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Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow characterized by increased proliferation of immature blast cells. It results from mutations that affect the common myeloid progenitor cell. Symptoms include fatigue, fever, bleeding, and infections. Diagnosis involves blood and bone marrow tests showing elevated white blood cell counts with immature blasts. Standard treatment is 7-day continuous cytarabine with 3-day daunorubicin induction chemotherapy, with hematopoietic stem cell transplant for high risk cases. Prognosis depends on risk factors like age and genetic abnormalities.

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ACUTE MYELOID LEUKAEMIA DR CHETAN
INTRODUCTION  Acute leukaemia's are stem cell disorders characterized by malignant neoplastic proliferation and accumulation of immature and non functional hematopoietic cells in the bone marrow.  The neoplastic cells show increased proliferation and/or decreased apoptosis.  If the defect primarily affects the common myeloid progenitor (CMP) then it is called Acute myeloid leukaemia.
 Acute myeloid leukaemia (AML) is a neoplastic disease characterized by infiltration of the blood, bone marrow, and other tissues by proliferative, clonal undifferentiated cells of the hematopoietic system.  AML is the result of a sequence of somatic mutations in a multipotential primitive hematopoietic cell or, in some cases, a more differentiated progenitor cell.  It can be slow growing or rapidly fatal.  AML is the predominant form of leukaemia during the neonatal period
 Incidence : 1.5/100,000/year in infants decreases to approximately 0.4 per 100,000 children ages 5 to 9 years, increases gradually to 1.0 persons per 100,000 until age 25 years, and thereafter increases exponentially until the rate reaches approximately 25/100,000 persons.  AML accounts for 15 to 20 percent of the acute leukemias in children and 80 percent of the acute leukemias in adults.  Men > Women (4.5 : 3)
ETIOLOGY  HEREDITY  1) Chromosomal aneuploidy like Trisomy 21 noted in Down syndrome  2) Defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, and Ataxia telangiectasia  3) Congenital neutropenia ie Kostmann syndrome  4) Germline mutations of CCAAT/enhancer-binding protein α (CEBPA), runt-related transcription factor 1 (RUNX1), and tumor protein p53 (TP53) have also been associated with a higher predisposition to AML
 RADIATION  Peaks after 5 to 7 yrs of exposure.  Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people also exposed to alkylating agents.  CHEMICAL AND OTHER EXPOSURES  Exposure to benzene, plastic, rubber, petroleum products, paint, ethylene oxide, herbicides and pesticides can increase the risk.  Smoking can also increase the risk
 DRUGS  Anticancer drugs are the leading cause of therapy-associated AML.  Alkylating agent–associated leukaemia occur on average 4–6 years after exposure, and affected individuals have aberrations in chromosomes 5 and 7.  Topoisomerase II inhibitor–associated leukaemia occur 1–3 years after exposure, and affected individuals often have aberrations involving chromosome 11q23.  Other agents like Chloramphenicol, phenylbutazone, and, less commonly, chloroquine and methoxy psoralen.
CLINICAL FEATURES  SYMPTOMS :  Present with nonspecific symptoms initially.  Fatigue is the first symptom  Fever with or without infection will be present in approximately 10% patients  Bleeding, easy bruising  occasionally, bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis  Rarely patients may present with symptoms from a myeloid sarcoma, a tumour mass
 PHYSICAL FINDINGS :  Splenomegaly, Hepatomegaly, Lymphadenopathy, Sternal tenderness  Evidence of infection and haemorrhage  Severe gastrointestinal bleeding, intrapulmonary haemorrhage, or intracranial haemorrhage occurs mostly in APL  Infiltration of the gingivae, skin, soft tissues, or meninges with leukemic blasts is characteristic of the monocytic subtypes.
LABORATORY FINDINGS  PERIPHERAL BLOOD  LEUCOCYTES  - Elevated count,  - 50% cases will have decreased or within reference interval.  - Counts ranges from <1000 to >100000/ml.  - Presence of blasts > 20% suggests AL diagnosis.  Typically the myeloblasts seen in AML is 20mcM in diameter with nucleus composed primarily of dispersed chromatin and variable prominent nucleoli.  Golgi apparatus is present but its not easily visible.  Granules may be present but not visible by bright field microscopy.
 ERYTHROCYTES  - Typically decreased and macrocytic,  - RDW is increased,  - Erythrocyte inclusions such as Howell-Jolly bodies, Pappenheimer bodies and basophilic stippling is seen.  -Nucleated RBCs can be present in proportion to anaemia or marrow damage.  PLATELETS  - Typically decreased  - Hypo granular forms and sometimes giant platelets.  - Qualitative platelet defect .
 The presence of AUER RODS in blasts excludes ALL. Presence of azurophilic granules is helpful in identifying myeloid nature of the leukaemia.  Other abnormal findings in blood smear include monocytosis and neutropenia.  Neutrophils shows dysplasia including hypo segmentation , hypo granulation and small nuclei with hyper condensed chromatin.  Eosinophils and Basophils are mild to markedly elevated.
 BONE MARROW  - Hypercellular with decreased fat content.  - predominance of blasts and sometimes with fibrosis.  - Auer rods are present in BM blasts in half of AML cases  OTHER LABORATORY FINDINGS  - Hyperuricemia and increased lactate dehydrogenase due to increased cell turn over  - Hypercalcemia due to increased bone resorption  - Increased serum and urine muramidase with monocytic component
CELL LINEAGE IDENTIFICATION  CYTOGENETICS  Common stains used are Myeloperoxidase (MPO), Sudan Black B (SBB), Naphthol AS-D Chloroacetate (specific esterase) and alpha naphthyl esterase (non specific esterase).  Granulocytic cells stain positive with MPO & SBB, whereas lymphoblasts are negative. So differentiates AML & ALL.  Granulocytic cell stains positive with specific esterase where as monocytic cell lineage stain positive with non specific esterase. So esterase helps to differentiate these two.
IMMUNOPHENOTYPING BY FLOW CYTOMETRY  Its done when morphological appearance and cytochemical reactions do not clearly define cell lineage or when presence of more than one neoplastic cell population is suspected.  First panel should differentiate AML from B cell ALL and T cell ALL., then second panel should be used to subtype the AML into granulocytic, monocytic, erythrocytic, and megakaryocytic lineages.
CYTOGENETIC OR MOLECULAR ANALYSIS  2/3 rd of patients with AML have detectable cytogenetic abnormalities which includes aneuploidies and translocations.  Commonly observed aneuploidies include trisomy 8 & 21 , monosomy 7 & 21, and loss of x & y chromosomes.  Random cytogenetic abnormalities are observed in AML with recurrent genetic abnormalities and therapy related myeloid neoplasms which are characteristic.
 Complete remission (CR) is traditionally defined by < 5 % blasts, absolute neutrophil count (ANC) < 1000/µL and platelets (plt) > 100000/µL in adult and > 80000/µL in paediatric AML.
STANDARD INDUCTION THERAPY  Includes a regimen based on a 7-day continuous infusion of cytarabine (100–200 mg/m2 /d) and a 3-day course of daunorubicin (60–90 mg/m2 /d).  IDAC : cytarabine 1.0–1.5 g/m2, 2 times per day  TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA: Tretinoin (all-trans-retinoic acid [ATRA]), an oral drug that induces the differentiation of leukemic cells bearing the t(15;17).  with or without anthracycline-based chemotherapy and possibly maintenance with tretinoin.  HSCT
ACUTE LYMPHOBLASTIC LEUKEMIA.
 Acute Lymphoblastic Leukaemia is defined as Malignant disease of marrow in which early lymphoid precursors proliferate and replace the normal Hematopoietic cells.  It is the most common Malignancy in children of 2-10 years of age, with peak incidence at 4-5 years of age.  Has Bimodal distribution with 2nd peak at 65 years of age.  Acute onset with short duration of history.  85% are B cell (Pre B ALL- Good prognosis)  15% are T cell
TREATMENT OF ALL  Induction therapy -  If Philadelphia Chromosome present - Steroid + Tyrosine Kinase Inhibitor  If other mutations - VADD regimen if Age <40 ( Vincristine, Asparaginase, Doxorubicin, Dexamethasone) Hyper CVAD regimen if Age > 40 ( Hyperfractionated Cyclophosphamide, Vincristine, Anthracycline/Doxorubicin, Dexamethasone)
CNS Prophylaxsis -  Intrathecal Methotrexate + Cytarabine  With or without WBRT (Whole Brain Radiotherapy) - in those with high risk features : 1. WBC count >50000 at the time of presentation 2. T Cell phenotype 3. Ph Chromosome positive 4. t(4;11)
 Remission is defined as <5% blasts in bone marrow.  Post Remission treatment is based on whether the patient belongs to Standard risk or High risk group.  For standard Risk, Consolidation therapy for 7 months , which is followed by Maintenance phase for 2-3 years.  For High risk, Re Induction with High Dose Chemotherapy, followed by Allogenic Stem Cell Transplantation.
LYMPHOMAS
HODGKINS LYMPHOMA • Hodgkin lymphoma encompasses adistinctive group of neoplasms thatare characterized by the presenceof a Reed-Sternberg cell. •Arise in a single lymph node orchain of lymph nodes and typically spread in a stepwise fashion toanatomically contiguous nodes. • Two majorsub-typesare now recognized : a) Classic Hodgkins Lymphoma b) NodularLymphocyte predominant Hodgkins lymphoma
CLINICAL FEATURES • Hodgkins Lymphoma patients presentwith peripheral lymphadenopathy. •Involved nodes are non tenderwith nooverlying skin changes,discreteand freely movable. • Characteristicclinical presentation is enlarged superficial lymph nodes in young adults. • Commonly involved lymph nodes arecervical and supraclavicular(60-80%), followed byaxillary lymph nodes. Inguinal and femoral lymph node groupsare less commonly involved. • Central lymphadenopathy is seen in somesub-types.
B SYMPTOMS A) FEVER (25-50%) B) DRENCHING NIGHT SWEATS C) WEIGHT LOSS D) OTHER NON-SPECIFIC SYMPTOMS (pruritus, fatigue and pain after drinking alcohol) SYMPTOMS OF EXTRA NODAL MANIFESTATION : a) Involvement of Liver and spleen Abdominal swelling secondary to hepatomegaly or hepatosplenomegaly Jaundice and ascites b) Signs of mediastinal involvement Retrosternal Chest pain Cough and shortnessof breath Pleural and pericardial effusion
INVESTIGATIONS A. DETAILED HISTORYWITH ATTENTION TO PRESENCE OR ABSENCE OF CLINICAL SYMPTOMS B. CAREFUL PHYSICAL EXAMINATION EMPHASIZING NODE CHAINS , WALDEYERS RING AND SIZE OF LIVER AND SPLEEN C. ROUTINE LABORATORYTESTS • Complete Blood Cell Count • Erythrocyte Sedimentation Rate • Liver Function Test
D. CHEST RADIOGRAPH • Lowcost method fordiagnosis and surveillance in Hodgkins Lymphoma • Useful fordetecting mediastinal disease
E. CT SCAN • Standard thoracicexamination for patients with HL • Useful fordetermination of sites on initial involvement as well as extent of disease • Helps in classification of earlystage patients into favourable orunfavourable prognosis.
F. FDG-PET SCAN • Whole body PET using 18F- fluorodeoxyglucose is asensitive indicator for disease. • It is used in initial evaluation aswell as in staging procedures after treatment to assess response to therapy. • Recommended whenotherdiagnostic modalities are inconclusive • FDG-PET moreaccurately identifies the correctpretreatment stage in HL compared with CECT (which tends to understage or overstage thedisease) • FDG-PET is able todistinguish viable/active tumorcells from fibrosisor necrosis in a residual massafter treatment
REED STERNBERG CELL • Thesinequa non of Hodgkin lymphoma is the Reed Sternberg (RS) cell • Thesearedifferent kinds of giant cells. • Usuallyderived from B lymphocytes. • Enormous bilobed or multilobate nucleus, exceptionally prominent nucleoli and abundant, usually slightlyeosinophilic cytoplasm. • Particularlycharacteristicarecells with two mirror-image nuclei , eachcontaining a large acidophilic nucleolus surrounded by aclearzone, features that impart an “owl- eye” Appearance.
CLASSIC HODGKINS LYMPHOMA • Monoclonal Lymphoid Neoplasm, composed of mononuclear Hodgkins cellsand multi- nucleated Reed Sternberg cells in an infiltrate containing a mixtureof eosinophils, small lymphocytes , neutrophils and histiocytes. • Subtypesof Classic Hodgkins Lymphoma( cHL): a) Nodular Sclerosis type b) Mixed cellularity c) Lymphocyte Rich d) Lymphocyte Depleted
NODULAR SCLEROSIS TYPE • It is the mostcommon subtype (of cHL) • Mostcommon in adolescents and young adults • Mediastinum and othersupra-diaphragmatic sites arecommonly involved PATHOLOGY : • Characterised by Collagen bands that surround at leastone nodule • “ Lacunar” type Reed Sternberg cells • Background consists of lymphocytes, histiocytes, plasmacells, eosinophils and neutrophils.
MIXED CELLULARITY TYPE • Thissubtypecomprises 15-30 % of Hodgkins Lymphoma cases. • Can occurat any age. • Abdominal Lymph nodes and spleen arecommonly involved. PATHOLOGY : •Infiltrate is usuallydiffuse orvaguely nodular • Consists of lymphocytes, eosinophils, cellsand histiocytes. • Reed Sternberg cellsareof theclassic, diagnostic type with bi-lobed, double or multiple nuclei.
LYMPHOCYTE RICH TYPE • Comprises of 5 % cases of Hodgkins Lymphoma • Predominant in males. • Isolated cervical oraxillary lymphadenopathy • Betterprognosis than othersub-typesof cHL PATHOLOGY • Background infiltrate consisting predominantly of lymphocytes with almost no eosinophils • presence of lymphohistiocytic variant RS cells that have a delicate multilobed, puffy Nucleus (“ Popcorn cells”)
LYMPHOCYTE DEPLETED TYPE • Leastcommon variant ( less than 1%) • Mostcommon in olderpatients, HIV positive individuals • Abdominal lymphadenopathy with involvement of spleen and mesenteric nodes. PATHOLOGY • Diffuse and hypocellular infiltrate. • Large numberof RS cellswith “sarcomatous” variants. • Paucity of other inflammatory cells
COTSWOLDS MODIFICATION OF ANN ARBOR CLASSIFICATION
STAGING OF HODGKINS LYMPHOMA
TREATMENT METHODS 1. RADIOTHERAPY 2. CHEMOTHERAPY 3. COMBINED TREATMENT MODALITY
RADIOTHERAPY • Radiation therapy is the mosteffective single therapeuticagent for treating early stage Hodgkins lymphoma.
DOSE: EARLYSTAGE : • IFRT 30Gy in daily 2Gy fractions over 2 to 3 weeks. ADVANCED STAGE : • Radiotherapy for residual diseaseafterchemotherapy includes doses of 30-34 Gy in 15-20 fractions of 1.8-2.0 Gyover 3 to 4 weeks.
CHEMOTHERAPY
EARLY FAVORABLE STAGES : • Treatment consists of a brief chemotherapy ( 2-3 cycles) plus IF-RT EARLY UNFAVORABLE STAGES : • Moderate amount of chemotherapy( around 4 cycles) plus IF-RT ADVANCED STAGES : • Extensive chemotherapy ( typically 8 cycles ) with orwithout radiotherapy
NODULAR LYMPHOCYTE PREDOMINANT HODGKINS LYMPHOMA • Rare sub-typeaccounting for 5 % of all thecases • Differ from cHL in termsof clinical features as well as immunophenotype •The RS cell variants( alsocalled Lymphocyte Predominant RS cellsor LP RS cells) express full program of B cell antigens. • More indolent clinical course. • Mostoften diagnosed in earlystages
CLINICAL FEATURES • Male patient presenting with a single siteof lymphadenopathy that has been enlarging for months toyears. • Commonly presents in middle age • Mostcommonly presents with peripheral lymphadenopathy , cervical, axillary and inguinal • Mediastinal and retroperitoneal lymph node involvement is rare • Relative absenceof B symptoms
PATHOLOGY • Monoclonal B cell neoplasm characterised bya nodularand diffuse proliferation of scattered large neoplasticcells known as LP RS cell variants. • LP cells have vesicular, poly-lobated nuclei and distinct but small, usually peripheral , nucleoli without perinuclear halos. • Absenceof classic RS cells •Background consists of predominantly lymphocytes, clustersof epithelioid histiocytes may bepresent.
TREATMENT A) EARLY FAVOURABLE STAGE • Radiotherapy is defined as the mainstay of treatment • Most largestudygroups recommend IF-RTas the standard of care forpatients with early favourable disease. B) EARLY UNFAVOURABLE AND ADVANCED STAGES • Treatment plan is identical to thatof cHL • Relapserate is higher in NLPHL ascompared tocHL
NON HODGKINS LYMPHOMA INTRODUCTION • Non-Hodgkin’s lymphomas (NHL) are neoplastic transformations of mature B, T, and natural killer (NK) cells. • In children diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma (BL), and lymphoblastic lymphomaare mostcommon. • DLBCL is also the most common histologic subtype in adults. • Poorerprognosis as compared to Hodgkins Lymphoma as complete cureachieved in less than 50% of patients(compared toover 80% in Hodgkins).
CELL OF ORIGIN OF DIFFERENT NHL’S
ETIOLOGY
CLINICAL FEATURES NHLs have been divided into groups based on clinical behaviour A) LOW-GRADE LYMPHOMAS • Peripheral adenopathy that is painless and slowlyprogressive. • Spontaneous regressionof enlarged nodes mayoccur (waxing and waning LN’s) • Primaryextra-nodal involvement and B symptoms are not common in patients with lowgrade disease. B) INTERMEDIATE OR HIGH GRADE • Peripheral lymphadenopathy • Morethan one third of patients presentwith extranodal involvement; the most common sites are thegastrointestinal tract , skin, bone marrow, sinuses, genitourinary tract, thyroid, and central nervous system .
•Involvement of retroperitoneal, mesenteric, and pelvic nodes is common in most histologic subtypes of NHL. • Primary lymphomas of bone arevery rare(5%)Mostcommon sitesare femur, pelvis and vertebrae. • Primary GI lymphomas often presentwith hemorrhage, pain, orobstruction • Mostcommon site is thestomach. Common histological subtypes presenting are Diffuse Large B Cell Lymphoma, Mantle Cell Lymphomaand MALT Lymphoms. • B-symptomsare morecommon( 30-40% of patients)
• Lymphoblastic lymphoma, a high-grade lymphoma, often manifests with an anterior superior mediastinal mass, superior vena cava (SVC) syndrome, and leptomeningeal diseasewith cranial nerve palsies. • Primary CNS lymphomas are high-grade neoplasms of B-cell origin. Most lymphomasoriginating in the CNS are largecell lymphomas or immunoblastomas, and theyaccount for 1% of all intracranial neoplasms. • Symptoms of primary NHL of the CNS include headache, lethargy, focal neurologic symptoms, seizures, and paralysis.
CLASSIFICATION
INVESTIGATIONS A) BIOPSY • INDICATION : lymph node largerthan 1.5 × 1.5 cm that is not associated with a documented infection and that persists longer than 4 weeks should beconsidered for a biopsy. • A biopsy should be performed immediately for patients with other findings suggesting malignancy B) LABORATORY INVESTIGATIONS • Complete Blood Count • Liver Function tests • Serum Protein Electrophoresis • LDH and b-2 microglobulin
C) IMAGING a) CT SCAN • Chest, abdominal and pelvic CT scansaredone routinely. • Essential foraccurate staging of the disease. b) PET SCAN • 18F-Fluorodeoxyglucose PET scan is highlysensitive fordetecting both nodal and extra-nodal disease. • Particularly useful for histologically aggressive lymphomas • PET scanning detectsan actively metabolizing tumor in residual masses following or during chemotherapy, and persistentabnormal uptake predicts for earlyrelapse and/orreduced survival. c) MRI SCAN is useful in detecting bone, bone marrow, and CNS diseases in the brain and spinal cord.
STAGING
• Concept of staging has less impact in NHL than in HL • Prognosis is more dependent on histologyand clinical parameters than the stage at presentation. • Staging in NHLs, therefore, is done to identify the minority of patients whocan be treated with local therapyorcombined modality treatment.
PROGNOSIS
FOLLICULAR LYMPHOMA • Second mostcommon lymphoma • Comprises of 20 % of all NHL’s PATHOLOGY •Follicular Lymphomas are malignant counterparts of normal germinal center B cells. • Neoplastic cellsconsist of a mixture of centrocytes and centroblasts. •Theclinical aggressiveness of the tumorcorrelateswith the numberof centroblasts thatare present.
PATHOLOGY CONTD.. • WHO GRADING OF FOLLICULAR LYMPHOMAS Grade 1 : 0-5 centroblasts per high powered field Grade 2 : 6-15 centroblasts per high powered field Grade 3 : >15 centroblasts per high powered field 3A : Predominantly centrocytes 3B : Sheets of centroblasts
• Small numberof T cellsand follicular dendritic cells arealso present • Involvement of the peripheral blood with malignant cells is commonly seen • Morphologically thesecells have notches and hence referred toas buttock cells.
CLINICAL FEATURES • Long standing lymphadenopathy whichwaxesand wanesover theyears • Bone marrow involvement is present in 70% of patients • Meanageat presentation is around 60 yearswith a female predominance. • Involvement of other non-lymphoid organs is uncommon. • Less than 20% of patients presentwith B symptoms
PROGNOSIS
TREATMENT TREATMENT OF EARLY STAGE DISEASE • Early Stage Disease Includes Stage I,II and IIIA • Less than 10% of patients with FL presentwith earlystage disease. • Radiotherapy is the treatment of choice( forearlystage disease) • A doseof 24 to 30 Gy is highlyeffective, with no evidence of benefit for higherdoses • Chemoradiotherapy improves Progression Free Survival as Compared To Radiotherapy Alone, but has no impact on Overall Survival.
TREATMENT OF ADVANCED STAGE DISEASE • The majority of patients presentwith advanced disease at diagnosis. • Indications for treatment include symptomatic nodal and extranodal disease, compromised end organ function, B symptoms, orcytopenias. • CHEMOTHERAPY REGIMENS a) CHOP-R : b) CVP-R c) R-FM d) BR : : : Cyclophosphamide, hydroxydaunorubicin, Oncovin , Prednisolone Rituximab cyclophosphamide, vincristine, prednisone, and rituximab Rituximab, fludarabine, and mitoxantrone Bendamustine, Rituximab
DIFFUSE LARGE B CELL LYMPHOMA • DLBCL constitutes 31% of all NHLs, and is the most common histologic subtype • DLBCLsconsist of adiffuse proliferation of largecells that havea high mitotic rate. • Cell of origin is usually Germinal Centerand Postgerminal centeractivated B cells. • Can prove to be rapidly fatal if left untreated.
CLINICAL FEATURES • Meanageat presentation is 64 years. • Patients presentwith rapidly enlarging masses, either nodal enlargement or extranodal disease. • Extranodal sitesarecommon, occurring in 40% of cases, including the GI tract, the testis, the bone, the thyroid, theskin and CNS. • DLBCL is highly invasive, with local compression of blood vessels, airways, involvement of peripheral nerves, and destruction of bone.
• Thediseasepresentsas Stage I or Stage II in approximately 40 % of thecases. • Stage IV disease is seen in another 40% of cases. • B symptoms are present in around 40 % of patients.
TREATMENT A) EARLY STAGE • This includes patients whopresentwith localised disease. • Therapyof earlystage Diffuse Large Cell Disease is controversial. • Recommended treatment is combination chemo-immunotherapy with additional IF-RT. • CHOP-R regimen : Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisolone and Rituximab ( usuallygiven as first line therapy) • Addition of IF-RTalso increases 5 year Progression Free Survival aswell as overall Survival( Total doseof 30-40 Gy)
B) ADVANCED STAGE DISEASE • Currentrecommendation for the treatmentof advanced stage DLBCL is combination chemotherapy with CHOP-R. C) RELAPSED OR REFRACTIVE DISEASE • The majorityof relapses from CHOP-R therapyareseen within the first 2 years after thecompletion of treatment. • Forpatients with poor performance status, particularlyelderly patients, thegoal is often palliation. •The majorityof patients with relapsed and refractory DLBCL receive high dose combination chemotherapy, often with rituximab.
MARGINAL ZONE LYMPHOMAS MZLsare indolent NHLs that include threediseasesarising from post-GC marginal zone B cells: A) Nodal Marginal Zone Lymphomas B) Splenic Marginal Zone Lymphoma C) Extranodal Marginal Zone Lymphoma
A) NODAL MARGINAL ZONE LYMPHOMA(MZL) • Constitute less than 1% of all lymphomas • Diseaseprocessrestricted to Lymph Nodes PATHOLOGY • Within lymph nodes, therearecollections of B cells in a parafollicular, perivascular, and perisinusoidal distribution. • Thesecells may surround reactive-appearing GCs and mantle zones
CLINICAL FEATURES • Majorityof patients presentwith Stage III/IV disease • Asymptomatic • The 5-yearsurvival for patients with nodal MZL is 55% to 79%. TREATMENT • Patients are frequently treated with chemoimmunotherapy • Regimens include eitheralkylating agents or purine analogs plus rituximab.
B) SPLENIC MARGINAL ZONE LYMPHOMA • Median ageat presentation is 65-70 years • Nogender predominance • Associated withviral infections like hepatitis C PATHOLOGY • Expansion of marginal zones in the spleen • Replacement of the lymphoid follicles of the white pulp with neoplastic cells. •Small darker lymphocytes in thecenter merging with pale staining cells in the periphery.
CLINICAL FEATURES • Patients typically presentwith splenomegaly and cytopenias • Lymphadenopathy is uncommon. • B symptoms and elevated LDH are uncommon. • More than 90% of cases have Stage IV diseaseatdiagnosis. • Survival of patients is in excessof 70% at 10 years
TREATMENT • Asymptomatic patients without splenomegaly or cytopenias can be observed. • Splenectomy results in relief of symptoms and reversal of cytopenias. • For those patients with Hepatitis C, treatmentof the infection results in regression of disease. • Radiation therapy is indicated in patients not fit forsurgery • Total doseof 150cGygiven to theentire spleen three times aweek.
EXTRANODAL MARGINAL ZONE LYMPHOMA • Also known as MALT Lymphoma or Mucosa Associated Lymphoid Tissue Lymphoma • The most common site is the stomach. • Associated with various chronic inflammatory and infectious conditions infections like H. Pylori, Borrelia, Chlamydia, and Hepatitis C Virus • MALT lymphoma behaves indolently. • Associated withauto-immune conditions like Sjogren’ssyndromeand autoimmune thyroiditis.
PATHOLOGY • MALT lymphomasare malignancies of antigen- stimulated B cells, which normallyreside in lymph nodes within the marginal zone • characterized bya monoclonal infiltrate of small- to medium-sized cellswith abundant cytoplasm and irregular nuclearcontours. • presenceof lymphoepithelial lesions created by the invasion of mucosal glands and crypts byaggregates of lymphoma cells
CLINICAL FEATURES • Clinical presentation depends upon the site of disease. a) Gastricand intestinal MALT lymphomas 1. Dyspepsiaand vague abdominal pain 2. Bowel Obstruction 3. Rarely bleeding b) Ocular Adnexa 1. Photophobia 2. Painless Conjunctival Injection
c) Bronchusassociated Lymphoid Tissue( BALT) 1. Usuallyseen in older men 2. Presentwith cough, feverand weight loss TREATMENT • Depends on stage and siteof disease EARLY STAGE DISEASE • For H.Pylori positive Lymphomas, eradication of H.Pylori with antibiotics • Radiotherapy is indicated in patients with H.Pylori negative lymphomas , those unresponsive toanti- H. Pylori treatment • RT is also indicated in lymphomaof ocularadnexa
ADVANCED STAGE DISEASE • If patient is asymptomatic, then observation till symptoms appear. • Chemoimmunotherapy with alkylating agents like chlorambucil and cyclophosphamide, purine analogs like cladribine and bortezomib.
MANTLE CELL LYMPHOMA • MCL is a malignancy of small- to medium-sized B cells in the mantle zone PATHOLOGY • Mantlecell lymphomasare neoplastic counterparts of naive Mantle zone cells. • Neoplastic cellsare small- to medium-sized and have irregular nuclei and scant cytoplasm.
CLINICAL FEATURES • Constitutes 7% of all NHLs • Malepredominance (75 % are males) • Mean ageat presentation of 63 years •Typical sites of involvement are the lymph nodes, spleen, liver, Waldeyer’s ring. • Can occasionally involve the GI tract, presenting as polyposis.
TREATMENT • The majority of patients with MCL have a disseminated disease requiring treatment. • Chemotherapy is the primary treatment modality. • The treatment of MCL involves single alkylating agents as well as combination chemotherapy (CVP, CHOP). • The median survival of patients with MCL is 4 to 5 years.
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AML ALL HL NHL.pptx

  • 1.
  • 2.
    INTRODUCTION  Acute leukaemia'sare stem cell disorders characterized by malignant neoplastic proliferation and accumulation of immature and non functional hematopoietic cells in the bone marrow.  The neoplastic cells show increased proliferation and/or decreased apoptosis.  If the defect primarily affects the common myeloid progenitor (CMP) then it is called Acute myeloid leukaemia.
  • 3.
     Acute myeloidleukaemia (AML) is a neoplastic disease characterized by infiltration of the blood, bone marrow, and other tissues by proliferative, clonal undifferentiated cells of the hematopoietic system.  AML is the result of a sequence of somatic mutations in a multipotential primitive hematopoietic cell or, in some cases, a more differentiated progenitor cell.  It can be slow growing or rapidly fatal.  AML is the predominant form of leukaemia during the neonatal period
  • 5.
     Incidence :1.5/100,000/year in infants decreases to approximately 0.4 per 100,000 children ages 5 to 9 years, increases gradually to 1.0 persons per 100,000 until age 25 years, and thereafter increases exponentially until the rate reaches approximately 25/100,000 persons.  AML accounts for 15 to 20 percent of the acute leukemias in children and 80 percent of the acute leukemias in adults.  Men > Women (4.5 : 3)
  • 6.
    ETIOLOGY  HEREDITY  1)Chromosomal aneuploidy like Trisomy 21 noted in Down syndrome  2) Defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, and Ataxia telangiectasia  3) Congenital neutropenia ie Kostmann syndrome  4) Germline mutations of CCAAT/enhancer-binding protein α (CEBPA), runt-related transcription factor 1 (RUNX1), and tumor protein p53 (TP53) have also been associated with a higher predisposition to AML
  • 7.
     RADIATION  Peaksafter 5 to 7 yrs of exposure.  Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people also exposed to alkylating agents.  CHEMICAL AND OTHER EXPOSURES  Exposure to benzene, plastic, rubber, petroleum products, paint, ethylene oxide, herbicides and pesticides can increase the risk.  Smoking can also increase the risk
  • 8.
     DRUGS  Anticancerdrugs are the leading cause of therapy-associated AML.  Alkylating agent–associated leukaemia occur on average 4–6 years after exposure, and affected individuals have aberrations in chromosomes 5 and 7.  Topoisomerase II inhibitor–associated leukaemia occur 1–3 years after exposure, and affected individuals often have aberrations involving chromosome 11q23.  Other agents like Chloramphenicol, phenylbutazone, and, less commonly, chloroquine and methoxy psoralen.
  • 9.
    CLINICAL FEATURES  SYMPTOMS:  Present with nonspecific symptoms initially.  Fatigue is the first symptom  Fever with or without infection will be present in approximately 10% patients  Bleeding, easy bruising  occasionally, bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis  Rarely patients may present with symptoms from a myeloid sarcoma, a tumour mass
  • 10.
     PHYSICAL FINDINGS:  Splenomegaly, Hepatomegaly, Lymphadenopathy, Sternal tenderness  Evidence of infection and haemorrhage  Severe gastrointestinal bleeding, intrapulmonary haemorrhage, or intracranial haemorrhage occurs mostly in APL  Infiltration of the gingivae, skin, soft tissues, or meninges with leukemic blasts is characteristic of the monocytic subtypes.
  • 11.
    LABORATORY FINDINGS  PERIPHERALBLOOD  LEUCOCYTES  - Elevated count,  - 50% cases will have decreased or within reference interval.  - Counts ranges from <1000 to >100000/ml.  - Presence of blasts > 20% suggests AL diagnosis.  Typically the myeloblasts seen in AML is 20mcM in diameter with nucleus composed primarily of dispersed chromatin and variable prominent nucleoli.  Golgi apparatus is present but its not easily visible.  Granules may be present but not visible by bright field microscopy.
  • 12.
     ERYTHROCYTES  -Typically decreased and macrocytic,  - RDW is increased,  - Erythrocyte inclusions such as Howell-Jolly bodies, Pappenheimer bodies and basophilic stippling is seen.  -Nucleated RBCs can be present in proportion to anaemia or marrow damage.  PLATELETS  - Typically decreased  - Hypo granular forms and sometimes giant platelets.  - Qualitative platelet defect .
  • 13.
     The presenceof AUER RODS in blasts excludes ALL. Presence of azurophilic granules is helpful in identifying myeloid nature of the leukaemia.  Other abnormal findings in blood smear include monocytosis and neutropenia.  Neutrophils shows dysplasia including hypo segmentation , hypo granulation and small nuclei with hyper condensed chromatin.  Eosinophils and Basophils are mild to markedly elevated.
  • 14.
     BONE MARROW - Hypercellular with decreased fat content.  - predominance of blasts and sometimes with fibrosis.  - Auer rods are present in BM blasts in half of AML cases  OTHER LABORATORY FINDINGS  - Hyperuricemia and increased lactate dehydrogenase due to increased cell turn over  - Hypercalcemia due to increased bone resorption  - Increased serum and urine muramidase with monocytic component
  • 15.
    CELL LINEAGE IDENTIFICATION CYTOGENETICS  Common stains used are Myeloperoxidase (MPO), Sudan Black B (SBB), Naphthol AS-D Chloroacetate (specific esterase) and alpha naphthyl esterase (non specific esterase).  Granulocytic cells stain positive with MPO & SBB, whereas lymphoblasts are negative. So differentiates AML & ALL.  Granulocytic cell stains positive with specific esterase where as monocytic cell lineage stain positive with non specific esterase. So esterase helps to differentiate these two.
  • 16.
    IMMUNOPHENOTYPING BY FLOWCYTOMETRY  Its done when morphological appearance and cytochemical reactions do not clearly define cell lineage or when presence of more than one neoplastic cell population is suspected.  First panel should differentiate AML from B cell ALL and T cell ALL., then second panel should be used to subtype the AML into granulocytic, monocytic, erythrocytic, and megakaryocytic lineages.
  • 17.
    CYTOGENETIC OR MOLECULARANALYSIS  2/3 rd of patients with AML have detectable cytogenetic abnormalities which includes aneuploidies and translocations.  Commonly observed aneuploidies include trisomy 8 & 21 , monosomy 7 & 21, and loss of x & y chromosomes.  Random cytogenetic abnormalities are observed in AML with recurrent genetic abnormalities and therapy related myeloid neoplasms which are characteristic.
  • 22.
     Complete remission(CR) is traditionally defined by < 5 % blasts, absolute neutrophil count (ANC) < 1000/µL and platelets (plt) > 100000/µL in adult and > 80000/µL in paediatric AML.
  • 23.
    STANDARD INDUCTION THERAPY Includes a regimen based on a 7-day continuous infusion of cytarabine (100–200 mg/m2 /d) and a 3-day course of daunorubicin (60–90 mg/m2 /d).  IDAC : cytarabine 1.0–1.5 g/m2, 2 times per day  TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA: Tretinoin (all-trans-retinoic acid [ATRA]), an oral drug that induces the differentiation of leukemic cells bearing the t(15;17).  with or without anthracycline-based chemotherapy and possibly maintenance with tretinoin.  HSCT
  • 24.
  • 25.
     Acute LymphoblasticLeukaemia is defined as Malignant disease of marrow in which early lymphoid precursors proliferate and replace the normal Hematopoietic cells.  It is the most common Malignancy in children of 2-10 years of age, with peak incidence at 4-5 years of age.  Has Bimodal distribution with 2nd peak at 65 years of age.  Acute onset with short duration of history.  85% are B cell (Pre B ALL- Good prognosis)  15% are T cell
  • 28.
    TREATMENT OF ALL Induction therapy -  If Philadelphia Chromosome present - Steroid + Tyrosine Kinase Inhibitor  If other mutations - VADD regimen if Age <40 ( Vincristine, Asparaginase, Doxorubicin, Dexamethasone) Hyper CVAD regimen if Age > 40 ( Hyperfractionated Cyclophosphamide, Vincristine, Anthracycline/Doxorubicin, Dexamethasone)
  • 29.
    CNS Prophylaxsis - Intrathecal Methotrexate + Cytarabine  With or without WBRT (Whole Brain Radiotherapy) - in those with high risk features : 1. WBC count >50000 at the time of presentation 2. T Cell phenotype 3. Ph Chromosome positive 4. t(4;11)
  • 30.
     Remission isdefined as <5% blasts in bone marrow.  Post Remission treatment is based on whether the patient belongs to Standard risk or High risk group.  For standard Risk, Consolidation therapy for 7 months , which is followed by Maintenance phase for 2-3 years.  For High risk, Re Induction with High Dose Chemotherapy, followed by Allogenic Stem Cell Transplantation.
  • 31.
  • 32.
    HODGKINS LYMPHOMA • Hodgkinlymphoma encompasses adistinctive group of neoplasms thatare characterized by the presenceof a Reed-Sternberg cell. •Arise in a single lymph node orchain of lymph nodes and typically spread in a stepwise fashion toanatomically contiguous nodes. • Two majorsub-typesare now recognized : a) Classic Hodgkins Lymphoma b) NodularLymphocyte predominant Hodgkins lymphoma
  • 33.
    CLINICAL FEATURES • HodgkinsLymphoma patients presentwith peripheral lymphadenopathy. •Involved nodes are non tenderwith nooverlying skin changes,discreteand freely movable. • Characteristicclinical presentation is enlarged superficial lymph nodes in young adults. • Commonly involved lymph nodes arecervical and supraclavicular(60-80%), followed byaxillary lymph nodes. Inguinal and femoral lymph node groupsare less commonly involved. • Central lymphadenopathy is seen in somesub-types.
  • 34.
    B SYMPTOMS A) FEVER(25-50%) B) DRENCHING NIGHT SWEATS C) WEIGHT LOSS D) OTHER NON-SPECIFIC SYMPTOMS (pruritus, fatigue and pain after drinking alcohol) SYMPTOMS OF EXTRA NODAL MANIFESTATION : a) Involvement of Liver and spleen Abdominal swelling secondary to hepatomegaly or hepatosplenomegaly Jaundice and ascites b) Signs of mediastinal involvement Retrosternal Chest pain Cough and shortnessof breath Pleural and pericardial effusion
  • 35.
    INVESTIGATIONS A. DETAILED HISTORYWITHATTENTION TO PRESENCE OR ABSENCE OF CLINICAL SYMPTOMS B. CAREFUL PHYSICAL EXAMINATION EMPHASIZING NODE CHAINS , WALDEYERS RING AND SIZE OF LIVER AND SPLEEN C. ROUTINE LABORATORYTESTS • Complete Blood Cell Count • Erythrocyte Sedimentation Rate • Liver Function Test
  • 36.
    D. CHEST RADIOGRAPH •Lowcost method fordiagnosis and surveillance in Hodgkins Lymphoma • Useful fordetecting mediastinal disease
  • 37.
    E. CT SCAN •Standard thoracicexamination for patients with HL • Useful fordetermination of sites on initial involvement as well as extent of disease • Helps in classification of earlystage patients into favourable orunfavourable prognosis.
  • 38.
    F. FDG-PET SCAN •Whole body PET using 18F- fluorodeoxyglucose is asensitive indicator for disease. • It is used in initial evaluation aswell as in staging procedures after treatment to assess response to therapy. • Recommended whenotherdiagnostic modalities are inconclusive • FDG-PET moreaccurately identifies the correctpretreatment stage in HL compared with CECT (which tends to understage or overstage thedisease) • FDG-PET is able todistinguish viable/active tumorcells from fibrosisor necrosis in a residual massafter treatment
  • 39.
    REED STERNBERG CELL •Thesinequa non of Hodgkin lymphoma is the Reed Sternberg (RS) cell • Thesearedifferent kinds of giant cells. • Usuallyderived from B lymphocytes. • Enormous bilobed or multilobate nucleus, exceptionally prominent nucleoli and abundant, usually slightlyeosinophilic cytoplasm. • Particularlycharacteristicarecells with two mirror-image nuclei , eachcontaining a large acidophilic nucleolus surrounded by aclearzone, features that impart an “owl- eye” Appearance.
  • 40.
    CLASSIC HODGKINS LYMPHOMA •Monoclonal Lymphoid Neoplasm, composed of mononuclear Hodgkins cellsand multi- nucleated Reed Sternberg cells in an infiltrate containing a mixtureof eosinophils, small lymphocytes , neutrophils and histiocytes. • Subtypesof Classic Hodgkins Lymphoma( cHL): a) Nodular Sclerosis type b) Mixed cellularity c) Lymphocyte Rich d) Lymphocyte Depleted
  • 41.
    NODULAR SCLEROSIS TYPE •It is the mostcommon subtype (of cHL) • Mostcommon in adolescents and young adults • Mediastinum and othersupra-diaphragmatic sites arecommonly involved PATHOLOGY : • Characterised by Collagen bands that surround at leastone nodule • “ Lacunar” type Reed Sternberg cells • Background consists of lymphocytes, histiocytes, plasmacells, eosinophils and neutrophils.
  • 42.
    MIXED CELLULARITY TYPE •Thissubtypecomprises 15-30 % of Hodgkins Lymphoma cases. • Can occurat any age. • Abdominal Lymph nodes and spleen arecommonly involved. PATHOLOGY : •Infiltrate is usuallydiffuse orvaguely nodular • Consists of lymphocytes, eosinophils, cellsand histiocytes. • Reed Sternberg cellsareof theclassic, diagnostic type with bi-lobed, double or multiple nuclei.
  • 43.
    LYMPHOCYTE RICH TYPE •Comprises of 5 % cases of Hodgkins Lymphoma • Predominant in males. • Isolated cervical oraxillary lymphadenopathy • Betterprognosis than othersub-typesof cHL PATHOLOGY • Background infiltrate consisting predominantly of lymphocytes with almost no eosinophils • presence of lymphohistiocytic variant RS cells that have a delicate multilobed, puffy Nucleus (“ Popcorn cells”)
  • 44.
    LYMPHOCYTE DEPLETED TYPE •Leastcommon variant ( less than 1%) • Mostcommon in olderpatients, HIV positive individuals • Abdominal lymphadenopathy with involvement of spleen and mesenteric nodes. PATHOLOGY • Diffuse and hypocellular infiltrate. • Large numberof RS cellswith “sarcomatous” variants. • Paucity of other inflammatory cells
  • 45.
    COTSWOLDS MODIFICATION OFANN ARBOR CLASSIFICATION
  • 46.
  • 47.
    TREATMENT METHODS 1. RADIOTHERAPY 2.CHEMOTHERAPY 3. COMBINED TREATMENT MODALITY
  • 48.
    RADIOTHERAPY • Radiation therapyis the mosteffective single therapeuticagent for treating early stage Hodgkins lymphoma.
  • 49.
    DOSE: EARLYSTAGE : • IFRT30Gy in daily 2Gy fractions over 2 to 3 weeks. ADVANCED STAGE : • Radiotherapy for residual diseaseafterchemotherapy includes doses of 30-34 Gy in 15-20 fractions of 1.8-2.0 Gyover 3 to 4 weeks.
  • 50.
  • 51.
    EARLY FAVORABLE STAGES: • Treatment consists of a brief chemotherapy ( 2-3 cycles) plus IF-RT EARLY UNFAVORABLE STAGES : • Moderate amount of chemotherapy( around 4 cycles) plus IF-RT ADVANCED STAGES : • Extensive chemotherapy ( typically 8 cycles ) with orwithout radiotherapy
  • 52.
    NODULAR LYMPHOCYTE PREDOMINANTHODGKINS LYMPHOMA • Rare sub-typeaccounting for 5 % of all thecases • Differ from cHL in termsof clinical features as well as immunophenotype •The RS cell variants( alsocalled Lymphocyte Predominant RS cellsor LP RS cells) express full program of B cell antigens. • More indolent clinical course. • Mostoften diagnosed in earlystages
  • 53.
    CLINICAL FEATURES • Malepatient presenting with a single siteof lymphadenopathy that has been enlarging for months toyears. • Commonly presents in middle age • Mostcommonly presents with peripheral lymphadenopathy , cervical, axillary and inguinal • Mediastinal and retroperitoneal lymph node involvement is rare • Relative absenceof B symptoms
  • 54.
    PATHOLOGY • Monoclonal Bcell neoplasm characterised bya nodularand diffuse proliferation of scattered large neoplasticcells known as LP RS cell variants. • LP cells have vesicular, poly-lobated nuclei and distinct but small, usually peripheral , nucleoli without perinuclear halos. • Absenceof classic RS cells •Background consists of predominantly lymphocytes, clustersof epithelioid histiocytes may bepresent.
  • 55.
    TREATMENT A) EARLY FAVOURABLESTAGE • Radiotherapy is defined as the mainstay of treatment • Most largestudygroups recommend IF-RTas the standard of care forpatients with early favourable disease. B) EARLY UNFAVOURABLE AND ADVANCED STAGES • Treatment plan is identical to thatof cHL • Relapserate is higher in NLPHL ascompared tocHL
  • 56.
    NON HODGKINS LYMPHOMA INTRODUCTION •Non-Hodgkin’s lymphomas (NHL) are neoplastic transformations of mature B, T, and natural killer (NK) cells. • In children diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma (BL), and lymphoblastic lymphomaare mostcommon. • DLBCL is also the most common histologic subtype in adults. • Poorerprognosis as compared to Hodgkins Lymphoma as complete cureachieved in less than 50% of patients(compared toover 80% in Hodgkins).
  • 57.
    CELL OF ORIGINOF DIFFERENT NHL’S
  • 58.
  • 59.
    CLINICAL FEATURES NHLs havebeen divided into groups based on clinical behaviour A) LOW-GRADE LYMPHOMAS • Peripheral adenopathy that is painless and slowlyprogressive. • Spontaneous regressionof enlarged nodes mayoccur (waxing and waning LN’s) • Primaryextra-nodal involvement and B symptoms are not common in patients with lowgrade disease. B) INTERMEDIATE OR HIGH GRADE • Peripheral lymphadenopathy • Morethan one third of patients presentwith extranodal involvement; the most common sites are thegastrointestinal tract , skin, bone marrow, sinuses, genitourinary tract, thyroid, and central nervous system .
  • 60.
    •Involvement of retroperitoneal,mesenteric, and pelvic nodes is common in most histologic subtypes of NHL. • Primary lymphomas of bone arevery rare(5%)Mostcommon sitesare femur, pelvis and vertebrae. • Primary GI lymphomas often presentwith hemorrhage, pain, orobstruction • Mostcommon site is thestomach. Common histological subtypes presenting are Diffuse Large B Cell Lymphoma, Mantle Cell Lymphomaand MALT Lymphoms. • B-symptomsare morecommon( 30-40% of patients)
  • 61.
    • Lymphoblastic lymphoma,a high-grade lymphoma, often manifests with an anterior superior mediastinal mass, superior vena cava (SVC) syndrome, and leptomeningeal diseasewith cranial nerve palsies. • Primary CNS lymphomas are high-grade neoplasms of B-cell origin. Most lymphomasoriginating in the CNS are largecell lymphomas or immunoblastomas, and theyaccount for 1% of all intracranial neoplasms. • Symptoms of primary NHL of the CNS include headache, lethargy, focal neurologic symptoms, seizures, and paralysis.
  • 62.
  • 63.
    INVESTIGATIONS A) BIOPSY • INDICATION: lymph node largerthan 1.5 × 1.5 cm that is not associated with a documented infection and that persists longer than 4 weeks should beconsidered for a biopsy. • A biopsy should be performed immediately for patients with other findings suggesting malignancy B) LABORATORY INVESTIGATIONS • Complete Blood Count • Liver Function tests • Serum Protein Electrophoresis • LDH and b-2 microglobulin
  • 64.
    C) IMAGING a) CTSCAN • Chest, abdominal and pelvic CT scansaredone routinely. • Essential foraccurate staging of the disease. b) PET SCAN • 18F-Fluorodeoxyglucose PET scan is highlysensitive fordetecting both nodal and extra-nodal disease. • Particularly useful for histologically aggressive lymphomas • PET scanning detectsan actively metabolizing tumor in residual masses following or during chemotherapy, and persistentabnormal uptake predicts for earlyrelapse and/orreduced survival. c) MRI SCAN is useful in detecting bone, bone marrow, and CNS diseases in the brain and spinal cord.
  • 65.
  • 66.
    • Concept ofstaging has less impact in NHL than in HL • Prognosis is more dependent on histologyand clinical parameters than the stage at presentation. • Staging in NHLs, therefore, is done to identify the minority of patients whocan be treated with local therapyorcombined modality treatment.
  • 67.
  • 68.
    FOLLICULAR LYMPHOMA • Secondmostcommon lymphoma • Comprises of 20 % of all NHL’s PATHOLOGY •Follicular Lymphomas are malignant counterparts of normal germinal center B cells. • Neoplastic cellsconsist of a mixture of centrocytes and centroblasts. •Theclinical aggressiveness of the tumorcorrelateswith the numberof centroblasts thatare present.
  • 69.
    PATHOLOGY CONTD.. • WHOGRADING OF FOLLICULAR LYMPHOMAS Grade 1 : 0-5 centroblasts per high powered field Grade 2 : 6-15 centroblasts per high powered field Grade 3 : >15 centroblasts per high powered field 3A : Predominantly centrocytes 3B : Sheets of centroblasts
  • 70.
    • Small numberofT cellsand follicular dendritic cells arealso present • Involvement of the peripheral blood with malignant cells is commonly seen • Morphologically thesecells have notches and hence referred toas buttock cells.
  • 71.
    CLINICAL FEATURES • Longstanding lymphadenopathy whichwaxesand wanesover theyears • Bone marrow involvement is present in 70% of patients • Meanageat presentation is around 60 yearswith a female predominance. • Involvement of other non-lymphoid organs is uncommon. • Less than 20% of patients presentwith B symptoms
  • 72.
  • 73.
    TREATMENT TREATMENT OF EARLYSTAGE DISEASE • Early Stage Disease Includes Stage I,II and IIIA • Less than 10% of patients with FL presentwith earlystage disease. • Radiotherapy is the treatment of choice( forearlystage disease) • A doseof 24 to 30 Gy is highlyeffective, with no evidence of benefit for higherdoses • Chemoradiotherapy improves Progression Free Survival as Compared To Radiotherapy Alone, but has no impact on Overall Survival.
  • 74.
    TREATMENT OF ADVANCEDSTAGE DISEASE • The majority of patients presentwith advanced disease at diagnosis. • Indications for treatment include symptomatic nodal and extranodal disease, compromised end organ function, B symptoms, orcytopenias. • CHEMOTHERAPY REGIMENS a) CHOP-R : b) CVP-R c) R-FM d) BR : : : Cyclophosphamide, hydroxydaunorubicin, Oncovin , Prednisolone Rituximab cyclophosphamide, vincristine, prednisone, and rituximab Rituximab, fludarabine, and mitoxantrone Bendamustine, Rituximab
  • 75.
    DIFFUSE LARGE BCELL LYMPHOMA • DLBCL constitutes 31% of all NHLs, and is the most common histologic subtype • DLBCLsconsist of adiffuse proliferation of largecells that havea high mitotic rate. • Cell of origin is usually Germinal Centerand Postgerminal centeractivated B cells. • Can prove to be rapidly fatal if left untreated.
  • 76.
    CLINICAL FEATURES • Meanageatpresentation is 64 years. • Patients presentwith rapidly enlarging masses, either nodal enlargement or extranodal disease. • Extranodal sitesarecommon, occurring in 40% of cases, including the GI tract, the testis, the bone, the thyroid, theskin and CNS. • DLBCL is highly invasive, with local compression of blood vessels, airways, involvement of peripheral nerves, and destruction of bone.
  • 77.
    • Thediseasepresentsas StageI or Stage II in approximately 40 % of thecases. • Stage IV disease is seen in another 40% of cases. • B symptoms are present in around 40 % of patients.
  • 78.
    TREATMENT A) EARLY STAGE •This includes patients whopresentwith localised disease. • Therapyof earlystage Diffuse Large Cell Disease is controversial. • Recommended treatment is combination chemo-immunotherapy with additional IF-RT. • CHOP-R regimen : Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisolone and Rituximab ( usuallygiven as first line therapy) • Addition of IF-RTalso increases 5 year Progression Free Survival aswell as overall Survival( Total doseof 30-40 Gy)
  • 79.
    B) ADVANCED STAGEDISEASE • Currentrecommendation for the treatmentof advanced stage DLBCL is combination chemotherapy with CHOP-R. C) RELAPSED OR REFRACTIVE DISEASE • The majorityof relapses from CHOP-R therapyareseen within the first 2 years after thecompletion of treatment. • Forpatients with poor performance status, particularlyelderly patients, thegoal is often palliation. •The majorityof patients with relapsed and refractory DLBCL receive high dose combination chemotherapy, often with rituximab.
  • 80.
    MARGINAL ZONE LYMPHOMAS MZLsareindolent NHLs that include threediseasesarising from post-GC marginal zone B cells: A) Nodal Marginal Zone Lymphomas B) Splenic Marginal Zone Lymphoma C) Extranodal Marginal Zone Lymphoma
  • 81.
    A) NODAL MARGINALZONE LYMPHOMA(MZL) • Constitute less than 1% of all lymphomas • Diseaseprocessrestricted to Lymph Nodes PATHOLOGY • Within lymph nodes, therearecollections of B cells in a parafollicular, perivascular, and perisinusoidal distribution. • Thesecells may surround reactive-appearing GCs and mantle zones
  • 82.
    CLINICAL FEATURES • Majorityofpatients presentwith Stage III/IV disease • Asymptomatic • The 5-yearsurvival for patients with nodal MZL is 55% to 79%. TREATMENT • Patients are frequently treated with chemoimmunotherapy • Regimens include eitheralkylating agents or purine analogs plus rituximab.
  • 83.
    B) SPLENIC MARGINALZONE LYMPHOMA • Median ageat presentation is 65-70 years • Nogender predominance • Associated withviral infections like hepatitis C PATHOLOGY • Expansion of marginal zones in the spleen • Replacement of the lymphoid follicles of the white pulp with neoplastic cells. •Small darker lymphocytes in thecenter merging with pale staining cells in the periphery.
  • 84.
    CLINICAL FEATURES • Patientstypically presentwith splenomegaly and cytopenias • Lymphadenopathy is uncommon. • B symptoms and elevated LDH are uncommon. • More than 90% of cases have Stage IV diseaseatdiagnosis. • Survival of patients is in excessof 70% at 10 years
  • 85.
    TREATMENT • Asymptomatic patientswithout splenomegaly or cytopenias can be observed. • Splenectomy results in relief of symptoms and reversal of cytopenias. • For those patients with Hepatitis C, treatmentof the infection results in regression of disease. • Radiation therapy is indicated in patients not fit forsurgery • Total doseof 150cGygiven to theentire spleen three times aweek.
  • 86.
    EXTRANODAL MARGINAL ZONE LYMPHOMA •Also known as MALT Lymphoma or Mucosa Associated Lymphoid Tissue Lymphoma • The most common site is the stomach. • Associated with various chronic inflammatory and infectious conditions infections like H. Pylori, Borrelia, Chlamydia, and Hepatitis C Virus • MALT lymphoma behaves indolently. • Associated withauto-immune conditions like Sjogren’ssyndromeand autoimmune thyroiditis.
  • 87.
    PATHOLOGY • MALT lymphomasaremalignancies of antigen- stimulated B cells, which normallyreside in lymph nodes within the marginal zone • characterized bya monoclonal infiltrate of small- to medium-sized cellswith abundant cytoplasm and irregular nuclearcontours. • presenceof lymphoepithelial lesions created by the invasion of mucosal glands and crypts byaggregates of lymphoma cells
  • 88.
    CLINICAL FEATURES • Clinicalpresentation depends upon the site of disease. a) Gastricand intestinal MALT lymphomas 1. Dyspepsiaand vague abdominal pain 2. Bowel Obstruction 3. Rarely bleeding b) Ocular Adnexa 1. Photophobia 2. Painless Conjunctival Injection
  • 89.
    c) Bronchusassociated LymphoidTissue( BALT) 1. Usuallyseen in older men 2. Presentwith cough, feverand weight loss TREATMENT • Depends on stage and siteof disease EARLY STAGE DISEASE • For H.Pylori positive Lymphomas, eradication of H.Pylori with antibiotics • Radiotherapy is indicated in patients with H.Pylori negative lymphomas , those unresponsive toanti- H. Pylori treatment • RT is also indicated in lymphomaof ocularadnexa
  • 90.
    ADVANCED STAGE DISEASE •If patient is asymptomatic, then observation till symptoms appear. • Chemoimmunotherapy with alkylating agents like chlorambucil and cyclophosphamide, purine analogs like cladribine and bortezomib.
  • 91.
    MANTLE CELL LYMPHOMA •MCL is a malignancy of small- to medium-sized B cells in the mantle zone PATHOLOGY • Mantlecell lymphomasare neoplastic counterparts of naive Mantle zone cells. • Neoplastic cellsare small- to medium-sized and have irregular nuclei and scant cytoplasm.
  • 92.
    CLINICAL FEATURES • Constitutes7% of all NHLs • Malepredominance (75 % are males) • Mean ageat presentation of 63 years •Typical sites of involvement are the lymph nodes, spleen, liver, Waldeyer’s ring. • Can occasionally involve the GI tract, presenting as polyposis.
  • 93.
    TREATMENT • The majorityof patients with MCL have a disseminated disease requiring treatment. • Chemotherapy is the primary treatment modality. • The treatment of MCL involves single alkylating agents as well as combination chemotherapy (CVP, CHOP). • The median survival of patients with MCL is 4 to 5 years.
  • 94.