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LYMPHOID NEOPLASMS

LYMPHOID NEOPLASMS. Definitions and Classification One confusing aspect concearns the use of the term LEUKEMIA and LYMPHOMA. LEUKEMIAS present with widespread involvement of the bone marrow and peripheral blood . LYMPHOMA is used for proliferations arising as discrete tissue masses .

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LYMPHOID NEOPLASMS

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  1. LYMPHOID NEOPLASMS

  2. Definitions and Classification Oneconfusingaspectconcearnstheuseofthe term LEUKEMIA and LYMPHOMA. LEUKEMIAS presentwithwidespreadinvolvementofthe bone marrow and peripheralblood. LYMPHOMA isusedforproliferationsarisingasdiscretetissuemasses. Originally, terms LEUKEMIA and LYMPHOMA wereconsistentdistinctentities, butthisdivision has blurred. Manylymphomasmayhaveleukemicpresentations and evolution to leukemiasisnotunusual. Conversely, leukemiassometimesariseassoft-tissuemasses. Bothtermsmerelyreflecttheusualtissuedistributionofeachdiseaseatpresentation.

  3. LYMPHOMAS are known in twocategories: Hodgkin´sLymphoma, treatable in a uniquefashion, and thefamilyofNHL. Theclinicalpresentationofthevariouslymphoidneoplasmsis most oftendetermined by theanatomicdistributionofthedisease. 2/3 ofNHLs and virtuallyall HL presentasenlargednon-tenderlymphnodes (› 2 cm). Theremaining 1/3 ofNHLspresentwithsymptomsrelated to involvementofextranodalsites: stomach, intestine, skin, brain. In NHL animportantgroupoftumorsisrepresented by theplasmacellneoplasms. Leukemiaspresentwithsymptomsrelated to thesupressionofhematopoesis. Multiplemyelomacauses bony destruction or paindue to pathologicfracture. Certaintumorsmay cause fever (HL) andsecretionofcirculatingfactors (e.g.amyloid) from plasma cells.

  4. HISTORY Theoldestclassificationscheme has usedonlyfewterms: lymphosarcoma, reticulosarcoma, lymphogranulatomasisPaltauf-Sternberg, M. Hodgkin. Rappaport: nodular– difuse involvementofthelymphnodes. Duringtheyears 1960 – 1980 theretemporarilyexistedseveralnationalclassifications (German, French, English, American (Florida andCalifornia) andinternational (REAL) , introducingnew basic andresearch-basedandclinicallyacceptedinformation. Soonafterwards, attheendofthe 20th century, WHO expertsfromseveralmedicalspecialitieshavedeveloped a unified, modernandopen internationalclassificationsystem (2001) based on morphological, immunophenotypic, genotypicandclinicalfeatures(interdisciplinaryacepted).

  5. The WHO ClassificationofLymphoidNeoplasms (2001) I Precursor B Cell Neoplasms B cell acutelymphoblasticleukemia/lymphoma (B - ALL) II Peripheral B Cell Neoplasms Chroniclymphocyticleukemia/smalllymphocyticlymphoma B cell prolymphocyticleukemia Lymphoplasmocyticlymphoma Splenicandnodalmarginalzonelymphoma Extranodalmarginalzonelymphoma Follicularlymphoma Marginalzonelymphoma Hairy cell leukemia Plasmacytoma/plasma cell myeloma Diffuselarge B cell lymphoma Burkittlymphoma

  6. The WHO ClassificationofLymphoidNeoplasms (2001) III Precursor T cell neoplasms T cell acutelymphoblasticleukemia/lymphoma (T – ALL) IV Peripheral T cell and NK cell neoplasms T cell prolymphocyticleukemia Largegranularlymphocyticleukemia Mycosisfungoides/Sézary syndrome Peripheral T cell lymphomaunspecified Anaplasticlarge cell lymphoma Angioimmunoblastic T cell lymphoma Enteropathy-associated T cell lymphoma Panniculitic T cell lymphoma Hepatosplenicgamma-delta T cell lymphoma Adult T cell leukemia/lymphoma Extranodal NK/T cell lymphoma NK cell lymphoma

  7. The WHO ClassificationofLymphoidNeoplasms (2001) • V  Hodgkinlymphoma • Classicalsubtypes • Nodularsclerosis type • Mixedcellularity type • Lymphocyte-richtype • Lymphocytedepletiontype • Lymphocytepredominance type

  8. Importantprinciplesoflymphoidneoplasms • Lymphoidneoplasmsmaybeclinicallysuspected, buthistologicexaminationisrequiredfordiagnosis. • In most lymphoidneoplasms, antigen receptor gene rearrangementpresentstransformation, hence, allofthedaughtercellsderivedfromthemalignantprogenitorsharethesameconfigurationandsequence, andsynthesiseidentical antigen receptor protein (Ig, T cell receptor). In contrast to reactive (polyclonal) proliferationsthelymphoidneoplasms are monoclonallymphoidproliferations. • These antigen gene rearrangementproduce a unique DNA sequencesthatconstitute a highlyspecificclonalmarker, detectable by MoAb. • Thevast majority (85-90%)oflymphoidneoplasms are of B-cell origin.

  9. Importantprinciplesoflymphoidneoplasms NK tumors are rare. B cell and T cell representsomerecognizablestageof B or T cell differentiation, a feature used in theirnomenclature/terminology. Benigncounterpartsoflymphomas do not exist. NeoplasticB and T cellsrecapitulatethebehaviouroftheirnormalcounterparts. Examples: follicularlymphomashome to germinalcenters, cutaneouslymphomashome to the skin. Thisisgoverned by particularadhesionmoleculesandchemokinereceptors. Variablenumer of B or T cellsrecirculatethroughthelymphaticsandbloodvessels, sothatattimeofdiagnosis most tumors are widelydisseminated. Exceptions: HodgkinlymphomaandMarginalzone B cell lymphoma. This feature remindsofthephysiologicaldailyrepeating multiple recirculationoflymphocytesbetweenthecentralandperipherallymphaticorgans. Hodgkinlymphomaspreads in anorderlyfashion. In contrast, most formsof NHL spreadwidelyearly in theircourse in a lesspredictablefashion. Therefore, stagingisof most utility in HL.

  10. PRECURSOR B cell and T cell neoplasms are composedofimmature B and T cells (lymphoblasts). About 85% are B-ALL anditisthe most commoncancerofchildrenup to 15 years. Adults are affectedlessfrequently. Individualcasesmaybe more orlessimmatureormature, sothatvarious CD markers: B: CD 10, 19, 20 andT: CD 1,2,3, 4, 5, 7 and 8 maybeexpressed in tumor cells. Approximately90% ofALLshavevariousnumericalorstructuralchromosomalchanges. PediatricALL isoneofthegreatsuccessstoriesofoncologywithcompleteremission in 95% ofchildrenand 30-40% ofadults. Clinicalfeatures: abruptonset, depressionof bone marrowfunctions, masseffect, CNS manifestations.

  11. Peripheral B-cell Neoplasms ChroniclymphocyticLeukemia (CLL)/SmalllymphocyticLymphoma (SLL) Representsthe most commonadultleukemiawithmedianageatdiagnosisbeing 60 years, 2:1 male preponderance in Western countriescomparingwithAsiancountriesand Japan. Microscopically: diffuseinfiltrationwithsmalllymphocyteswithproliferationcenters in thelymphnodes, bone marrow, spleen and liver. Expressionof CD 19, 20, 23 and 5, surfaceIgM. Clinically, fatigability, anorexia, weightloss, lymphadenopathy, hepatosplenomegaly, hypogammaglobulinemia, relativelyslowcourse , tendency to transformation to more aggressiveforms (Richter syndrome). Possible use ofimmunotherapy, chemotherapyandtransplantation.

  12. FollicularLymphoma • Anindolent ,most common NHL in middleagewithunevenfrequency in the Word. • Typicalcell is a smalllymphocytewithirregular/cleavednuclei (centrocyte) in predominantfollicular arrangement. • Immunophenotype:CD 10, 19, 20, surfaceIg, BCL 6. • Clinically: generalized, painlesslymphoadenopathy, andrelativelyuncommoninvolvementofextranodalsites. Mediansurvival: 7-9 years, withpossibletransformation to diffuselargeB cell lymphoma(durationlessthan 1 year).

  13. Diffuselarge B-cell Lymphoma • Themost common NHL withmedianageof 60 years, mayaffectevenchildren. • Microscopicallythese tumorsgrowdiffuselyandcontainrelativelylargecells. • Immunophenotype: CD 19, 20, sometimesalso CD10 and BCL-6. • Cytogeneticgene expressionisheterogenous. • Specialforms: Immunodeficiency-associatedlarge B cell LymphomaandPrimaryeffusionlymphoma in AIDS andelderly. • Ifuntreated, isanaggressive tumor affecting many sitesandrapidlyfatal. • Immunotherapyimprovesresponsesandoutcome/prognosis.

  14. BurkittLymphoma (BL) • African(endemic) BL • Sporadic (non-endemic) BL • Aggressivelymphoma in AIDS • Microscopically: a starry-skyappearance, highmitoticindex • Immunophenotype: CD 10, 19, 20, BCL-6, sIgM • Molecularpathogenesis: Translocationsofthe C MYC gene on chromosome 8 • EndemicandsporadicBLsare formedmainly in childrenandyoungadultsmostly in extranodalsites (mandible, kidneys, ovaries, adrenals) Tumorsare aggresivebuttreatable

  15. Plasma Cell NeoplasmsandRelatedDisorders(dyscrasias) Containplasma cellssecretingmonoclonalIgor a Ig fragment. Theworst type isMultiple myeloma (plasma cell myeloma). Specialterms are usedfor these neoplasms: monoclonalgammopathy, dysproteinemia, paraproteinemia, primaryamyloidosisorimmunocyte-associatedamyloidosis. Plasmocytoma(solitarymyeloma)isaninfrequent variant thatrepresentsas a single (isolated) mass in bone or in soft tissue. Smolderingmyelomawithlackofsymptomsandhigh plasma M. component. Waldenströmmacroglobulinemiais a syndrome: monoclonalgammopathy, bloodhyperviscosityandincurablelympho-plasmocyticlymphoma. HeavychaindiseaseandMonoclonalgammopathyofundeterminedsignificance (MGUS), common in elderly, with a constantrateoftransformation to myeloma.

  16. Mantle Cell Lymphoma Isa rare, prognosticallypoorformoflymphomawithpainlessgeneralizedlymphadenopathy in elderlywith male predominance. Smallcellsresemblethenormal mantle zone B cellssurrounding germinalcenters. Immunophenotype: CD 5, 19, 20, cyclinD1. MarginalZoneLymphoma Encompassesa heterogenousgroupof B cell tumorsarisingwithinlymphnodes, spleen orextranodally (e.g. mucousmembranes, „maltoma“). Theyoftenarisewithintissuesinvolved by chronicinflammatorydisordersofautoimmune (Sjögren, Hashimoto) orinfectious etiology (H. pylori) withpossibleregressionfollowingsuccessfultreatmentof H. pylori.

  17. Hairy Cell leukemia Isa rare, distinctive B cell NHL (2%) withmassivesplenomegalyandfrequentinfections. Males are affected more frequently (5:1), medianageis 55 years. Overallprognosisisexcellent. Immunophenotype: CD 11c, CD 19, 20, 25 and 103. PeripheralT cell and NK cell Lymphomas Becauseofproblemswithcategorization, many forms are classified as Peripheral T cell Lymphomas, unspecified. These tumorseffacelymphnodesdiffuselyand are composedofpleomorphicmixtureofvariouslysizedmalignant T cellsandintensveangiogenesis. Immunophenotype: CD 2, 3, 4, 5, 8, andalpha/beta orgamma/delta T cell receptors. These tumorspresentwithgeneralizedlymphadenopathy, weightloss, fever, andeosinophilia.

  18. AnaplasticLarge cell Lymphoma(ALK positive) • Iscomposedofanaplasticlargecellswithhorseshoe-shapednuclei, so-called„HALLMARK CELLS“, mimickingmetastaticcarcinoma. • Immunophenotype: ALK cytoplasmicfusionprotein expression, a reliableindicatorofan ALK gene rearrangement. • These tumorsoccur in childrenandyoungadults, involve soft tissuesandcarry a verygoodprognosis. • AdultT cell Leukemia/Lymphoma • Thisadult tumor is a rapidlyprogressivediseasedespiteaggressivetherapy. ItdevelopsafterinfectionwithHTLV-1 (retrovirus) in specificgeographicareas. In someinstances, thisinfectionmaygiverise to a progressivedemyelinizatingdiseaseofthe CNS andspinal cord.

  19. MycosisFungoides/Sézary Syndrome Are differentmanifestationsof a CD4+ helper T cell diseaseaffecting skin (MF) withthreestages: premycoticinflammatorystage, plaquephase, and a tumor stagewithsimultaneousinvolvementoflymphnodesand bone marrow. In Sézary syndrome the skin manifestationsrepresentgeneralizedexfoliativeerythrodermaandleukemiawithcerebriformnuclei in peripheralblood. These are indolenttumors (up to 9 years) withimmunophenotype: adhesionmoleculeCLA, chemokine receptor CC4, CCR 10, and CD4 T cell. Largegranule LymphocyticLeukemia Rarein twovariants (T cell, CD3, indolent) and (NK, CD56, more aggressive) ofanadultdisease. Despitetherelativepaucityofmarrowinfiltration, neutropeniaandanemiadominatetheclinicalpicture. ExtranodalNK/T cell Lymphoma Israre in Europeand USA and more frequent in Asia. Presents as a destructivenasopharyngealmass in associationwith EBV infection, alsoaffectingtestisand skin. Surroundingandinfiltratingsmallvessels, itleadsto extensiveischemicnecroses. This tumor ishighlyaggressiveandwithpoorprognosis.

  20. HODGKIN LYMPHOMA Isa groupoflymphoidneoplasmsdifferingfrom NHL in severalrespects. Themaindifferences are tabularized: IdentificationofReed-Sternbergcells(andtheirvariantsand „mumification“) in a prominent background of a groupofinflammatorycellsisprincipalforthediagnosis.

  21. HODGKIN LYMPHOMA Immunophenotypefor 1-4: CD 15, 30, PAX5, excellentorlessfavorableprognosis, for 5: CD 20, BCL6. RS cellsproducesignals (cytokines IL-5, 10,13, TGF-beta) andchemokines (ARC, MDC, IP-10, CCL-28), thatattractreactivecells. Onceattracted, thereactivecellsproducefactorsthat support thegrowthandsurvivalof RS cells, furthermodifyingthereactive cell response. Clinicalfeaturesof HL Painlesslymphadenopathy, fever, nightsweats, weightloss, immunedysregulation, dyspnoe, etc. Thespreadisremarkablystereotyped: nodes, spleen, liver, othertissues. Thestaging not onlydeterminestheprognosis, butalsoguidestherapy. Radiationtherapymaybecurative in many patients.

  22. HODGKIN LYMPHOMA StagingofHL I Involvementof a single node or a single extranodal organ site II Involvementof 2 or more lymphnode regions on thesamesideofdiaphragm III Involvementoflymphnode regions on bothsidesofdiaphragmwithoutlocalizedinvolvementofanextralymphatic organ/site IV Diffuseinvolvementof 1 or more extranodalorgans/siteswithout/withlymphaticinvolvement Additionalfeaturesincludedintostagingprocedure: fever, kachexia, nightsweats Withcurrentprotocols, tumor stage (betterthanbiopsy) isthe most importantprognosticvariable. Survivalofstage I-II – 90%, III-IV – 60-70%. Increasedrisk ofsurvivors by secondcancers, especiallybecauseofappliedirradiationtogetherwithfibrosisandatherosclerosis, whichcanbeavoided by moderntherapy.

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