MALIGNANT LYMPHOMASMALIGNANT LYMPHOMAS

Dr. Manjit Singh SarenDr. Manjit Singh Saren

MBBS, MCPS, DTM&H, DCP, D. PathMBBS, MCPS, DTM&H, DCP, D. Path

MAHSA University CollegeMAHSA University College

LYMPHOID NEOPLASIA

Malignant monoclonal proliferation of lymphoid cells.Involves lympho-reticular sites:Liver, spleen, GIT and bone marrow.Involvement of bone marrow causes leukemiaConversely leukemia to lymphoma

LYMPHOMA CLASSIFICATION

B-Cell Lymphoma:Derived from follicular centre or post follicular centre. T-Cell Lymphoma:Thymic in originMigration of lymphocytes to thymus

LYMPHOID MALINANCIES

FREQUENCY:

Non Hodgkin’s Lymphoma 62 %Plasma Cell Disorders 15 %Hodgkin’s Lymphoma 8 %Chronic Lymphocytic Leukemia 9%Acute Lymphocytic Leukemia 4%

HODGKIN’S DISEASEHODGKIN’S DISEASE

HODGKIN’S LYMPHOMAHODGKIN’S LYMPHOMA

RYE’S CLASSIFICATION PROGNOSIS

i) Nodular sclerosis 70% Very goodii) Lymphocyte rich 5% Excellentiii) Mixed cellularity 22% Goodiv) Lymphocyte depletion 1% Poor

HODGKIN’S LYMPHOMA

Incidence: 8% of lymphoid malignancies.Features:Distinct group of neoplasm.Affects contiguous nodes or extra-nodal sitesAge:Bimodal: 15-35 yrs : 50 yrs +

HODGKIN’S LYMPHOMA

Etiology:i) Hereditary: 99 X in identical twinsii) Familial incidence: (HLA histo-compatibility)iii) Virus: Ebstein- Bar virus genome EB Virus:70% cases of mixed cellularity

HODGKIN’S LYMPHOMA

Micro:

“Abnormal giant cells with multi-lobed nuclei, prominent acidophilic nucleoli giving a Mirror Image or OWL’S EYE appearance” Known as: Dorothy-Reed-Sternberg cells

REED STERNBERG CELL

H.D. PATHOGENESIS:

Reed Sternberg cells secrete cytokines:i. IL-8 (Attracting eosinophils)ii. IL-5 (growth factor for eosinophils)iii. IL-13 (stimulation of R-S cells)iv. Growth factor-B (fibro-genesis)

HODGKIN’S LYMPHOMA

Clinical Features:1. Cervical and mediastinal lymphadenopathy Painless, mobile and firm.2. Hepato-splenomegaly 3. Fever 4. Night sweats.4. Weight loss, fatigue and malaise

Micro:Micro:

1.Dorothy-Reed Sternberg Cells1.Dorothy-Reed Sternberg Cells2.’Pop corn’ cells2.’Pop corn’ cells (Lympho-Histiocytes)(Lympho-Histiocytes)3.Lacunar cells3.Lacunar cells4.Eosinophils4.Eosinophils

LABORATORY DIAGNOSIS

1. Normocytic hypochromic anemia.2. EosinophiliaHISTOPATHOLOGICAL i. Haematoxylin and Eosin stains ii. Immuno-histochemical stains: CD 20 for B Cells CD 15 and CD 30 for Hodgkin’s Cellsiii. X Ray and CT scan Chest and Abdomen

ANN ARBOR STAGING

I. Single lymph node group or extra lymphatic organ or site

II. Multiple lymph nodes ( same side of diaphragm)

III. L. Nodes on both sides of diaphragmIV. Multiple extra nodal sites and Marrow Bulk>10cm: Extra nodal extension

PROGNOSIS

5 year survival:Ann Arbor Staging. I, II, III, IVStage I and II: 100 %Advanced stage: 50 %Lymphocyte predominant: Best prognosisLymphocyte depleted: Poor prognosis.

Treatment:Aggressive chemo-radiotherapy

NON- HODGKIN’S LYMPHOMASNON- HODGKIN’S LYMPHOMAS

Dr. Manjit Singh SarenDr. Manjit Singh SarenMAHSA UniversityMAHSA University CollegeCollege

Subcapsular Sinus

Cortex Medulla

B cells

T cells

Lymphoid Follicle

B cells

Germinal Centre

Lymphoid Follicle

INTRODUCTION

NHL: Rising incidence.Group of lympho-proliferative disorder.Affects B and T and Natural Killer lymphocytesHigh mortality rate.

Incidence:

B-CELL lymphomas: 80-90%T-CELL lymphomas:15-20%NK Lymphomas: Rare

In Malaysia: NHL 3rd commonest cancer

WHO CLASSIFICATION

1. B-CELL LYMPHOMA2. T-CELL LYMPHOMA3. NATURAL KILLER CELL LYMPHOMA (NK)

1. B CELL: NON HODGKIN’S LYMPHOMA

i ) MALT Lymphoma 6%*ii) Follicular Lymphoma 22%*iii) Diffuse large cell Lymphoma 31 %*iv) Burkitt’s Lymphoma 2.5%*

2. T CELL: NON HODGKIN’S LYMPHOMA

1. Extra nodal NK cell lymphoma (Nasal Type)*2. Mycosis Fungoides/Sezary syndrome*

B and T CELL LYMPHOMA

1. IMMATURE CELL LYMPHOMA 2. MATURE CELL LYMPHOMA

CLINICAL MANIFESTATIONS:

1. Lymphadenopathy2. Extra-nodal involvement: i. Splenomegaly ii. Anterior mediastinal mass (with Supra-Vena Cava obstruction)iii. Bone Marrowiv. Central Nervous System

A. IMMATURE B CELL and T CELL: LYMPHOBLASTIC LYMPHOMA Age: children/young adultsCells: Immature lymphocytes i) B Cells: > Lymphoblasts ii) T Cells: > LymphoblastsTransforms: Acute Lymphoblastic Leukemia

IMMATURE B CELL:

LYMPHOBLASTIC LYMPHOMA:

Clinical Presentation:i) Lymphadenopathy.ii) Hepato-splenomegaly.iii) CNS and cutaneous infiltration.iv) Blood and Marrow involvement.Complication: LEUKEMIA

Cervical lymphadenopathyCervical lymphadenopathy

IMMATURE B CELL LYMPHOMA:

LYMPHOBLASTIC LYMPHOMA

INVESTIGATIONS:CBC: Anaemia, Thrombocytopenia and NeutropeniaPBF: Lymphoblasts and smudge cells.Bone Marrow:Malignant undifferentiated cellsMegakaryocytes: Reduced

INVESTIGATIONS: IMMATURE B CELL LYMPHOMA Stains : i) Periodic Acid Schiff: + ve (PAS) ii) Myelo-peroxidase: - veImmunophenotypes: B Cells: CD 20 +ve T Cells: CD 3 and 5 +veCytogenetics: t(9;20) Philadelphia +ve A.L.L.

MATURE B CELL LYMPHOMAS

SMALL CELL LYMPHOMAAssociated with:Breakdown immune regulationsHypogamma-globulinemia

AUTO-ANTIBODIES: 1. AIHA 2. ThrombocytopeniaComplication: Large B-Cell Lymphoma

NON HODGKIN’S T CELL LYMPHOMA

Clinical Presentation:

LymphadenopathyHepatosplenomegalyLeukemia (marrow invasion)Immuno-phenotype: CD 3 and 5+ve CD 20 -ve

LABORATORY DIAGNOSIS. SMALL CELL LYMPHOMAi) Anaemia (20% AIHA)ii) 90% mature lymphocytes + ‘smudge cells’iii) Platelets: reducedL.N. Biopsy: Diffuse replacement by small mature B lymphocytes

1. FOLLICULAR B CELL LYMPHOMAAge: Elderly

Clinical Presentation:LymphadenopathyMicro: Grades: 1,2,3.Loss of normal architecture.Replaced by nodal patternNo mitosis or apoptosis

FOLLICULAR LYMPHOMAETIOLOGY:B Cl 2 oncogene

Immune-phenotype:

CD 20 and B Cl 2 +ve40% > Diffuse large B cell.

Prognosis: BAD

2. MALT B-CELL LYMPHOMA

Extra Nodal LymphomaMALTOMA= Commonest gastric lymphoma Etiology: Helicobacter PyloriInactivation: p53 Tumour suppressor gene. Micro: Diffuse sheets of small lymphocytesImmuno-phenotype: CD: 20+ve CD: 3 and 5-ve

Most common. Age: Elderly

Clinical Presentation:i. Lymphadenopathyii. Extra nodal mass: Bone marrow or GIT, Primary CNS massMediastinal mass with effusionAbdominal mass

3. DIFFUSE LARGE B CELL LYMPHOMA

DIFFUSE LARGE B CELL LYMPHOMA

Predisposing Factors:1) Congenital & acquired immunodeficiency2) EBV in immuno-deficiency states3) Human Herpes Virus Type 8 (HHV-8)4) Tumour suppression p53 gene inactivation

DIFFUSE LARGE B CELL LYMPHOMA

Micro: Diffuse nodal effacementLarge cells with large nuclei and nucleoli.Immuno-phenotype: CD 20 and CD10 +ve CD 3 and 5 -vePrognosis: PoorVery aggressive

BURKITT’SBURKITT’S LYMPHOMA LYMPHOMA

BURKITT’S LYMPHOMA :30% NHLAffects children/adultsSite: Mandible and neck (Extra-nodal)Etiology:Immune deficiency and HIV states Types:Endemic: EBV (90% in viral DNA)Non-endemic: EBV DNA –ve

DIAGNOSIS:1. Micro: Round nuclei with 2-5 Nucleoli. Mitosis++ KI 67 +veCytoplasmic vacuolation Macrophages: ‘Starry Sky Pattern’2. Immunophenotype: CD20 and CD 10 +ve

CD3 and 5 –ve 3. Oncogenes: C-myc ongene +ve

B Cl 2 oncogene +ve

MATURE T CELL LYMPHOMA

Aggressive T-cell lymphomasCommon in young adultsBone marrow involvement TYPES:1. MYCOSIS FUNGOIDES2. EXTRA NODAL ANAPLASTIC LARGE T/NK CELL LYMPHOMA NASAL TYPE

MYCOSIS FUNGOIDES T CELL LYMPHOMA

PERIPHERAL MATURE T CELL LYMPHOMA

1) MYCOSIS FUNGOIDESCutaneous T-cell lymphomaNHL in adultsEnd result: Leukemia with Sezary cells in blood

MYCOSIS FUNGOIDES

Non fungal Cutaneous T cell lymphomaAge: ElderlyCD 4 -T Helper CellsRash like skin lesions:Micro: Pautrier’s microabscess CD4 (T cells) with cerebriform nucleiSpreads to nodes.

Blood Smear: CD 4+ ve T cells “Flower Cells”(Sezary Cells)Extra-cutaneous lesions:Lymph nodesHepatosplenomegalyOut come: Poor

COMPLICATIONS:

Hodgkin’s lymphomaNon Hodgkin’s lymphomaInfections: Staphylococcus aureus Pseudomonas Sezary Syndrome: Dissemination 1.Lympadenopathy2.Blood spread3.Hepatosplenomegaly4.Generalized erythroderma

Cutaneous T Cell LymphomaCerebreform nucleiCTCL

SEZARY CELLS IN BLOOD

PERIPHERAL MATURE T CELL LYMPHOMA

2. ANAPLASTIC LARGE NK CELL LYMPHOMAInvolves nasal sinuses and lymph nodes. Etiology: EBV Age: 18 + yrsMicro:.Destructive and aggressive lesionImmunophenotype: CD30 + veInfiltrates skin: Large T-cell lymphoma

NASOPHARYNGEAL CARCINOMA

NASOPHRNGEAL CARCINOMAEpidemiology:Chinese and Eskimo. Common in S. E. AsiaGenetic: HLA histo-compatibilityEnvironmental factors:EBV (‘finger print’) in tumour cells

NASOPHRYNGEAL CARCINOMA

Symptoms:Nasal discharge or bleedNasal stuffiness/blockageTinnitusConvergent squintCervical lymphadenopathy

WHO CLASSIFICATIONType I: 25 %Moderate-well differentiated( keratinizing)Type 2: 12 %Non-keratinizingType 3: 60 %Undifferentiated (d/d: Lymphoma)Diverse Group: i) Lympho-epithelioma ii) Anaplastisc

DIAGNOSISi) Humoral response:>Detection of circulating EBV IgA antibodyii) PCR and gel electrophoresis >97-100% EBV in DNA of tumour cellsHigh antibody titres to EBVGold Standard: (i) Histology & IHC (EMA +ve; CK7 –ve) (ii) Viral detection in biopsy

TREATMENT

RadiotherapyNPC are radiosensitive

Outlook: Poor/Fatal

MANTLE B - CELL LYMPHOMA

ETIOLOGY: Cyclin D1 oncogeneInfiltrates:Bone marrow, peripheral blood and GIT (polyp-like growths)Micro: Diffuse growthImmunophenotype: CD 20 Cyclin D1 oncogene +vePrognosis: Aggressive

Reed-Sternberg Cell IHC Stain)Reed-Sternberg Cell IHC Stain)

Hodgkin’s LymphomaHodgkin’s Lymphoma

“ “Pop Corn Cell”Pop Corn Cell”

Outcome of Patients:

Highly variableHistology is the major determinant of treatment outcome and prognosis

MIXED CELLULARITY

Most common after 50th yrMicro:Pathogonomic Reed Sternberg cells ++ Eosinophils Neutrophils Plasma cells

HODGKIN’S LYMPHOMA

A)NODULAR SCLEROSISMost common in youngCervical and supra-clavicular lymph nodesMicro: LACUNAR CELLS (Multilobed nucleus with retracted cytoplasm)Eosinophils and fibrosisR-S cells infrequentImmunophenotype: CD 20+ve Diagnostic I.H.C. CD 15 and CD 30 +ve

LYMPHOCYTE DEPLETED

Micro: Small lymphocytes and histiocytesEosinophils R-S cells: scanty /absentImmunophenotype: CD 15 & CD 30 -veL.H.Cells (Lympho-Histiocytic Cells)i.e. variants of R-S cells with puffy nuclei.Called “POP CORN” nucleiTransforms : Diffuse Large B Cell Lymphoma

COMLPICATIONS OF TREATMENT.

i. Acute non- lymphocytic leukemiaii. Lung canceriii. Non Hodgkin’s lymphomaiv. Cancer stomachv. Malignant melanoma

PERIPHERAL MATURE T CELL LYMPHOMA

2) Adult T-cell Lymphoma/Leukemia

Uncommon : T-cell NHLClinically: Lymphadenopathy Hepatosplenomegaly and skin involvement.Associated with: i) Retro virusii) Human T cell Lymphotrophic Virus-1 (HTLV-1)

GENERAL PRINCIPLES OF DIAGNOSIS i) H&E stainsii)Immuno-histochemistry stains iii)CLUSTER OF DIFFERENTIATION NUMBERImmuno-histochemistry stains:B Cells: CD45, CD 20, 21, 79 (CD 3 & 5-ve) T Cells: CD 3 and CD 5.iii) Flow cytometryiv) Molecular Cyto-genetics (specific chromosomal translocations)In Burkitt’s lymphoma:c-myc translocation (t8;14)

DIAGNOSIS NON HODGKIN’S LYMPHOMA

CBC, ESR, Peripheral Blood PictureChest X-rayCT Scan chestPET-CT and MRI spine (cord compression) Cerebrospinal Fluid cytologyBiochemical: Alkaline phosphatase, LFT ,LDHCreatinine, serum electrolytes, uric acid.Serology: HIV, Hepatitis B and C virus.Lymph node biopsy and bone marrow examination

WHAT CAUSES NON HODGKIN’S LYMPHOMA

Etiology: not knownAssociated with: 1. Chronic inflammatory diseases: MALT “Mucosa Associated Lymphoid Tissue lymphomas” and Helicobacter Pylori infections. 2. Autoimmune diseases: (Hashimoto’s thyroiditis and Rheumatoid arthritis) 3. Immune suppression 4. Solid organ transplantation and iatrogenic immuno-suppression with drugs 5.HIV infections

GENERAL CHARACTERISTICS

1. Geographic location: >Burkitt’s Lymphoma in Africa and S. America>Adult T Cell lymphoma: Japan and W. Indies2. Age: Children -Hodgkin’s Lymphoma -Burkitt’s Lymphoma

Adults -Follicular Lymphoma3. Sex: Males -Hodgkin’s Lymphoma

GENERAL CHARACTERISTICS1.Lymphadenopathy2. Hepato-splenomegaly3. Mediastinal mass4. CNS and CSF involvement(a).Hodgkin’s Disease(b).Diffuse Large B Cell lymphoma(c). Adult T Cell Lymphoma5. Fever, malaise, weight loss, anemia, dyspnoea6. Cutaneous Lymphoma: Mycosis Fungoides7. Bone Marrow: Lymphoma-Leukemia-Lymphoma

GENERAL CHARACTERISTICS

Etiology: VIRAL ASSOCIATEDHerpes virus:Burkitt’s lymphomaPrimary CNS lymphoma in AIDSHodgkin’s Lymphoma in all R-S cellsAnaplastic Nasopharyngeal carcinoma Kaposi’s Sarcoma -Human Herpes Virus-8 and EBVReactive lymphadenitis: Human Herpes Virus-6 (HHV-6)

COMPLICATIONS

1) Disrupts normal immune regulatory mechanisms.2) Leukemia3)CNS involvement in:DLBCL, Mantle Cell Lymphoma4) Extra nodal spread5) Bone marrow infiltration> leukemia6) Extra Nodal G.I.T. Lymphomas (MALT)

INVESTIGATIONSINVESTIGATIONSCBCCBCLymph node biopsy and I.H.C.Lymph node biopsy and I.H.C.Serum Lactate dehydogenaseSerum Lactate dehydogenaseRenal and liver function testsRenal and liver function testsUric acidUric acidComputed Tomography-chest/abdomenComputed Tomography-chest/abdomenHIV screenHIV screenHepatitis B and CHepatitis B and CCardiac functionsCardiac functionsBone marrow aspirate Bone marrow aspirate Spinal tap-CSFSpinal tap-CSF