LymphomaLymphoma

Haematological Neoplasia - Haematological Neoplasia - OverviewOverview

Leukemias:Leukemias: Acute & Chronic, Acute & Chronic, Myeloid & LymphoidMyeloid & Lymphoid

Lymphomas:Lymphomas: Hodgkins & Non-Hodgkins Hodgkins & Non-Hodgkins

Premalignant:Premalignant: Myeloproliverative - MPS Myeloproliverative - MPS Myelodysplastic - MDSMyelodysplastic - MDS

It is primary malignant proliferative Tumour arising from the peripheralLymphoreticular system( nodal and extra nodal)

Central lymphoreticuular system is thymus & BM

Hodgkin lymphomaHodgkin lymphoma

Thomas Hodgkin(1798-1866)

Epidemiology of lymphomasEpidemiology of lymphomas

55thth most frequently diagnosed cancer most frequently diagnosed cancer overall for both males and femalesoverall for both males and females

males > femalesmales > females incidenceincidence

NHL increasing over timeNHL increasing over time Hodgkin lymphoma stableHodgkin lymphoma stable less frequent than non-Hodgkin less frequent than non-Hodgkin

lymphomalymphoma overall M>F = 3 :1overall M>F = 3 :1 peak incidence in 3rd decadepeak incidence in 3rd decade

Associated (etiological?) factorsAssociated (etiological?) factors

EBV infectionEBV infection smaller family sizesmaller family size higher socio-economic statushigher socio-economic status caucasian > non-caucasiancaucasian > non-caucasian possible genetic predispositionpossible genetic predisposition other: HIV? occupation? herbicides?other: HIV? occupation? herbicides?

Hodgkin lymphomaHodgkin lymphoma

cell of origin: germinal centre B-cell cell of origin: germinal centre B-cell Reed-Sternberg cells (or RS variants) Reed-Sternberg cells (or RS variants)

in the affected tissuesin the affected tissues most cells in affected lymph node are most cells in affected lymph node are

polyclonal reactive lymphoid cells, polyclonal reactive lymphoid cells, not neoplastic cellsnot neoplastic cells

B-cell developmentB-cell development

stemcell

lymphoidprecursor

progenitor-B

pre-B

immatureB-cell

maturenaiveB-cell

germinalcenterB-cell

memoryB-cell

plasma cell

DLBCL,FL, BL, HL

LBL, ALL

CLLMCL

MM

MZLCLL

A possible model of A possible model of pathogenesispathogenesis

germinalcentreB cell

transformingevent(s)

loss of apoptosis

RS cellinflammatory

response

EBV?

cytokines

Lymphoma - GrossLymphoma - Gross

Hodgkins lymphomaHodgkins lymphoma

Reed-Sternberg cellReed-Sternberg cell

Hodgkins lymphoma cellsHodgkins lymphoma cells

The Scream, 1893 Edvard Munch

Reed-Sternberg cell

RS cell and variantsRS cell and variants

popcorn celllacunar cellclassic RS cell

(mixed cellularity) (nodular sclerosis) (lymphocytepredominance)

Hodgkins Lymphoma:Hodgkins Lymphoma: Painless, firm lymphadenopathy, Painless, firm lymphadenopathy, Fever* EosinophiliaFever* Eosinophilia Only Reed-Sternberg cells malignant (B Only Reed-Sternberg cells malignant (B

cell)cell) Classification(WHO): Classification(WHO): Classic HodgkinsClassic Hodgkins::

Lymphocyte predominant.Lymphocyte predominant. Nodular Sclerosis.Nodular Sclerosis. Mixed cellularity.Mixed cellularity. Lymphocyte depleted.Lymphocyte depleted.

Nodular lymph. predominant Nodular lymph. predominant (non-classic)(non-classic)

Hodgkin’s DiseaseHodgkin’s Disease

Nodular SclerosingNodular Sclerosing < 80%< 80% Supraclavicular & Supraclavicular &

mediastinalmediastinal Stage I&II bStage I&II b

From, Diagnostic Surgical Pathology of the Head and Neck, From, Diagnostic Surgical Pathology of the Head and Neck, W.B.Saunders, p 750 & 764.W.B.Saunders, p 750 & 764.

Lymphocyte Lymphocyte PredominantPredominant

5 %5 % Cervical LNCervical LN Stage I &II aStage I &II a

Hodgkin’s DiseaseHodgkin’s Disease

Mixed CellularityMixed Cellularity > 20 %> 20 % RetroperitonealRetroperitoneal Stage II & IIIStage II & III

From, Diagnostic Surgical Pathology of the Head and Neck, From, Diagnostic Surgical Pathology of the Head and Neck, W.B.Saunders, p 750.W.B.Saunders, p 750.

Lymphocyte DepletedLymphocyte Depleted < 5 %< 5 % Extra nodal systemExtra nodal system Stage III & IVStage III & IV

Hodgkin’s DiseaseHodgkin’s Disease

PresentationPresentation Asymmetric lymphadenopathy—90%Asymmetric lymphadenopathy—90%

Firm, rubberyFirm, rubbery Supraclavicular fossaSupraclavicular fossa

Spleen, liver (Spleen, liver (extranodal sites relatively extranodal sites relatively uncommon except in advanced diseaseuncommon except in advanced disease

Constitutional symptoms—1/3 of casesConstitutional symptoms—1/3 of cases Fever, night sweats, anorexia, weakness, Fever, night sweats, anorexia, weakness,

weight lossweight loss

Lymphadenopathy in HLLymphadenopathy in HL Number Number one or two one or two

groupsgroups SiteSite mostly cervical mostly cervical SizeSize usually small usually small ShapeShape discrete discrete ConsistencyConsistency india india

rubbery or firmrubbery or firm MobileMobile No skin involvement No skin involvement No tendernessNo tenderness No fixation No fixation

Lymphadenopathy in NHLLymphadenopathy in NHL

Number Number multiple multiple SiteSite mostly extra nodal mostly extra nodal SizeSize usually large usually large ShapeShape matted matted ConsistencyConsistency hard & hard &

cysticcystic FixedFixed skin stretched & redskin stretched & red tendertender fixation fixation

Lymphadenopathy in Lymphadenopathy in LymphomaLymphoma

HLHL Number Number one or two one or two

groupsgroups SiteSite mostly cervical mostly cervical SizeSize usually small usually small ShapeShape discrete discrete ConsistencyConsistency india india

rubbery or firmrubbery or firm MobileMobile No skin involvement No skin involvement No tendernessNo tenderness No fixation No fixation

NHLNHL Number Number multiple multiple SiteSite mostly extra nodal mostly extra nodal SizeSize usually large usually large ShapeShape matted matted

ConsistencyConsistency hard & hard & cysticcystic

FixedFixed skin stretched & redskin stretched & red tendertender fixation fixation

(1) Cervical lymphadenopathy

(2) Hilar LN bronchial compression which cause segmental atelectasis

(3) Mediastinal

(a)SVC compression --- dilated Neck veins

(b) RLN ---hoarsness of voice

(c) Trachea & bronchi--- cough& dyspnea

(d) Lung--- Dyspnea & effusion (4) Splenomegally dt infiltration or hyperplasia

(5) Hepatomegally--- Ascites dt•Hepatic dysfunction•Peritoneal invasion

(6) jaundice

Prehepatic •hemolytic autoimmune•hypersplenism

Hepatic– • cholestatic• hepatitis

Posthepatic – LN at porta hepatis

(7) Stomach & bowel malabsorption syndromes

(8) Bone deposites•Sever pain•Pathological fractures

(9) Neurological • cord compression• Cranial nerve palsy• Root pains

(10) Skin nodules

(11) Mycosis fungoids

(12)AnaemiaHypersplenismBM infiltrationCytotoxic drugs

Extranodal manifestations

The challenge of lymphoma The challenge of lymphoma classificationclassification

Clinically useful classification

Diseases that have distinct• clinical features• natural history• prognosis• treatment

Biologically rational classification

Diseases that have distinct• morphology• immunophenotype• genetic features• clinical features

Stage I Stage II Stage III Stage IV

Staging of lymphomaStaging of lymphoma

A: absence of B symptomsB: fever, night sweats, weight loss

Hodgkin DiseaseHodgkin Disease

LymphomaLymphoma

Row of enlarged lymph nodes

Diagnosis:Diagnosis:

Hodgkin’s DiseaseHodgkin’s Disease

EvaluationEvaluation H&PH&P Biopsy = Reed-Biopsy = Reed-

Sternberg cellsSternberg cells Staging w/uStaging w/u

Similar to NHLSimilar to NHL LaparotomyLaparotomy

ControversialControversial

From, Principles and Practice of PediatricFrom, Principles and Practice of PediatricOncology, Lippincott Williams & Wilkins,Oncology, Lippincott Williams & Wilkins,P 640.P 640.

Hodgkin’s DiseaseHodgkin’s Disease

Localized diseaseLocalized disease Extended field XRTExtended field XRT

Disseminated diseaseDisseminated disease MOPP = nitrogen mustard, vinblastine, MOPP = nitrogen mustard, vinblastine,

procarbazine, prednisoneprocarbazine, prednisone ABVD = adriamycin bleomycin, ABVD = adriamycin bleomycin,

vincristine, dacarbazinevincristine, dacarbazine

Laboratory Diagnosis:Laboratory Diagnosis: HaematologicalHaematological: :

Normocytic normochromic anemia, High ESR*Normocytic normochromic anemia, High ESR* Leucocytosis, Eosinophilia, lymphopeniaLeucocytosis, Eosinophilia, lymphopenia Leukoerythroblastic picture - BM infiltration*Leukoerythroblastic picture - BM infiltration*

BoneBone marrowmarrow:: Normal, or late involvement.Normal, or late involvement. Trephine biopsy- diffuse or follicular infiltrationTrephine biopsy- diffuse or follicular infiltration

BiochemicalBiochemical:: High serum LDH – poor prognosisHigh serum LDH – poor prognosis Hypercalcemia, Alkaline phosphatase, Uric acid.Hypercalcemia, Alkaline phosphatase, Uric acid. Serum transaminases & Bilirubin – LiverSerum transaminases & Bilirubin – Liver

Laboratory Diagnosis:Laboratory Diagnosis: HaematologicalHaematological: :

Normocytic normochromic anemia, High ESR*Normocytic normochromic anemia, High ESR* Leucocytosis, Eosinophilia, lymphopeniaLeucocytosis, Eosinophilia, lymphopenia Leukoerythroblastic picture - BM infiltration*Leukoerythroblastic picture - BM infiltration*

BoneBone marrowmarrow:: Normal, or late involvement.Normal, or late involvement. Trephine biopsy- diffuse or follicular infiltrationTrephine biopsy- diffuse or follicular infiltration

BiochemicalBiochemical:: High serum LDH – poor prognosisHigh serum LDH – poor prognosis Hypercalcemia, Alkaline phosphatase, Uric acid.Hypercalcemia, Alkaline phosphatase, Uric acid. Serum transaminases & Bilirubin – LiverSerum transaminases & Bilirubin – Liver

Laboratory Diagnosis:Laboratory Diagnosis: Immunological:Immunological:

Monoclonal gammopathy –B cell NHL, Monoclonal gammopathy –B cell NHL, MyelomaMyeloma

Low normal gammaglobulinsLow normal gammaglobulins Autoimmune hemolytic anemia – auto ab.Autoimmune hemolytic anemia – auto ab.

Karyotypic/Genetic:Karyotypic/Genetic: t(14;18) – B cell follicular (14* heavy t(14;18) – B cell follicular (14* heavy

chain)chain) t(11;14) – diffuse NHLt(11;14) – diffuse NHL

RadiologicalRadiological

Chest x rayChest x ray Bone scanBone scan Bone x ray if +ve bone scan or bone Bone x ray if +ve bone scan or bone

painspains CT scan of chest & abdomen & pelvisCT scan of chest & abdomen & pelvis Ga 67 scanGa 67 scan

SPRCTSPRCT PET to evaluate residualsPET to evaluate residuals

Mediastinal Lymph nodes-NHLMediastinal Lymph nodes-NHL

LN biopsyLN biopsy

Must whole LN asMust whole LN as destruction of the architecture is of destruction of the architecture is of

diagnostic value and diagnostic value and also Reed Sternberg in HL id diagnostic also Reed Sternberg in HL id diagnostic

Additional work up in NHLAdditional work up in NHL

Flow cytometryFlow cytometry Peripheral bloodPeripheral blood Bone marrow detect haematological Bone marrow detect haematological

involvementinvolvement Diagnostic spinal tabDiagnostic spinal tab in in

Lymphoblastic lymphomaLymphoblastic lymphoma Burkitt’s lymphomaBurkitt’s lymphoma

Upper GIT& small bowel series & Upper GIT& small bowel series & endoscopyendoscopy in S&S of GIT in S&S of GIT

Diagnostic laparotomyDiagnostic laparotomy

Indicated only in HL stage I&IIa Indicated only in HL stage I&IIa ( as ( as supraclavicular enlargment = 40% abdominal involvement)supraclavicular enlargment = 40% abdominal involvement)

TechniqueTechnique1.1. Systemic LN examinationSystemic LN examination

2.2. Biopsy from suspicious LNBiopsy from suspicious LN

3.3. SplenectomySplenectomy

4.4. Wedge biopsy from liverWedge biopsy from liver

5.5. OvariopexyOvariopexy

6.6. AppendectomyAppendectomy

7.7. Putting silver clips at the site of involved LNPutting silver clips at the site of involved LN

Hodgkin’s DiseaseHodgkin’s Disease Localized disease (Stage I & II)Localized disease (Stage I & II)

Extended field XRT Extended field XRT Above diaphragm -------- MantleAbove diaphragm -------- Mantle below diaphragm --------Inverted Ybelow diaphragm --------Inverted Y

Recently IFRT + new modality chemotherapy ABVDRecently IFRT + new modality chemotherapy ABVD Stage III aStage III a

Extended field RTExtended field RT IFRT + ABVDIFRT + ABVD Multi agent chemotherapy ABVD or MOPPMulti agent chemotherapy ABVD or MOPP

Disseminated disease (Stage III b & IV )Disseminated disease (Stage III b & IV ) MOPP = nitrogen mustard, vinblastine, procarbazine, MOPP = nitrogen mustard, vinblastine, procarbazine,

prednisoneprednisone ABVD = adriamycin bleomycin, vincristine, dacarbazineABVD = adriamycin bleomycin, vincristine, dacarbazine

RadiotherapyRadiotherapy

Treatment and PrognosisTreatment and Prognosis

StageStage TreatmeTreatmentnt

Failure-Failure-free free

survivalsurvival

Overall 5 Overall 5 year year

survivalsurvival

I,III,II ABVD x 4 ABVD x 4 & &

radiationradiation

70-80%70-80% 80-90%80-90%

III,IVIII,IV ABVD x 6ABVD x 6 60-70%60-70% 70-80%70-80%

Hodgkin’s DiseaseHodgkin’s Disease

SurvivalSurvival Stages I, II, and III = 90%Stages I, II, and III = 90% Stage IV = 75-80%Stage IV = 75-80%

Long term complications of Long term complications of treatmenttreatment

infertilityinfertility MOPP > ABVD; males > femalesMOPP > ABVD; males > females sperm banking should be discussedsperm banking should be discussed premature menopausepremature menopause

secondary malignancysecondary malignancy skin, AML, lung, MDS, NHL, thyroid, skin, AML, lung, MDS, NHL, thyroid,

breast...breast... cardiac diseasecardiac disease

Non-Hodgkins Non-Hodgkins Lymphoma (NHL)Lymphoma (NHL)

Mechanisms of lymphoma-Mechanisms of lymphoma-genesisgenesis

Genetic alterationsGenetic alterations InfectionInfection Antigen stimulationAntigen stimulation Immuno-suppressionImmuno-suppression

NHL – Classification:NHL – Classification: According to cell type According to cell type

T cell, B cell, Histiocytic & Misc. NHL T cell, B cell, Histiocytic & Misc. NHL According to Clinical grade According to Clinical grade

Low grade, Intermediate & High grade Low grade, Intermediate & High grade NHL.NHL.

HistopathologicalHistopathological Diffuse/Follicular NHL, Diffuse/Follicular NHL, Small, Intermediate & Large cell NHLSmall, Intermediate & Large cell NHL

Ex: Lennert’s lymphoma is a low grade T cell Ex: Lennert’s lymphoma is a low grade T cell NHL. NHL.

Burkitt’s lymphoma, a high grade B cell NHLBurkitt’s lymphoma, a high grade B cell NHL

Kiel Classification of NHLKiel Classification of NHL B Cell NHL:B Cell NHL:

Low Grade:Low Grade: lymphocytic, plasmacytic, lymphocytic, plasmacytic, centrocytic, mixed centrocytic centroblastic.centrocytic, mixed centrocytic centroblastic.

High Grade:High Grade: Centroblastic, Immunoblastic, Centroblastic, Immunoblastic, Burkitts, lymphoblastic.Burkitts, lymphoblastic.

T Cell NHL:T Cell NHL: Low Grade:Low Grade: lymphocytic, mycosis, Lennerts lymphocytic, mycosis, Lennerts High Grade:High Grade: immunoblastic, lymphoblastic immunoblastic, lymphoblastic

etc.etc. Rare types:Rare types:

NCI – Working FormulationNCI – Working Formulation Low-grade NHL:Low-grade NHL:

Small lymphocyticSmall lymphocytic Follicular small cleavedFollicular small cleaved

Intermediate-grade NHL:Intermediate-grade NHL: Follicular large cellFollicular large cell Diffuse small cleavedDiffuse small cleaved

High-grade NHL:High-grade NHL: ImmunoblasticImmunoblastic LymphoblasticLymphoblastic

MiscellaneousMiscellaneous: Histiocytic, Mycosis : Histiocytic, Mycosis etc.etc.

Non-Hodgkin lymphomaNon-Hodgkin lymphomaIncidenceIncidence

Diffuse large B-cell lymphoma

Follicularlymphoma

Other NHL

Follicular lymphomaFollicular lymphoma

most common type of “indolent” most common type of “indolent” lymphomalymphoma

usually widespread at presentationusually widespread at presentation often asymptomaticoften asymptomatic not curable (some exceptions)not curable (some exceptions) associated with BCL-2 gene associated with BCL-2 gene

rearrangement [t(14;18)]rearrangement [t(14;18)] cell of origin: germinal center B-cellcell of origin: germinal center B-cell

Diffuse large B-cell lymphomaDiffuse large B-cell lymphoma

most common type of “aggressive” most common type of “aggressive” lymphomalymphoma

usually symptomaticusually symptomatic extranodal involvement is commonextranodal involvement is common cell of origin: germinal center B-cellcell of origin: germinal center B-cell treatment should be offeredtreatment should be offered curable in ~ 40%curable in ~ 40%

Diffuse - & - Follicular Diffuse - & - Follicular

NHL- Histologic types

Small – Intermed. – Large Small – Intermed. – Large

NHL- Histologic typesNHL- Histologic types

Lymphoma classificationLymphoma classification(based on 2001 WHO)(based on 2001 WHO)

B-cell neoplasmsB-cell neoplasms PrecursorPrecursor B-cell neoplasms (2 types) B-cell neoplasms (2 types) MatureMature B-cell neoplasms (19) B-cell neoplasms (19) B-cell proliferations of uncertain malignant potential (2)B-cell proliferations of uncertain malignant potential (2)

T-cell & NK-cell neoplasmsT-cell & NK-cell neoplasms PrecursorPrecursor T-cell neoplasms (3) T-cell neoplasms (3) MatureMature T-cell and NK-cell neoplasms (14) T-cell and NK-cell neoplasms (14) T-cell proliferation of uncertain malignant potential (1)T-cell proliferation of uncertain malignant potential (1)

Hodgkin lymphomaHodgkin lymphoma Classical Hodgkin lymphomas (4)Classical Hodgkin lymphomas (4) Nodular lymphocyte predominant Hodgkin lymphoma (1)Nodular lymphocyte predominant Hodgkin lymphoma (1)

Clinical manifestationsClinical manifestations VariableVariable

severity: asymptomatic to extremely illseverity: asymptomatic to extremely ill time course: evolution over weeks, months, or time course: evolution over weeks, months, or

yearsyears

Systemic manifestationsSystemic manifestations fever, night sweats, weight loss, anorexia, fever, night sweats, weight loss, anorexia,

pruritispruritis

Local manifestationsLocal manifestations lymphadenopathy, splenomegaly most lymphadenopathy, splenomegaly most

commoncommon any tissue potentially can be infiltratedany tissue potentially can be infiltrated

Lymphadenopathy in NHLLymphadenopathy in NHL

Number Number multiple multiple SiteSite mostly extra nodal mostly extra nodal SizeSize usually large usually large ShapeShape matted matted ConsistencyConsistency hard & hard &

cysticcystic FixedFixed skin stretched & redskin stretched & red tendertender fixation fixation

(1) Cervical lymphadenopathy

(2) Hilar LN bronchial compression which cause segmental atelectasis

(3) Mediastinal

(a)SVC compression --- dilated Neck veins

(b) RLN ---hoarsness of voice

(c) Trachea & bronchi--- cough& dyspnea

(d) Lung--- Dyspnea & effusion (4) Splenomegally dt infiltration or hyperplasia

(5) Hepatomegally--- Ascites dt•Hepatic dysfunction•Peritoneal invasion

(6) jaundice

Prehepatic •hemolytic autoimmune•hypersplenism

Hepatic– • cholestatic• hepatitis

Posthepatic – LN at porta hepatis

(7) Stomach & bowel malabsorption syndromes

(8) Bone deposites•Sever pain•Pathological fractures

(9) Neurological • cord compression• Cranial nerve palsy• Root pains

(10) Skin nodules

(11) Mycosis fungoids

(12)AnaemiaHypersplenismBM infiltrationCytotoxic drugs

Extranodal manifestations

Non HodgkinNon Hodgkin

Lymphoma spread to SpleenLymphoma spread to Spleen

Lymphoma IntestineLymphoma Intestine

A practical way to think of lymphomaA practical way to think of lymphomaCategory Survival of

untreated patients

Curability To treat or not to treat

Non-Hodgkin lymphoma

Indolent Years Generally not curable

Generally defer Rx if asymptomatic

Aggressive Months Curable in some

Treat

Very aggressive

Weeks Curable in some

Treat

Hodgkin lymphoma

All types Variable – months to years

Curable in most

Treat

Staging of LymphomaStaging of Lymphoma

Burkitt’s LymphomaBurkitt’s Lymphoma

Unusual, B-Lymphoblastic high Unusual, B-Lymphoblastic high gradegrade

Young african children, jaw bonesYoung african children, jaw bones Isolated histiocytes, starry sky Isolated histiocytes, starry sky

patternpattern EBV infection related. t(8;14)EBV infection related. t(8;14) Chemotherapy – good responseChemotherapy – good response But relapse usual, 30% cure.But relapse usual, 30% cure.

Burkitt’s LymphomaBurkitt’s Lymphoma

Burkitt’s LymphomaBurkitt’s Lymphoma

Burkitt’s Lymphoma L.N.Burkitt’s Lymphoma L.N.

Non specific LNNon specific LN

Tuberculosis of LNTuberculosis of LN

Metastasis LNMetastasis LN