyte precursorslymphocytes or lymphocyte precursors

Lymphoma vs lymphoid leukemia:Lymphoma vs lymphoid leukemia: Lymphoma – a neoplasm manifesting Lymphoma – a neoplasm manifesting

primarily as a tumor of lymph nodes or primarily as a tumor of lymph nodes or related organs (e.g. spleen, liver)related organs (e.g. spleen, liver)

Leukemia – proliferation of abnormal Leukemia – proliferation of abnormal cells (lymphocytes or lymphocytes cells (lymphocytes or lymphocytes precursors) in the bone marrow and precursors) in the bone marrow and bloodblood

Normal lymph node Normal lymph node architecturearchitecture

1.1. Afferent lymphatic Afferent lymphatic vesselvessel

2.2. SinusSinus3.3. Nodule (follicle): Nodule (follicle):

germinal center, mantle zone, marginal zone

4.4. CapsuleCapsule5.5. MedullaMedulla6.6. Valve to prevent Valve to prevent

backflowbackflow7.7. Efferent lymphatic Efferent lymphatic

vesselvessel

Human lymphatic Human lymphatic systemsystem

Principles of the Principles of the classification of classification of lymphomalymphoma There are two main categories:There are two main categories: Non-Hodgkin lymphomaNon-Hodgkin lymphoma• B-cell lymphomasB-cell lymphomas• T-cell lymphomasT-cell lymphomas Hodgkin disease (lymphoma)Hodgkin disease (lymphoma)

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001)(2001)I. B-cell neoplasms1. Precursor B-cell neoplasms• Precursor B lymphoblastic

leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)

2. Mature (peripheral) B-cell neoplasms with leukemic presentation

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001) (2001) (cont.)(cont.)2. Mature (peripheral) B-cell neoplasms

with leukemic presentation• Chronic lymphocytic leukemia (CLL)/B-

cell small lymphocytic lymphoma (SLL)• B-cell prolymphocytic leukemia• Lymphoplasmacytic lymphoma

(Waldenström’s Primary Macroglobulinemia)

• Splenic marginal zone B-cell lymphoma (+/- villus lymphocytes) (SMZL)

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001) (2001) (cont.)(cont.)2. Mature (peripheral) B-cell

neoplasms with leukemic presentation (cont.)

• Hairy cell leukemia (HCL)• Plasma cell neoplasms• Extranodal marginal zone B-cell

lymphoma of MALT type (MALT lymphoma)

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001) (2001) (cont.)(cont.)3. Mature (peripheral) B-cell neoplasms

node-based• Nodal marginal zone B-cell lymphoma

(MZL)• Follicular lymphoma (FL)• Mantle cell lymphoma (MCL)• Diffuse large B-cell lymphoma

(DLBCL)• Burkitt’s lymphoma/leukemia• Lymphomatoid granulomatosis

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001) (2001) (cont.)(cont.)II. T-cell and NK-cell neoplasms1. Precursor T-cell neoplasms• Precursor T lymphoblastic

leukemia/lymphoma (precursor T-cell acute lymphoblastic leukemia)

2. Mature (peripheral) T-cell neoplasms with leukemic presentation

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001) (2001) (cont.)(cont.)2. Mature (peripheral) T-cell neoplasms

with leukemic presentation• T-cell prolymphocytic leukemia• T-cell large granular lymphocytic

leukemia• Aggressive NK-cell leukemia• Adult T-cell lymphoma/leukemia

(HTLV1+)

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001) (2001) (cont.)(cont.)3. Mature (peripheral) T-cell neoplasms,

various types of presentation• Extranodal NK/T-cel lymphoma, nasal

type• Enteropathy-type T-cell lymphoma• Hepatosplenic T-cell lymphoma• Subcutaneous panniculitis-like T-cell

lymphoma• Blastic NK-cell lymphoma

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001) (2001) (cont.)(cont.)3. Mature (peripheral) T-cell neoplasms,

various types of presentation (cont.)• Mycosis fungoides/Sézary syndrome• Primary cutaneous CD30+ T-cell

lymphoproliferative disorders• Peripheral T-cell lymphoma,

unspecified• Angioimmunoblastic T-cell lymphoma• Primary systemic anaplastic large cell

lymphoma

The World Health The World Health Organization Classification Organization Classification of Lymphoid Neoplasms of Lymphoid Neoplasms (2001) (2001) (cont.)(cont.)III. Hodgkin’s lymphoma (Hodgkin’s

disease)• Nodular lymphocyte predominant

Hodgkin’s lymphoma• Classical Hodgkin’s lymphoma Nodular sclerosis (most common) Mixed cellularity Lymphocyte depleted (extremely

rare)

Grouping lymphomas Grouping lymphomas by clinical behaviourby clinical behaviour

A.A. IndolentIndolent (slow growing) but (slow growing) but usually usually incurableincurable

1)1) CLL/SLLCLL/SLL

2)2) FL except the large-cell typeFL except the large-cell type

3)3) Some MZL, gastric MALT Some MZL, gastric MALT lymphoma is often curable in the lymphoma is often curable in the early stagesearly stages

Grouping lymphomas Grouping lymphomas by clinical behaviourby clinical behaviour

B.B. Fairly Fairly aggressiveaggressive if untreated, if untreated, but but may bemay be curedcured with with appropriate therapyappropriate therapy

1)1) HDHD

2)2) FL large-cell typeFL large-cell type

3)3) DLBCLDLBCL

Grouping lymphomas Grouping lymphomas by clinical behaviourby clinical behaviour

C.C. Fairly Fairly aggressiveaggressive and and incurableincurable

1)1) MCLMCL

D.D. Extremely aggressiveExtremely aggressive if if untreated, but untreated, but potentiallypotentially curablecurable with appropriate therapy with appropriate therapy

1)1) Burkitt lymphomaBurkitt lymphoma

2)2) Lymphoblastic lymphomaLymphoblastic lymphoma

DLBCL31%

FL22%

CTCL2%

Burkitt L2%

MCL6%

MZL2%

Others12%

CLL/ SLL7%

Mature T-cell L.8%

MALT8%

Frequency of lymphoid Frequency of lymphoid neoplasms (WHO)neoplasms (WHO)

Diagnosis of Diagnosis of lymphomalymphoma HistoryHistoryo Age of the patient (pediatric/adult)Age of the patient (pediatric/adult)o History of nodes (rapid, slow growth) History of nodes (rapid, slow growth) o PainPaino Local or systemic symptoms (unexplained Local or systemic symptoms (unexplained

fever, weight loss, night sweats)fever, weight loss, night sweats)o FatigueFatigueo PruritusPrurituso Dermatosis, rashDermatosis, rasho Overall performance statusOverall performance status

Diagnosis of Diagnosis of lymphomalymphoma Physical examinationPhysical examinationo Areas of palpable Areas of palpable

lymphadenopathy (size, location, lymphadenopathy (size, location, tenderness)tenderness)

o Size of liver and spleenSize of liver and spleeno Bony tendernessBony tendernesso Neurologic abnormalitiesNeurologic abnormalities

Diagnosis of Diagnosis of lymphomalymphoma Laboratory studiesLaboratory studieso CBC (complete blood count), CBC (complete blood count),

differential and platelet count,differential and platelet count,o Erythrocyte sedimentation rate (esp. Erythrocyte sedimentation rate (esp.

for HD)for HD)o Serum alkaline phosphatase, lactic Serum alkaline phosphatase, lactic

dehydrogenase, albumin, uric aciddehydrogenase, albumin, uric acido Renal function (creatinine, blood urea Renal function (creatinine, blood urea

nitogen–BUN) tests nitogen–BUN) tests o Liver function testsLiver function tests

Diagnosis of Diagnosis of lymphomalymphoma Radiologic studiesRadiologic studieso Chest radiographChest radiographo Computed tomography scan of the Computed tomography scan of the

chest, abdomen and pelvischest, abdomen and pelviso Bone scan or radiograph if symptoms Bone scan or radiograph if symptoms

of bone involvement are presentof bone involvement are presento Gallium or positron emission Gallium or positron emission

tomography (PET) scan, especially tomography (PET) scan, especially when other radiologic studies are when other radiologic studies are equivocalequivocal

Diagnosis of Diagnosis of lymphomalymphoma BiopsiesBiopsieso Diagnostic biopsy of affected lymph Diagnostic biopsy of affected lymph

node (reviewed by experienced node (reviewed by experienced hematopathologist !!!)hematopathologist !!!)

o Bone marrow biopsy, especially when Bone marrow biopsy, especially when treatment may be modifiedtreatment may be modified

o Biopsy of suspicious disseminated Biopsy of suspicious disseminated extranodal sites (e.g. pulmonary or extranodal sites (e.g. pulmonary or liver lesions) if clinically indicatedliver lesions) if clinically indicated

Differential diagnosis Differential diagnosis of lymphadenopathyof lymphadenopathy Infections (such as common cold, local acute or Infections (such as common cold, local acute or

chronic infections, infectious mononucleosis, chronic infections, infectious mononucleosis, tuberculosis, syphilis, toxoplasmosis, tuberculosis, syphilis, toxoplasmosis, cytomegalovirus, HIV, cat-scratch fever)cytomegalovirus, HIV, cat-scratch fever)

Drugs (e.g. phenytoin)Drugs (e.g. phenytoin) Connective tissue disorders (e.g. systemic Connective tissue disorders (e.g. systemic

lupus erytematosus, dermatomyositis, lupus erytematosus, dermatomyositis, scleroderma)scleroderma)

Metastatic cancerMetastatic cancer Primary lymphoid malignancies (e.g. non-HL, Primary lymphoid malignancies (e.g. non-HL,

HD) HD)

Distinctions between Distinctions between palpable lymph nodespalpable lymph nodes

NormalNormal ReactiveReactive MalignantMalignant•Small (0.5-1.0 Small (0.5-1.0 cm)cm)•Soft, flat, Soft, flat, ellipsoid, fixedellipsoid, fixed•NontenderNontender•Usually multipleUsually multiple•Usually high Usually high neck, neck, submandibular, submandibular, submentalsubmental•Usually stableUsually stable

•Moderately large Moderately large (<2cm)(<2cm)•Firm, spherical, Firm, spherical, movablemovable•Tender or Tender or nontendernontender•Single to multiple Single to multiple (depends on (depends on disease)disease)•Usually cervicalUsually cervical•Should resolve 1-2 Should resolve 1-2 mo after acute mo after acute process stopsprocess stops

•Large(>1cm, Large(>1cm, esp.>2cm)esp.>2cm)•Firm, spherical, Firm, spherical, esp. mattedesp. matted•Usually Usually nontendernontender•Single or multiple Single or multiple (depends on type (depends on type of neoplasm)of neoplasm)•Any anatomic Any anatomic nodal areanodal area•Progressive Progressive growthgrowth

Non-Hodgkin lymphomas – selected Non-Hodgkin lymphomas – selected examples (clinical features, examples (clinical features, prognostic factors, staging prognostic factors, staging systems, treatment)systems, treatment)

CLLCLL FLFL DLBCLDLBCL

Mycosis fungoides/Sezary Mycosis fungoides/Sezary SyndromeSyndrome

Chronic lymphocytic Chronic lymphocytic leukemia (B-cell CLL)leukemia (B-cell CLL) Most common leukemia in the Western Most common leukemia in the Western

Hemisphere (40% of all leukemias over Hemisphere (40% of all leukemias over the age 65 years)the age 65 years)

Median age of presentation is between Median age of presentation is between 65 and 70 years, but 20-30% of 65 and 70 years, but 20-30% of patients is under the age of 55 yearspatients is under the age of 55 years

20-30 times commoner in Europe, 20-30 times commoner in Europe, North American white and black North American white and black populations than in India, China or populations than in India, China or JapanJapan

Male/female ratio is appr. 2:1Male/female ratio is appr. 2:1

Chronic lymphocytic Chronic lymphocytic leukemia (B-cell CLL)-leukemia (B-cell CLL)-diagnosisdiagnosis1.1. Lymphocytes > 5 x 10Lymphocytes > 5 x 1099/L; ≥ 1 B-cell /L; ≥ 1 B-cell

marker (CD19, CD20, CD23) + CD5 marker (CD19, CD20, CD23) + CD5 (without other pan-T cell markers), B-cell (without other pan-T cell markers), B-cell is monoclonal (expression of either is monoclonal (expression of either κκ or or λλ, low density of surface immunoglobulin , low density of surface immunoglobulin sIgsIg

2.2. Atypical cells (e.g. prolymphocytes) < Atypical cells (e.g. prolymphocytes) < 55%55%

3.3. Duration of lymphocytosis – none Duration of lymphocytosis – none requiredrequired

4.4. Bone marrow lymphocytes ≥ 30%Bone marrow lymphocytes ≥ 30%

Chronic lymphocytic Chronic lymphocytic leukemia (B-cell CLL) – leukemia (B-cell CLL) – Rai staging systemRai staging system

StageStage FeaturesFeatures % of % of patientspatients

RiskRisk

OO Lymphocytosis onlyLymphocytosis only 3030 lowlow

II LymphadenopathyLymphadenopathy 2525 lowlow

IIII Hepato- or Hepato- or splenomegalysplenomegaly

2525 intermediateintermediate

IIIIII Haemoglobin < 11 Haemoglobin < 11 g/dLg/dL

1010 highhigh

IVIV Platelet < 100 x Platelet < 100 x 101099/L/L

1010 highhigh

B-CLL – Binet staging B-CLL – Binet staging systemsystem

StageStage FeaturesFeatures % of % of patientspatients

riskrisk

AA Hb≥10g/dl, PLT≥100 x Hb≥10g/dl, PLT≥100 x 101099/L and < 3 /L and < 3

lymphoid areas lymphoid areas involvedinvolved

6060 lowlow

BB as above and ≥ 3 as above and ≥ 3 lymphoid areas lymphoid areas

involvedinvolved

3030 intermediateintermediate

CC Hb<10g/dL and/or Hb<10g/dL and/or PLT<100 x 10PLT<100 x 1099/L/L

1010 highhigh

B-CLL prognostic B-CLL prognostic factorsfactors

FactorFactor Low riskLow risk High riskHigh risk

GenderGender FemaleFemale MaleMale

Clinical stageClinical stage Binet A; Rai Binet A; Rai 0, I0, I

Binet B, C; Rai Binet B, C; Rai II, III, IVII, III, IV

Lymphocyte Lymphocyte morphologymorphology

TypicalTypical AtypicalAtypical

Pattern of marrow Pattern of marrow infiltrationinfiltration

Non-diffuseNon-diffuse DiffuseDiffuse

B-CLL prognostic B-CLL prognostic factors (cont.)factors (cont.)FactorFactor Low riskLow risk High riskHigh risk

LDTLDT >12 months>12 months < 12 months< 12 months

Serum markers Serum markers (LDH, (LDH, ββ2-microglobulin)2-microglobulin)

NormalNormal RaisedRaised

CD38 expressionCD38 expression <20-30%<20-30% >20-30%>20-30%

Genetic Genetic abnormalitiesabnormalities

None; del 13q None; del 13q (sole)(sole)

Del 11q23; Del 11q23; loss/mutation loss/mutation

of p53of p53

IgVH gene statusIgVH gene status MutatedMutated UnmutatedUnmutated

B-CLL – indications for B-CLL – indications for treatmenttreatment

Progressive marrow failure-the development or Progressive marrow failure-the development or worsening of anaemia and/or thrombocytopeniaworsening of anaemia and/or thrombocytopenia

Massive (>10cm) or progressive Massive (>10cm) or progressive lymphadenopathylymphadenopathy

Massive (>6cm) or progressive splenomegalyMassive (>6cm) or progressive splenomegaly Progressive lymphocytosis:Progressive lymphocytosis:• >50% increase over 2 months>50% increase over 2 months• Lymphocyte doubling time (LDT)<6 monthsLymphocyte doubling time (LDT)<6 months Systemic symptomsSystemic symptoms Autoimmune cytopenias (AIHA, ITP)Autoimmune cytopenias (AIHA, ITP)

Management of B-CLLManagement of B-CLL

Patient-related factors (age, PS, co-Patient-related factors (age, PS, co-morbid conditions, patient wishes)morbid conditions, patient wishes)

Disease-related factors (the Disease-related factors (the severity of symptoms, adverse severity of symptoms, adverse prognostic factors)prognostic factors)

Treatment-related factors (the Treatment-related factors (the degree and duration of response to degree and duration of response to prior treatments, contra-indications prior treatments, contra-indications to, side-effects from)to, side-effects from)

Treatment strategy for Treatment strategy for B-CLLB-CLL

Early stage CLL „watchfull waiting” „Treatment of early stage with chlorambucil is not

indicated” (grade A recomendation, level Ia evidence)

Advanced or progressive disease Alkylating agents (chlorambucil +/-prednison, COP,

CHOP) Purine analogues (fludarabine, cladribine – alone or

in combinations with cyclophosphamide, mitoxantrone)

Monoclonal antibodies (alemtuzumab, rituximab – as a second line treatment)

Transplantation in CLL: autologous transplantation; allogeneic transplantation with low intensity conditioning regimens (RIC-alloTx)

Lymphomatous Lymphomatous transformation in CLLtransformation in CLL 5-10% of patients with CLL develop 5-10% of patients with CLL develop

more aggressive form of lymphoma - more aggressive form of lymphoma - Richter’s transformation of CLL (Richter, Richter’s transformation of CLL (Richter, 1928)1928)

No standard therapy can be No standard therapy can be recommended for Richter’s syndrome recommended for Richter’s syndrome (CHOP, experimental therapy with (CHOP, experimental therapy with monoclonal antibodies, monoclonal antibodies, cisplatin/fludarabine based cisplatin/fludarabine based chemotherapy is used)chemotherapy is used)

Diffuse large B-cell Diffuse large B-cell lymphoma (DLBCL)lymphoma (DLBCL) The most frequent type of non-The most frequent type of non-

Hodgkin’s lymphomaHodgkin’s lymphoma An aggressive disease if An aggressive disease if

untreateduntreated Quite responsive to Quite responsive to

chemotherapy chemotherapy

((~~ 50% of pts may be cured) 50% of pts may be cured)

Ann Arbor staging Ann Arbor staging systemsystem (for non-Hodgkin’s (for non-Hodgkin’s lymphoma and for Hodgkin’s lymphoma and for Hodgkin’s disease)disease)

StageStage DescriptionDescription

II

IIII

Involvement of a single lymph node Involvement of a single lymph node region (I) or a single extralymphatic region (I) or a single extralymphatic organ or site (IE)organ or site (IE)

Involvement of two or more lymph Involvement of two or more lymph node regions on the same side of node regions on the same side of diaphragm (II) or local involvement of diaphragm (II) or local involvement of an extralymphatic organ or site and an extralymphatic organ or site and one or more lymph node regions on te one or more lymph node regions on te same side of diaphragm (IIE)same side of diaphragm (IIE)

Ann Arbor staging Ann Arbor staging systemsystem (for non-Hodgkin’s (for non-Hodgkin’s lymphoma and for Hodgkin’s lymphoma and for Hodgkin’s disease) cont.disease) cont.

StageStage DescriptionDescription

IIIIII

IVIV

Involvement of lymph node regions on Involvement of lymph node regions on both sides of diaphragm (III), which both sides of diaphragm (III), which may also be accompanied by may also be accompanied by involvement of the spleen (IIIS) or by involvement of the spleen (IIIS) or by local involvement of an local involvement of an extralymphatic organ or site (IIIE) or extralymphatic organ or site (IIIE) or both (IIISE)both (IIISE)

Diffuse or disseminated involvement Diffuse or disseminated involvement of one or more extralymphatic organs of one or more extralymphatic organs or tissues, with or without lymph node or tissues, with or without lymph node involvementinvolvement

Ann Arbor staging Ann Arbor staging (cont.)(cont.) „„B” symptoms: fever, night B” symptoms: fever, night

sweats or unexplained loss of sweats or unexplained loss of 10% or more body weight in the 6 10% or more body weight in the 6 months preceding diagnosismonths preceding diagnosis

„„A” – absence of these symptomsA” – absence of these symptoms „„E” – involvement of an E” – involvement of an

extralymphatic siteextralymphatic site „„S” – splenic involvementS” – splenic involvement

IPI for DLBCL (and IPI for DLBCL (and aggressive aggressive nonnon--Hodgkin’s lymphomas) Hodgkin’s lymphomas)

I.I. Age (<60 vs ≥60)Age (<60 vs ≥60)

II.II. Tumor stage (I-II vs III-IV)Tumor stage (I-II vs III-IV)

III.III. The number of extranodal sites The number of extranodal sites (≤1 vs >1)(≤1 vs >1)

IV.IV. PS (0-1 vs ≥2)PS (0-1 vs ≥2)

V.V. LDH level (normal vs elevated) LDH level (normal vs elevated)

IPI for DLBCL (and IPI for DLBCL (and aggressive aggressive nonnon--Hodgkin’s lymphomas) Hodgkin’s lymphomas)

RISK:RISK: Low: 0-1 risk factorsLow: 0-1 risk factors Low-intermediate: 2 risk factorsLow-intermediate: 2 risk factors High-intermediate: 3 risk High-intermediate: 3 risk

factorsfactors High: 4-5 risk factorsHigh: 4-5 risk factors

IPI for DLBCL (and IPI for DLBCL (and aggressive aggressive nonnon--Hodgkin’s lymphomas) Hodgkin’s lymphomas)

IPIIPI Expected Complete Expected Complete Remission RateRemission Rate

Predicted 5-year Predicted 5-year Survival RateSurvival Rate

0-10-1

22

33

4-54-5

87%87%

67%67%

55%55%

44%44%

73%73%

51%51%

43%43%

26%26%

DLBCL - treatmentDLBCL - treatment

Always chemotherapy (CHOP, Always chemotherapy (CHOP, other regimens)other regimens)

Chemoimmunotherapy Chemoimmunotherapy (CHOP+rituximab)(CHOP+rituximab)

High-dose chemotherapy with High-dose chemotherapy with autologous-SCTautologous-SCT

Follicular lymphoma Follicular lymphoma (FL)(FL) Common in the Western HemisphereCommon in the Western Hemisphere FL cells closely mimic the cells of the FL cells closely mimic the cells of the

normal germinal center of the normal germinal center of the lymphoid folliclelymphoid follicle

Indolent – fewer mitotic figures and Indolent – fewer mitotic figures and less cell turnover than its benign less cell turnover than its benign counterpart follicular hyperplasiacounterpart follicular hyperplasia

Most cases t(14;18), which juxtaposes Most cases t(14;18), which juxtaposes the the bcl-2bcl-2 gene to Ig Heavy-chain gene gene to Ig Heavy-chain gene

FL – International FL – International Prognostic Index Prognostic Index (FLIPI)(FLIPI)I.I. Age (>60 years vs ≤ 60 years)Age (>60 years vs ≤ 60 years)II.II. Ann Arbor stage (III-IV vs I-II)Ann Arbor stage (III-IV vs I-II)III.III. Hb level (<12 g/dL vs ≥12 g/dL)Hb level (<12 g/dL vs ≥12 g/dL)IV.IV. Number of nodal areas (>4 vs ≤4)Number of nodal areas (>4 vs ≤4)V.V. Serum LDH level (above normal vs Serum LDH level (above normal vs

normal or below)normal or below) Low risk (0-1 adverse factor, 36% Low risk (0-1 adverse factor, 36%

pts)pts) Intermediate risk (2 factors, 37%)Intermediate risk (2 factors, 37%) Poor risk (≥3 factors, 27% pts)Poor risk (≥3 factors, 27% pts)

FL - treatmentFL - treatment Chemotherapy (COP, CHOP, others)Chemotherapy (COP, CHOP, others) Rituximab (monoclonal antibody anti-CD20) alone Rituximab (monoclonal antibody anti-CD20) alone

or in combination with chemotherapy (COP-R, or in combination with chemotherapy (COP-R, CHOP-R)CHOP-R)

SCT for FL (autologous-SCT mostly; allogeneic-SCT SCT for FL (autologous-SCT mostly; allogeneic-SCT mortality 30%)mortality 30%)

Radioimmunotherapy (combines the antibody- and Radioimmunotherapy (combines the antibody- and complement-dependent cytotoxicity of standard complement-dependent cytotoxicity of standard monoclonal antibodies with free radical-mediated monoclonal antibodies with free radical-mediated apoptosis induced by the radioactive isotope):apoptosis induced by the radioactive isotope):

131-Iodine Tositumomab (Bexxar)131-Iodine Tositumomab (Bexxar) 90-Yttrium Ibritumomab Tiuxetan (Zevalin)90-Yttrium Ibritumomab Tiuxetan (Zevalin) New agents (galiximab = anti-CD80, zanolimumab New agents (galiximab = anti-CD80, zanolimumab

= anti-epitope of CD20, temsirolimus, = anti-epitope of CD20, temsirolimus, bortezomib=Velcade)bortezomib=Velcade)

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL)Lymphoma (CTCL) Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma Spektrum of disesases composed Spektrum of disesases composed

of malignant clonal helper T of malignant clonal helper T lymphocytes of CD4 phenotypelymphocytes of CD4 phenotype

Median pts’ age is 50-55 yearsMedian pts’ age is 50-55 years Male to female ratio is 2:1Male to female ratio is 2:1 Unpredictable courseUnpredictable course

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL)Lymphoma (CTCL) Mycosis fungoidesMycosis fungoides (patches, (patches,

infiltrated plaques, tumors)infiltrated plaques, tumors) Sezary syndromeSezary syndrome (the leukemic (the leukemic

variant of CTCL): generalized variant of CTCL): generalized erythroderma, leukemia and erythroderma, leukemia and lymphadenopathy;lymphadenopathy;malignant T cells with malignant T cells with hyperconvoluted cerebriform nuclei hyperconvoluted cerebriform nuclei circulate in the blood (Sezary cells)circulate in the blood (Sezary cells)

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL) - Lymphoma (CTCL) - diagnosisdiagnosis

characteristic clinical characteristic clinical manifestationsmanifestations

routine histologyroutine histology immunophenotyping, flow immunophenotyping, flow

cytometry, T-cell receptor gene cytometry, T-cell receptor gene rearrangementrearrangement

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL) – Lymphoma (CTCL) – clinical featuresclinical features

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL) – Lymphoma (CTCL) – clinical featuresclinical features

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL) – Lymphoma (CTCL) – clinical featuresclinical features

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL) – Lymphoma (CTCL) – clinical featuresclinical features

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL) – Lymphoma (CTCL) – clinical featuresclinical features

Cutaneous T-cell Lymphoma Cutaneous T-cell Lymphoma (CTCL) – staging and (CTCL) – staging and prognosisprognosis

TNM (tumor-node-metastasis system)TNM (tumor-node-metastasis system) 3 prognostic groups:3 prognostic groups:1)1) Good-riskGood-risk pts with patch or plaque skin lessions pts with patch or plaque skin lessions

without lymph node, blood or visceral without lymph node, blood or visceral involvement (median survival involvement (median survival ~~ 12 years) 12 years)

2)2) Intermediate-riskIntermediate-risk pts with plaques, tumors or pts with plaques, tumors or erythroderma with lymph node and/or blood erythroderma with lymph node and/or blood involvement but no visceral disease (median involvement but no visceral disease (median survival survival ~~ 5 years) 5 years)

3)3) Poor-riskPoor-risk pts with visceral involvement or pts with visceral involvement or complete lymph node effacement (median complete lymph node effacement (median survivalsurvival~~2.5 years) 2.5 years)

Cutaneous T-cell Cutaneous T-cell Lymphoma (CTCL) – Lymphoma (CTCL) – treatmenttreatment Skin-directed therapies (psolaren with Skin-directed therapies (psolaren with

UVA irradiation=PUVA, topical UVA irradiation=PUVA, topical chemotherapy with BCNU, photopheresis chemotherapy with BCNU, photopheresis with 8-MOP)with 8-MOP)

Interferon Interferon 2a2a Systemic chemotherapySystemic chemotherapy Hu-Max-CD4 (monoclonal antibody IgG1 Hu-Max-CD4 (monoclonal antibody IgG1

anti-CD4)anti-CD4) Denileukin diftitox (Ontak – a recombinat Denileukin diftitox (Ontak – a recombinat

fusion protein consisted of fragments of fusion protein consisted of fragments of diphteria toxin linked to human IL-2)diphteria toxin linked to human IL-2)

Hodgkin’s lymphoma Hodgkin’s lymphoma (disease)(disease)

A distinct type of lymphomaA distinct type of lymphoma In a lymph node affected by Hodgkin disease In a lymph node affected by Hodgkin disease

histologically we can see largely of an histologically we can see largely of an inflammatory (i.e. nonneoplastic) reaction to the inflammatory (i.e. nonneoplastic) reaction to the neoplastic cellsneoplastic cells

Neoplastic cell type of HL is known as the Reed-Neoplastic cell type of HL is known as the Reed-Sternberg cell (Hodgkin cell): is large with bilobed Sternberg cell (Hodgkin cell): is large with bilobed nuclei, each nuclear lobe contains a large nuclei, each nuclear lobe contains a large nucleolus imparting an owl’s-eye appearancenucleolus imparting an owl’s-eye appearance

Bimodal age distribution (it peaks at 20-29 years Bimodal age distribution (it peaks at 20-29 years of age, and again at 60)of age, and again at 60)

Male moderate predominance Male moderate predominance

Hodgkin’s lymphoma Hodgkin’s lymphoma (disease)(disease)

Hodgkin’s lymphoma Hodgkin’s lymphoma (disease) – clinical (disease) – clinical presentationpresentation

HL generally spreads in a contiguous HL generally spreads in a contiguous fashion from one anatomic lymph fashion from one anatomic lymph node group to anothernode group to another

Gross splenomegaly is rare in HLGross splenomegaly is rare in HL Pruritus, pain soon after drinking Pruritus, pain soon after drinking

alcohol is associated with HLalcohol is associated with HL „„B” symptoms B” symptoms

WHO Classification of WHO Classification of HLHL

Hodgkin’s lymphoma (Hodgkin’s disease)

• Nodular lymphocyte predominant Hodgkin’s lymphoma

• Classical Hodgkin’s lymphoma Nodular sclerosis (most common) Mixed cellularity Lymphocyte depleted (extremely

rare)

LPHL-nodular LPHL-nodular lymphocyte-predominant lymphocyte-predominant HLHL Accounts approximately 5% of all cases Accounts approximately 5% of all cases

of HLof HL Flow cytometry features: CD20Flow cytometry features: CD20++, CD15, CD15--, ,

CD30CD30--.. Cells of LPHL differ from classic Cells of LPHL differ from classic

„popcorn” HL cells„popcorn” HL cells Radioterapy alone can be effectiveRadioterapy alone can be effective Rituximab in this type of HL can be Rituximab in this type of HL can be

effective effective

Classical Hodgkin’s Classical Hodgkin’s lymphoma (disease) – lymphoma (disease) – unfavorable factors unfavorable factors

Early-stage diseaseEarly-stage disease Advanced diseaseAdvanced disease

Bulky diseaseBulky disease

Any mass > 10 cmAny mass > 10 cm

Erythrocyte Erythrocyte sedimentation rate sedimentation rate ESR > 50 mm/hESR > 50 mm/h

More than three sites More than three sites of disease of disease

Albumin < 4.0g/dLAlbumin < 4.0g/dL

Hb < 10 g/dLHb < 10 g/dL

WBC > 15 x 10WBC > 15 x 1099/L/L

Lymphopenia 0.6 x Lymphopenia 0.6 x 101099/L or < 8% of total /L or < 8% of total WBCWBC

MaleMale

Age > 45 yearsAge > 45 years

Stage IV Anbor ArborStage IV Anbor Arbor

HL – prognosis for advanced HL – prognosis for advanced disease according to the disease according to the number of unfavorable factorsnumber of unfavorable factors

No of No of factorsfactors

% of % of populationpopulation

Freedom from Freedom from progression at 5 progression at 5 years (%)years (%)

00

11

22

33

44

5+5+

77

2222

2929

2323

1212

77

8484

7777

6767

6060

5151

4040

HL-combined-modality HL-combined-modality treatmenttreatment Treament of early-stageTreament of early-stage HL, HL, goodgood

prognosisprognosis – ABVD (adriamycin, – ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) +/- bleomycin, vinblastine, dacarbazine) +/- radiation (RT)radiation (RT)

Treatment of early-stageTreatment of early-stage HL, HL, poor poor prognosisprognosis (age>50, male gender, MC or (age>50, male gender, MC or LD histology, 4-5 nodal sites of LD histology, 4-5 nodal sites of involvement, „B” symptoms, bulky involvement, „B” symptoms, bulky mediastinal disease) – ABVD followed by mediastinal disease) – ABVD followed by RT, BEACOPP (?)RT, BEACOPP (?)

HL-combined-modality HL-combined-modality treatmenttreatment Treatment for advancedTreatment for advanced HL – escalated HL – escalated

BEACOPPBEACOPP (bleomycin, etoposide, (bleomycin, etoposide, doxorubicin, cyclophosphamide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), vincristine, procarbazine, prednisone), MOPP(COPP)/ABVD for older patients, MOPP(COPP)/ABVD for older patients, Stanford VStanford V regimen regimen (mechlorethamine, doxorubicine, (mechlorethamine, doxorubicine, etoposide, vincristine, vinblastine, etoposide, vincristine, vinblastine, bleomycine, prednisone)bleomycine, prednisone)

HL-combined-modality HL-combined-modality treatmenttreatment Treatment for relapsedTreatment for relapsed HL – HL –

radiotherapy (?), radiotherapy (?), autologous-SCT autologous-SCT (high-dose chemotherapy BEAM (high-dose chemotherapy BEAM followed by ASCT)followed by ASCT)

New single or combination therapies New single or combination therapies for relapsed HL – for relapsed HL – gemcitabinegemcitabine alone, alone, GNDGND (gemcytabine, (gemcytabine, vinorelbine and liposomal vinorelbine and liposomal doxorubicin)doxorubicin)

Case report 1.Case report 1.

A 60-year-old man complains of a A 60-year-old man complains of a new lump in the right groin for new lump in the right groin for the past 6 weeksthe past 6 weeks

In the history: the node is not In the history: the node is not painful, the patient noted other painful, the patient noted other enlarged nodes, he has not fevers enlarged nodes, he has not fevers or sweats, but he has lost about 5 or sweats, but he has lost about 5 kg over the past 6 months.kg over the past 6 months.

Case report 1.Case report 1.

Case report 1.Case report 1.

Physical examination: pale Physical examination: pale mucosa, generalized (cervical, mucosa, generalized (cervical, supraclavicular, axillary, supraclavicular, axillary, inguinal) lymph nodes inguinal) lymph nodes enlargement (to 2-3 cm); spleen enlargement (to 2-3 cm); spleen enlarged to 6 cm below the enlarged to 6 cm below the costal margincostal margin

Case report 1.Case report 1.Differential Differential

diagnosisdiagnosisGeneralized adenopathyGeneralized adenopathy Localized inguinal Localized inguinal adenopathyadenopathy

•Reactive hyperplasia due to HIVReactive hyperplasia due to HIV•Secondary syphilisSecondary syphilis•EBV infectionEBV infection•TuberculosisTuberculosis•LymphomaLymphoma•CMV infectionCMV infection•BrucillosisBrucillosis•ToxoplasmosisToxoplasmosis•SarcoidosisSarcoidosis

•Cat-scratch fever Cat-scratch fever (bartonella)(bartonella)•Herpes simplex Herpes simplex type IItype II

Case report 1.Case report 1.

Laboratory studies and Laboratory studies and procedures: CBC- WBC-2 x 10procedures: CBC- WBC-2 x 1099/L, /L, Hb-8.3g/dL, PLT-80 x 10Hb-8.3g/dL, PLT-80 x 1099/l, /l, peripheral smear does not show peripheral smear does not show abnormal lymphoid cellsabnormal lymphoid cells

LDH – 875 IU/LLDH – 875 IU/L

Case report 1. Case report 1. Bone marrow aspirate.Bone marrow aspirate.

Case report 1.Case report 1.

Bone marrow biopsy Bone marrow biopsy

Case report 1.Case report 1.

Flow cytometry: coexpression of CD5 Flow cytometry: coexpression of CD5 positive, CD19 positive, CD20 positive, CD19 positive, CD20 positive, CD22 positive, CD79b positive, CD22 positive, CD79b positive, CD23 negative.positive, CD23 negative.

Molecular studies: cytogenetics shows Molecular studies: cytogenetics shows t(11,14)(q13,q32), FISH t(11,14)(q13,q32), FISH (fluorescent in situ hybridization (fluorescent in situ hybridization technique) shows cyclin D1 technique) shows cyclin D1 translocationtranslocation

Case report 1. CT scan: abdominal – Case report 1. CT scan: abdominal – diffuse involvement of the diffuse involvement of the retroperitoneal nodesretroperitoneal nodes

Case report 1.Case report 1.

CT scan: abdominal – diffuse CT scan: abdominal – diffuse involvement of the retroperitoneal involvement of the retroperitoneal nodesnodes

Lymph node biopsy (should this be a: Lymph node biopsy (should this be a: fine needle aspirate?, core needle fine needle aspirate?, core needle biopsy? or excisional biopsy?)biopsy? or excisional biopsy?)

Surgical removal of the entire Surgical removal of the entire lymph node is strongly preferred lymph node is strongly preferred in all non-HL and HL !!!in all non-HL and HL !!!

Case report 1.Case report 1.

Diagnosis: B-cell non-Hodgkin Diagnosis: B-cell non-Hodgkin Lymphoma, Mantle cell Lymphoma, Mantle cell lymphomalymphoma

Prognosis-poor (IV B stage acc. AA)Prognosis-poor (IV B stage acc. AA)

Treatment: chemotherapy (FCM, Treatment: chemotherapy (FCM, FCM-R, Zevalin, hyperCVAD)FCM-R, Zevalin, hyperCVAD)

Case report 2.Case report 2.

48 year-old woman, examined for 48 year-old woman, examined for recurrent infection for last six recurrent infection for last six months and weakness. Medical months and weakness. Medical hitory not important.hitory not important.

Physical examination: pallor, Physical examination: pallor, spleen palpable 8 cm below spleen palpable 8 cm below costal margin.costal margin.

Case report 2.Case report 2.

Laboratory findings: Hb-9.4 g/dL, Laboratory findings: Hb-9.4 g/dL, RBC-2.76 T/l, WBC-2.3 x 10RBC-2.76 T/l, WBC-2.3 x 1099/L, ANC-/L, ANC-0.4 x 100.4 x 1099/L, Lymphocytes-1.8 x 10/L, Lymphocytes-1.8 x 1099/L, /L, PLT-83 x 10PLT-83 x 1099/L; chemistry OK./L; chemistry OK.

Bone marrow apirate with 84.1% Bone marrow apirate with 84.1% lymphatic cells, 76.5% cells with low lymphatic cells, 76.5% cells with low nuclear-cytoplasmatic ratio, nuclear-cytoplasmatic ratio, abundant cytoplasm forms a lot of abundant cytoplasm forms a lot of villi.villi.

Case report 2.Case report 2.

Case report 2.Case report 2.

Flow cytometry: CD19 positive, CD20 Flow cytometry: CD19 positive, CD20 positive, CD22 positive, positive, CD22 positive, CD103CD103 positive, CD5 negative, positive, CD5 negative, FMC7FMC7 positive. positive.

CT scan: only splenomegaly, no CT scan: only splenomegaly, no enlarded lymph nodesenlarded lymph nodes

Final diagnosis: Hairy cell leukemiaFinal diagnosis: Hairy cell leukemia Treatment: 2-CDA (2-Treatment: 2-CDA (2-

chlorodeoxyadenosine)chlorodeoxyadenosine) Prognosis: goodPrognosis: good