leucemia introducere tr

7/29/2019 Leucemia Introducere Tr

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FIZIOPATOLOGIA SERIEILEUCOCITARE

LEUCEMIA ACUTA


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T e on y person w oe on y person w onever makes a mistakenever makes a mistake

is the person whois the person who

never doesnever doesanything!anything!

- Theodore Roosevelt- Theodore Roosevelt


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LEUCEMIA INTRODUCERE Leucemia este o afectiune maligna

characterizata prin proliferareaneregulata a unui tip celular. Poate interesa oricare dintre liniile celulare,

una sau mai multe linii celulare, sau celulelestem.

Leucemiile sunt clasificate in doua grupemajore: Cronice, la care debutul, de regula, este insidios,

boala este mai putin agresiva, iar celuleleimplicate sunt, de regula, mature

Acute, la care debutul, de regula, este rapid,boala este foarte agresiva iar celulele implicatesunt slab diferentiate cu multi blasti.


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Modificari cantitative ale

seriei leucocitare Leucocitoza (cresterea numarului de leucocite peste

9.000/mmc) - poate apare in conditii fiziologice, prinmodificari de distributie in arborele circulator sau

prin solicitarea fiziologica a sistemului leucocitar(activitate fizica intensa, expunere la frig, digestieintestinala, graviditate, emotii, stres) saupatologice, prin intensificarea leucopoiezei medulare si prinmobilizarea leucocitelor aflate in circulatie sau intesuturi ( infectii, hemoragii, inflamatii, afectiuni

endocrine, neurologice, leucemii). Leucopenia (scaderea numarului de leucocite

sub 4000/mmc) - apare de obicei in conditiipatologice: de distributie ( soc anafilactic, frisoane),prin inhibitie medulara ( infectii), de epuizare, prin

inhibitia leucopoiezei ( dupa iradiere cu raze X,toxice chimice).


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Neutrofilia ( cresterea numarului de granulociteneutrofile peste 7000/mmc)- apare prin mobilizarearezervelor medulare sau prin cresterea productiei de

granulocite ( infectii bacteriene, necrozeinflamatorii, tulburari metabolice, administrarea decorticosteroizi, hemoragii acute si hemolize,afectiuni mieloproliferative).

Neutropenia ( scaderea numarului de neutrofilesub 2500/mmc) - apare ca urmare a productieiscazute de neutrofile ( prin proliferare medulararedusa, granulocitopoieza ineficienta) sau ca urmarea scaderii duratei de supravietuire in circulatie aneutrofilelor ( prin accelerarea trecerii in tesuturi aneutrofilelor in infectii, inflamatii, sau prin

distrugerea neutrofilelor de catre anticorpi-hipersplenism, defecte de maturatie).


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Eozinofilia ( cresterea numarului de granulocite eozinofile peste400/mmc) -apare in afectiuni alergice, parazitare, dermatologice,hematologice, tumori, imunodeficiente, sau asociate altorafectiuni ( sindrom Loffler, aspergiloza bronhopulmonara,

pleurezia cu eozinofile, poliartrita reumatoida, poliarteritanodoasa, dermatomiozita, fasciita eozinofilica, sindromul Churg-Strauss, sarcoidoza, boli renale cronice, etc), postiradiere,eozinofilia ereditara. Sindromul hipereozinofilic primar - definesteo eozinofilie cu valori inalte, peste 1500/mmc, de etiologieneprecizata, care persista peste 6 luni, asociata cu disfunctiaunor organe, consecutiva infiltrarii lor cu eozinofile.

Eozinopenia ( scaderea numarului de granulocite eozinofilesub 200/mmc)- datorata hiperfunctiei CSR. Apare in stari destres, posttraumatic, post interventii chirurgicale, dupacorticoterapie, vitamina C in doze mari si insulina, in cursulinfectiilor acute cu neutrofilie, dupa expunere la frig, eforturifizice mari. Aneozinofilia este patognomonica pentru febra

tifoida.


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Bazofilia ( cresterea numarului de granulocite bazofile peste80/mmc)- apare in sindroame mieloproliferative, colite ulcerative,artrite reumatoide, urticarie, mixedem, postsplenectomie.

Bazopenia - scaderea numarului de granulocite bazofile nu

are nici o semnificatie diagnostica, Apare in stari de stres, infectiiacute, hipertiroidie, administrare de corticosteroizi. Monocitoza ( cresterea numarului absolut de monocite peste

800/mmc) - apare ca urmare a stimularii productiei medulare demonocite de catre FSC-M. Se intalneste in boli infectioase,neoplazii, LES, sarcoidoza, sprue, colita ulceroasa, boli

mieloproliferative, leucemii monocitare, limfoame maligne,mielom multiplu, neutropenii cronice, anemii hemoliticeautoimune, unele reactii medicamentoase.

Monocitopenia ( scaderea numarului de monocite sub150/mmc) - apare in aplazia medulara, leucemia cutricholeucocite, dupa corticoterapie.


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Limfocitoza ( cresterea numarului de limfocite peste 3000/mmc) -apare in modificari primare neoplazice ale seriei limfatice( leucemia limfocitara cronica, limfoame maligne) ca limfocitozareactiva ( infectii virale, boli infectioase acute si cronice, rahitism,

hipertiroidie). Limfocitopenia (scaderea numarului de limfocite sub

1500/mmc) -apare ca urmare a productiei scazute( imunodeficiente, malnutritie, dupa tratament citostatic,corticoterapie, boala hodgkin, mixedem, boala Cushing), prinmodificari in circulatia limfocitelor, tranzitorii, mediate decresterea glucosteroizilor endogeni ( stres) sau prin distructiicrescute ( boli autoimune, infectii virale) ori pierderi ( rupturi saufistule ale canalului toracic, enteropatii cu pierdere de proteine,insuficiente cardiace grave).

Plasmocitoza ( cresterea numarului de plasmocite peste180/mmc)- este expresia unei sinteze crescute deimunoglobuline. Apare in boli infectioase, ciroza hepatica, alergia

la penicilina, boala serului.

M difi i lit ti l


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Modificari calitative aleelementelor seriei

leucocitare Defectele calitative ale neutrofilelordetermina

alterari ale fagocitozei. Anomaliile pot fi :congenitale ( deficitele lizei microbiene -

granulomatoza cronica familiala, deficienta severade G-6-PD, deficienta de MPO din granulatiileneutrofile si monocite; anomalii de structuracelulara - sindromul Chediak-Higasi, anomalia Adler,anomalia Pelger-Huet, anomalia May-Hegglin,

deficitul de adeziune leucocitara I) sau dobandite( defecte intrinseci ale neutrofilului - in leucemiileacute si cronice, HPN, sindromul leucocitelor lenese;defecte extrinseci neutrofilului - diabet zaharat,uremie, mielom multiplu, arsuri severe)


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Disfunctii ale monocitelor

si macrofagelor apar inosteopetroza ( deficit izolat al

osteoclastelor, cu diminuarea

resorbtiei osoase si formarea " oaselorde marmura"), boala granulomatoasacronica, sindromul Chediak-Higashi,

candidioza mucocutanata diseminata,terapia cu glucocorticoizi, fumatul.


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SINDROAME

MIELODISPLAZICE (SMD) Sindroamele mielodisplazice (stri preleucemice) sunt afeciuni clonale

ale celulei stem caracterizate prin citopenii periferice cu mduv hiper-sau normocelular, cu semne de dishematopoiez uni- sau multilineari frecvente anomalii cromozomiale.

Factori de risc implicai n apariia SMD: factori genetici i constituionali: sindromul Down, anemia Fanconi, boala

von Recklinghausen; iradierea cu doze mari sau repetate de radiaii ionizante ( raze X sau

gamma); substane chimice sau medicamentoase : benzen, ageni alchilani; aplazia medular tratat cu imunosupresoare, neutropenia congenital

tratat cronic cu G-CSF. SMD sunt tulburri clonale dobndite, rezultnd ca urmare a

transformrii neoplazice a CSP, cu afectarea n special a celulei stemorientate mieloid (rar a celor limfoide), care sufer o tulburare profunda proceselor de maturare i difereniere celular, cu hematopoiezineficient prin hiperapoptoz i o producie inadecvat de celulesanguine mature cu modificri displazice.

SMD pot fi primare i secundare (terapiei citostatice, imunosupresoare ,induse de factori ocupaionali i de mediu, HIV).


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Leucemiile Leucemiile sunt afeciuni maligne

clonale, caracterizate prin proliferarea

nelimitat de leucocite anaplazice, cuaberaii cromozomiale, avnd caracterinvadant i infiltrativ la nivelul mduvei

osoase hematogene i teritoriilorextramedulare. Leucemiile pot fi acutesau cronice.


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LEUCEMIA INTRODUCERE Atat cele cronice, cat si cele acute se clasifica functie de

linia celulara predominant proliferativa: Daca linia celulara predominanta apartine seriei mieloide

este vorba despre o leucemie mielocitara (denumita,

uneori si leucemie granulocitara) Daca linia celulara predominanta apartine seriei limfoide

este vorba despre o leucemie limfocitara Prin urmare, exista patru tipuri majore de leucemie

Leucemia mieloida acuta (Acute Mielocytic leukemia AML)- care include mieloblasti, promielocite, monocite,mielomonocite, eritrocite si megakariocite)

Leucemia Limfocitara Acuta (Acute lymphocyticleukemia ALL) care include celule T , B si celule NK(Natural Killer cell- Null cell)

Leucemia Mielocitara Cronica (Chronic myelocyticleukemia CML) care include myelocite simielomonocite)


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LEUCEMIA INTRODUCERE Leucemia Limfocitara Cronica (Chronic lymphocytic

leukemia CLL) care include plasmocite {mielommultiplu}, celule paroase, prolimfocite, large granularcell lymphocytic, Sezarys syndrome, and circulating

lymphoma)

Etiologie cauza exacta este frecventnecunoscuta, dar se cunosc factori predispozanti: Factori ai gazdei

Some individuals have an inherited increased predispositionto develop leukemia

There is an increased incidence in those with an inheritedtendency for chromosome fragility or abnormality or thosewith increased numbers of chromosomes (such as Downssyndrome). Many of these diseases are characterized by

chromosomal translocations.


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Leucemia Introducere Incidenta crescuta la cei cu imunodeficiente

ereditare. Incidenta crescuta la cei cu disfunctii

medulare cronice cum ar fi bolimieloproliferative, sindr mielodisplazice,anemia aplastica, hemoglobinuria paroxisticanocturna.

Factori de mediu: Expunere radiatii ionizante Expunere la mutagene chimice si anumite

subst medicam Infectia virala


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LEUCEMIA INTRODUCERE Incidenta

Acute leukemias can occur in all age

groups ALL (Acute Lymphoblastic Leukemia) is more

common in children AML (Acute Myeloid Leukemia) is more common

in adults

Chronic leukemias are usually a disease ofadults

CLL (Chronic Lymphocytic Leukemia) isextremely rare in children and unusual beforethe age of 40

CML (Chronic Myeloid Leukemia) has a peak


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LEUCEMIA INTRODUCERE Comparatie lecucemie acuta vs cronica: Acute ChronicVarsta all ages usually adults

Debut Clinic sudden insidious

Evolutie (netratata) 6 mo. or less 2-6 years

Celule Leucemice immature >30% blasts more maturecells

Anemia prominent mild

Thrombocytopenia prominent mildNr leucocite variable increased

Limphadenopaie mild present;often prominent

Splenomegalie mild present;often prominent


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LEUCEMIA INTRODUCERE Leucemia Acuta

Este rezultatul: Transformarii maligne a celulei stem conducand la

proliferare neregulata si Oprind maturarea la stadiul de blasti primitivi.

Remember that a blast is the most immature cell thatcan be recognized as committed to a particular cellline.

Aspecte clinice Proliferare Leucemica, accumulare si invazie a

tesuturilor normale, incluzand ficatul, splina, ggllimfatici, sist nerv central, pilele.

Posibil un mediator umoral secretat de celulele

leucemice ar inhiba proliferarea celulelor normale.


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LEUCEMIA INTRODUCERE Insuficienta maduvei si hematopoezei

normale poate conduce la pancitopenie simoarte prin hemoragii si infectii.

Evaluare de laborator Diagnosticul de laborator de bazeaza pe

doua aspecte

Aparitia unei cresteri semnificative deelemente imature in maduva incluzand blasti,promielocite, promonocite (>30% blasti estesemn diagnostic)

Identificarea liniei celulare leucemice


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LEUCEMIA INTRODUCERE Sangele periferic:

Anemia (normocroma, normocitara) Scadere plachete Numar leucocite Variabil

The degree of peripheral blood involvementdetermines classification:

Leukemic increased WBCs due to blasts Subleukemic blasts without increased WBCs Aleukemic decreased WBCs with no blasts

Clasificarea celulelor imature implicatetrebuie facuta prin:


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LEUCEMIA INTRODUCERE Morfologie an experienced

morphologist can look at the size of theblast, the amount of cytoplasm, thenuclear chromatin pattern, thepresence of nucleoli and the presenceof auer rods (are a pink staining,splinter shaped inclusion due to a rodshaped alignment of primary granulesfound only in myeloproliferative

processes) to identify the blast type: AML mieloblastul este un blast mare

cu cantitate moderata de citoplasma,cromatina fina, nucleoli proeminenti.10-40% dintre mieloblasti contin corpi

Auer.Myeloblast cu corpi Auer


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LEUCEMIA INTRODUCERE ALL (Leuc Limfoblastica acuta) in contrast cu

cea mieloblastica, th limfoblastul este un blastmic cu insuficienta citoplasma, cromatina

densa, nucleoli nedistinctivi si fara corpii Auer.

Limfoblast


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LEUCEMIA INTRODUCERE

Citocimia ajuta laclasificarea linieicelulare leucemice

(mieloida versuslimfoida) Mieloperoxidaza se

afla in granulatiileprimare ale celgranulocitare

incepand cu stadiulde blast tarziu.Monocitele pot fi slabpositive.


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Negru Sudan Negru Sudan coloreaza

phospholipidele, grasimileneutre si sterolii aflati in

granulele primare si secundareale celulei granulocitare si maiputin in lizozomii monocitelor.Rareori apare positivitate incelulele limfoide


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Esteraza Nonspecifica

Esteraza Nespecifica este

utilizata pentru a identifica celmonocitare care sunt difuzpozitive. Limfocitele T pot aveacolorari focale


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Fosfataza Acida Fosfataza Acida poate fi gasita in

mieloblasti si limfoblasti.Limfocitele T au un nivel cresut de

fosfataza acida si pot fi utilizatepentru a ajuta diagnosticulleucemiei acute T limfocitare.


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Fosfataza alcalina

leucocitara Fosfataza alcalina leucocitara

este localizata in granuleletertiare ale neutrofilelorsegmentate si in metamielocite.Scorul FAL este determinatnumarand 100 neutrofile maturescorand de la 0 la 5 fiecarecelula. The total LAP score iscalculated by adding up the

scores for each cell.


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Fosfataza alcalina

leucocitara


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LEUCEMIA INTRODUCERE Markerii imunologici (imunofenotiparea) sunt utilizati

mai ales pentru limfocite, i.e., pentru determinarealiniilor B sau T. Se bazeaza pe anticorpii anti markerispecifici de suprafata. Constituie ceea ce numim

anticorpi primari . Fluorescently labeled antibody(secondary antibody) against the primary antibody isadded and allowed to react and then unboundsecondary antibody is washed away. The cells are thensent through a flow cytometer that will determine thenumber of cells that have a fluorescent tag and whichare thus positive for the presence of the surface markerto which the primary antibody was made. In a directassay, the primary antibody is fluorescently labeled.


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Direct versus indirect

labeling of antigens


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Flow cytometer


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Deoxytidyl transferaza

terminala (TDT) Este o DNA polimeraza unica

prezenta in celulele stem si in

precursorii B si T limfoizi celulari.Niveluri crescute se gasesc in 90%din leucemia limfoblastica. It can

also be detected using appropriateantibodies and flow cytometry.


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LEUCEMIA INTRODUCERE Citogeneza studiile citogenetice pot fi cum

utilizate pentru diagnostic si pentruprognosticul afectiunilor hematologice

maligne. Many leukemias (and lymphomas) are characterized

by specific chromosomal abnormalities, includingspecific translocations and aneuploidy. The specifictype of malignancy can be identified based on thespecific abnormality or translocation. These may beidentified by

Looking at the karyotypes of the chromsomesfrom the abnormal cells

DNA based tests these tests are very useful forfollowing the course of the disease

A normal karyotype is usually associated with a


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Chromosomal

translocation


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Chromosome karyotyping


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Leucemiile acute Leucemia limfoblastica

acuta They may be classified on

the basis of the cytologicalfeatures of thelymphoblasts into; L1 - This is the most common

form found in children and ithas the best prognosis. Thecell size is small with fine orclumped homogenous nuclearchromatin and absent orindistinct nucleoli. Thenuclear shape is regular,occasionally clefting or


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ALL-L2

Leucemia limfoblasticaacuta:L2 This is the mostfrequent ALL found inadults. The cell size islarge and heterogenouswith variable nuclear

chromatin andprominent nucleoli. Thenucleus is irregular,clefting and indented.

The cytoplasm isvariable and oftenmoderate to abundant,the basophilia is variableand may be deep, andvacuoles are variable.


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Leucemiile acute L3 This is the rarest

form of ALL. The cell sizeis large, with fine,

homogenous nuclearchromatin containingprominent nucleoli. The

The nucleus is regular

oval to round. Thecytoplasm is moderatelyabundant and is deeplybasophilic andvacuolated.


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Leucemiile acute ALL may also be classified on the

basis of immunologic markers into:

Early pre-B ALL Pre-B ALL B ALLT ALL Null or unclassified ALL (U ALL) - lack B

or T markers and may be the committedlymphoid stem cell)


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B cell maturation


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T cell maturation


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Leucemiile acute Incidenta ALL este caracteristica

copiilor mici (2-5 ani), dar poate

aparea si la adulti Clinica pancitopenia cu astenia,

paloare, febra, scadere in greutate,iritabilitate, infectii, anorexie, dureri

osoase, sangerari. L1 occurs in children, L2 in adults,

and L3 is called Burkitts leukemia


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Leucemiile acute Prognoza varsta, nr de leucocite si tipul de

celula sunt cei mai importanti indicatori deprognostic Patients younger then 1 and greater than 13 have

a poor prognosis If the WBC count is < 10 x 109/L at presentation,

the prognosis is good; If the WBC count is > 20 x109/L at presentation the prognosis is poor

T cell ALL (more common in males) has a poorerprognosis than any of the B cell ALLs which havea cure rate of 70%


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Leucemiile acute Acute leukemias with mixed lineage

there are occasionally acute leukemiasthat are biphenotypic and displayphenotypes for two different lineages B lymphoid/myeloid T lymphoid/myeloid B/T lymphoid Myeloid/Natural killer A rare trilineage leukemia has also been

seen (was B/T lymphoid/myeloid!)


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Leucemiile acute Leucemia mieloblastica acuta (sau

Leucemia granulocitara acuta) clasificarea se bazeaza pe Morfologia blastilor medulari Gradul maturarii celulare Reactii citochimice Imunofenotipare AML is divided into 7 different classifications:

M1 myeloblastic without maturation The bone marrow shows 90% blasts and < 10%

promyelocytes The disease occurs in older adults


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AML M1 Note the myeloblasts and the auer

rod:


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Leucemiile acute M2 myeloblastic with maturation

The bone marrow shows 30-89% blasts and > 10%promyelocytes;

This is characterized by an 8,21 chromosomal

translocation This occurs in older adults

M3 hypergranular promyelocytic This form of AML has a bone marrow with >30%

blasts

Is more virulent than other forms Occurs with a medium age of 39 The WBC count is decreased Treatment causes a release of the granules and

may send the patient into disseminatedintravascular coagulation and subsequent bleeding

It is characterized by a 15,17 chromosomaltranslocation


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AML M2 Note myeloblasts and

hypogranulated PMNs:


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AML M3 Note hypergranular

promyelocytes:


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Leucemiile acute M3m hypogranular promyelocytic

The bone marrow has > 30% blasts The WBC count is increased.

Like the M3 type, treatment causes a release of thegranules and may send the patient intodisseminated intravascular coagulation andsubsequent bleeding and

It is characterized by a 15,17 translocation

M4 acute myelomonoblastic leukemia Both myeloblasts and monoblasts are seen in the

bone marrow and peripheral blood Infiltration of extramedullary sites is more common

than with the pure granulocytic variants


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AML M3m Note hypogranular promyelocytes:


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AML M4 Note monoblasts and

promonocytes:


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Leucemiile acute M5 acute monoblastic leukemia

>80% of the nonerythroid cells in the bone marrow aremonocytic

There is extensive infiltration of the gums, CNS, lymph

nodes and extramedullary sites This form is further divided into

M5A - Poorly differentiated (>80% monoblasts) M5B - Well differentiated (


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AML M5A Note monoblasts:


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AML-M5B Note monoblasts, promonocytes,

and monocytes:


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AML M6 Note M1 type monoblasts


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Leucemiile acute M7 - Acute megkaryoblastic leukemia

This is a rare disorder characterized by extensiveproliferation of megakaryoblasts, atypicalmegakaryocytes and thrombocytopenia

Tratamentul leucemiilor Are doua scopuri:

Eradicarea masei celulare leucemice Actiuni de suport

Except for ALL in children, cures are notcommon but complete remission (absenceof any leukemia related signs andsymptoms and return of bone marrow andperipheral blood values to within normal

values) is


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Leucemiile acute

Exista patru tipuri generale de terapie Chimioterapia usually a combination of

drugs is usedTransplantul de maduva Radioterapia Immunoterapia stimulate the patients

own immune system to mount a responseagainst the malignant cells

leucemia introducere tr

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