non neoplastic wbc disorders

8/11/2019 Non Neoplastic Wbc Disorders

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HEMATOLOGY LECTURE NOTES

Dr. Brady-West

White Blood Cell Disorders

Learning Objectives:

At the end of these lectures, the student should understand:

1. The normal process of white cell production, differentiation and

maturation.

2. The etiolog and patholog of reactive changes in the number andmorpholog of granuloctes

!. The etiolog and patholog of reactive changes in the number and

morpholog of lmphoctes and monoctes

". The difference between a leu#emia and a leu#emoid reaction

$. The indication, procedure and interpretation of the leu#octe

al#aline phosphatase test %LA&'

(. The morphological definition and the implication of a leuco)

erthroblastic blood picture

*. The epidemiolog clinical features, laborator diagnosis, andcomplications of +nfectious ononucleosis

-. The clinical, morphological, ctochemical and immunological

basis for the diagnosis and classification of leu#emia

. The general scheme of treatment of acute leu#emia, and the

prognostic factors which affect the outcome of such therap

1/.The definition, classification, differential diagnosis and

management of the eloproliferative diseases

11.The epidemiolog, ctogenetics, clinical features, laborator

diagnosis, natural evolution and therapeutic options of 0hroniceloid Leu#emia


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WHTE CELL DSORDERS

euirements for leu#opoesis %white cell production':1 a. Adeuate numbers of normal stem cells

b. 3uitable microenvironment provided b a stromal matri4 on which adherent

stem cells can proliferate and differentiatec. Adeuate levels of growth factors %0olon 3timulating 5actors'

6ranulocte maturationThe earliest identifiable granulocte precursor is the !yelo"last, usuall found in small

numbers in the bone marrow but absent from the peripheral blood in health individuals.There are three pools of marrow granuloctes

a. The mitotic pool which comprises all cells from the meloblast to themelocte. These are all capable of self 7renewal b mitosis. 8ifferentiation

into neutrophil basophil and eosinophil is evident atthe melocte stage.

b. The maturation pool which e4tends from the metamelocte to the maturegranulocte

c. The storage pool of mature granuloctesThere are two components of the peripheral blood granulocte pool

a. circulatingb. marginating % adherent to endothelium of small venules and capillaries'

6ranuloctosis ma occur b several mechanisms

a. obili9ation of marginating cellsb. +ncreased rate of maturation

c. +ncreased rate of mitosis

6ranules&rimar % a9urophilic ' seen at the meloblast and promelocte stage ,and

contain the en9me eopero4idase

3econdar : these appear at the melocte stage. The are neutral staining in the

neutrophil, red) orange in the eosinophil and blue in the basophil.

eutrophilumber 2.$ 7 *.$41/;L5unction %see illustration'

a. igration to the site of infection or inflammation

b. &hagoctosisc.


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+ncubate in a phosphate solution, then rinse and counterstain.

+nterpretation: assess the number and intensit of blue ctoplasmic granules in

1// cells.5or each cell score /)". a4imum score is "//. ormal !$ )1//

/: o stained granules

1: few granules2: moderate staining

!: umerous granules, strongl positive

": umerous intensel stained granules

eutropenia8efined as a neutrophil count of less than 2.$ 4 1/ ;L. Bsuall smptomatic at

C1./ 4 1/ ;L., with recurrent infections, oral ulcers. 3erious or life)threatening reactions

occur at C /.2 1/ ;L.

Classi,i*atio%@enign familial

0clic: neutrophil counts fall at 21 da intervals and remain low for $)*das. 8ue to failure of normal humoral feedbac# mechanism

3econdar: due to viral infections, autoimmune disease or

drug induced 7 most common adult cause of isolated neutropenia, associated withanti)inflammator, antithroid, antihpertensive and oral hpoglcemic agents

osinophilia

8efined as an absolute eosinophil count D /.* 4 1/;l0auses

&arasitic infestation, especiall b organisms which invade tissuesAllergic disorders : bronchial asthma, urticariaE ha fever8rug reactions

=ematologic diseases: 0hronic meloid leu#emia. &ernicious anemia,

=odg#in disease

@asophils

3imilar to mast cells found in tissues+nvolved in +g mediated hpersensitivit reactions. 3ubseuent to reaction

between allergen and +g the release of basophil granule contents e.g. histamine, lead to

the recogni9ed clinical features of allerg or hpersensitivit.

0auses of @asophilia

=pothroidism

eloproliferative diseases 0hic#en po4


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ononuclear 0ells

Lmphoctes : &roduced in the bone marrow from pluri) potent stem cells.

T lmphoctes account for ($)-/F of peripheral blood lmphoctes and

are functionall divided into T helper cells %predominate in blood' and T suppressor cells%predominate in marrow'

@ lmphoctes : these have endogenousl produced +g molecules on the

cell surface , which act as receptors for specific antigens.Lmphoctosis : absolute lmphocte count D "./4 1/ ;l. Levels are higher in

infanc and graduall decrease toward adult levels.

Ca'ses o, ly!&ho*ytosis

1. Acute infections : pertussis, hepatitis, infectious mononucleosis2. 0hronic infections : tuberculosis , congenital sphilis

!. Lmphoma or leu#emia

orphologic variations in lmphoctes in reactive states:

1. increased si9e

2. increase in ctoplasm cf to the nucleus

Mo%o*ytes

@one marrow monoctes arise from the same precursor cell as granuloctes. @one

marrow monoctes give rise to peripheral blood monoctes and tissue macrophages.Tissue macrophages constitute part of the !o%o%'*lear &ha$o*yte syste!.

Mor&holo$y o, !o%o*ytes

?ariable si9eAbundant gra ctoplasm, often vacuolated

Larger than lmphoctes+ndented nuclei

a combine to form giant cells


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Mo%o*ytosis: 0auses

1. @acterial infections % most cause neutrophilia' sphilis, bacterial endocarditis

2. ecover from acute infections!. &roto9oan infections

". 0ollagen vascular diseases

$. chronic steroid therap(. 6ranulomatous diseases: sarcoidosis, ulcerative colitis.

Case History

A 2/)ear)old student presents with a *)da histor of fever sore throat, letharg and

tender enlarged glands in the nec#.

&hsical e4amination reveals fever, mild jaundice, inflamed pharngeal mucosa and

cervical adenopath@lood results

=bE 12.$ g;dl, wbc 1-./41/;l , differential !/F neutrophils "/F lmphoctes !/Fabnormal lmphoctes. &latelets 1// 41/;l

Throat swab: o bacterial growth

=+? test negativeonospot test: positive

%,e*tio's Mo%o%'*leosis

0aused b infection with pstein)@arr virus %@?' and characteri9ed b:5ever and pharngitis

Lmphadenopath and mild splenomegal

+ncreased circulating atpical mononuclear cells=igh titers of heterophile antibodies

&ea# incidence at ages 1$ 72$ rs.

Cli%i*al ,eat'res

. +ncubation period of $)- wee#s

. &hangitis with edema and adenoidal hpertroph

. Lmphadenopath 7 tender, bilateral and smmetrical

. ild to moderate splenomegal in $/)*$ F

. Atpical features include s#in rash, hepatitis and encephalitis

Di,,ere%tial dia$%osis

1. Acute viral pharngitis caused b other organisms ) serological tests are

negative

2. Acute leu#emia 7 usuall significant anemia and ;or thromboctopeniaE also

peripheral blood lmphoid cells are blasts %with nucleoli'. &eripheral blood


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picture will be the same or worse after 1/)1" das %will show improvement in

+..'

He!atolo$i*al ,eat'res

1. Leucoctosis of 12)1- 41/;l with atpical mononuclear cells. The majorit of

these are activated T lmphoctes.

2. Anemia and thromboctopenia are uncommon, and usuall autoimmune innature

Serolo$i*al eat'res

1. @?) specific antibodies

a. Antibodies to ?iral 0apsid Antigen %?0A' : +g antibodies produced

during incubation period and pea# after 2)! wee#s then decline. +g6

antibodies subseuentl appear and persist for lifeb. Antibodies to uclear antigen %@A' begin wee#s after onset of

illness and persist indefinitel

2. Autoantibodies: uncommon, ma cause autoimmune anemia or

thromboctopenia

!. =eterophil antibodies

These are non)specific serum agglutinins that will agglutinate sheep or

horse red cells. + heterophile antibodies are differentiated b thefailure to be absorbed b guinea pig #idne cells. This is the basis

of the GonospotH test.

Therap

1. Treatment is smptomatic and antibiotics do not positivel alter the course of

the illness

2. 3teroids are indicated for severe and complicated cases eg autoimmunectopenias or encephalitis


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Acute Leu#emia

8efinitionA leu#emia is a clonal neoplastic proliferation of white cells in blood and;or bone

marrow .

0lassification of leu#emia

Acute eloid %AL' or Acute Lmphoblastic %ALL'

0hronic eloid %0L' or 0hronic Lmphoctic %0LL'

Case History

A ( ear old female presents with a ! wee# histor of fever, being less active than normaland becoming easil tired.

3he also has bleeding gums and eas bruising for 1 wee#&hsical 4amination:

&ale and febrile

Tender over ribs and sternumultiple cutaneous hemorrhagic lesions

nlarged cervical lmph nodes

nlarged spleen

Laborator results=b. (./g;dlE plats. 124 1/;lE >@0 -$41/;l

/F blasts

0I: enlarged hilar lmph nodes@ aspirate D /F blasts

Cli%i*al ,eat'res o, a*'te le')e!ia

a. 8ue to organ infiltration

@one pain

Lmphadenopath or hepatosplenomegal

b. @one marrow failure

Anemia 7 dspnea, fatigue, palpitations

eutropenia 7 fever, infectionsThromboctopenia 7 bleeding from s#in or mucosa

c. =permetabolic state5ever

8renching night sweats


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pidemiolog

ost common childhood malignanc is ALL

-/:2/ ALL: AL in childhood, the ratio is reversed in adultsnvironmental ris# factors

@en9ene

+oni9ing radiation

0hemotherap6enetic disorders

8owns sndrome


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&rognostic factors in AML

Age less than 2 or greater than (/ ears

&receding hematological disorder

>@0 greater than 1//

Tpes / , ( and *

&rognostic factors in ALL

5avorable BnfavorableAge : 2)1/ ears C 2 or D 1/ ears

>@0: 1/ or less D $/6ender: female male

Tpe: L1 ; 0)ALL L! ; @)ALL

emission: earl late8: absent present

Treatment and outcome of AL

+nduction of remission with intensive chemotherap with 0tosine, 8aunorubicin0onsolidation therap with repeated courses of similar agents

($)-/F achieve complete remission

1/)!/F cure rate

Treatment and outcome of ALL : treatment is stratified according to ris#emission induction

0onsolidation; intensification

03 prophla4is with intrathecal methotre4ate and ;or radiationaintenance %prevention of bone marrow relapse' for 2) ! ears

@one marrow transplantation

1/ ear survival "/ 7-/ F


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elodsplasia

elodsplastic 3ndromes %83'

8efinition : =eterogenous group of clonal disorders characteri9ed b :

1. peripheral blood ctopenias with normal or increased marrow cellularit2. morphological and functional abnormalities

!. pea# incidence in the elderl

0auses

ost are idiopathic4posure to al#lating agents

+oni9ing radiation

0linical features

Anemiaecurrent infections

Abnormal bleeding

8splastic changes in peripheral blood or marrowacroctic anemia

egaloblastoid erthropoesis

Agranular neutrophilsinged sideroblasts

monoctosis

Therap and outcome

Treatment depends on age, tpe of 83, general condition of the patient

3upportive therap with transfusion of red cells or platelets0hemotherap for advanced disease similar to treatment for AL

@one marrow transplant 7onl in relativel oung patients.

Outcome is variableE 2$)"$F transform to AL


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MYELO+ROLERATE DSEASES

De,i%itio%: These are a group of related chronic marrow diseases that have in commonthe hperplasia of cellular and ;or stromal bone marrow components. The are classified

based on the nature of the &redo!i%a%tproliferating cell line:

1. &rimar polcthemia % erthroid'2. ssential thrombocthemia %mega#aroctic'

!. 0hronic meloid leu#emia % granuloctes'

". &rimar melofibrosis % fibrous tissue'

Cli%i*al ,eat'res1. on)specific features common to all, due to a hpermetabolic state

a. 5ever , weight loss and drenching night sweatsb. 3plenomegal : most prominent in 5 and 0L

2. 3pecific features such as bleeding or thrombosis in &? and T

!. All ma be incidentall discovered on routine phsical or laborator tests

Dia$%osis

1. 4clude a secondar or reactive state that can mimic the primar disorder.There are four such reactive conditions

a. 3econdar polcthemia %vs. &?'

b. eactive thromboctosis %vs. T'c. Leu#emoid reaction %vs. 0L'

d. 3econdar melofibrosis %vs. 5'

2. +dentif the specific &8 b the presence of diagnostic criteria eg.

a. +ncreased red cell mass or pac#ed cell volumeb. &latelet count above (//4 1/;l

c. &hiladelphia chromosome

d. @one marrow fibrosis D 1;!

0ase =istor

A $- ear old 0aucasian man is admitted for elective repair of an inguinal hernia.

outine 0@0 : =b. 21.$ g;dl, &0? /.(1E >@0 1( 4 1/;LE platelets $2/4 1/;L&hsical e4amination: enlarged spleen


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=e admits to having recurrent headache and blurred vision for the past ( months

+ri!ary +oly*ythe!ia /+R0

&olcthemia is defined as an elevation of the pac#ed cell volumeE and ma be:

1. Absolute &olcthemia: the red cell mass is actuall increasedE this increasema be :

a. +diopathic : this is primar proliferative polcthemia %&?'

b. 3econdar to underling diseases which produce increased &Oi' =po4ic states eg. 0anotic heart disease, chronic lung

disease

ii' +nappropriate &O production eg. enal csts, renal cancer,

phaeochromoctoma2. elative polcthemia: there is no increase of red cell mass, but a relative

decrease in plasma volume causes an increased &0?

+ri!ary +oly*ythe!ia

&ea# incidence in the (thdecade, but ma be seen in oung adults0ommon signs and smptoms

&lethoric s#in

3plenomegal=eadache and di99iness

?enous or arterial thrombosis

0riteria for diagnosis

+ncreased &0? D /.$$Arterial o4gen saturation D 2 F

3plenomegal

Leucoctosis ; thromboctosis

anagement1. reduce blood volume b phlebotom 1)2 per wee# until &0? is

C"$

2. allopurinol to prevent urate nephropath

!. elosuppression with hdro4urea". adioactive phosphorus in older patients


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+ri!ary !yelo,i"rosis

&resents with smptoms of anemia or of massive splenomegal .

Laborator features

1. leucoerthroblastic blood picture which comprises:a. tear drop shaped red cells

b. nucleated red cells in peripheral blood

c. immature granuloctes2. ormochromic anemia

!. ?ariable white cell and platelet counts

". levated LA& score

$. &rogressive bone marrow fibrosis

0auses of secondar fibrosis must be e4cludedE

1.arrow infiltration b lmphoma, leu#emia or solid tumors2. 6ranulomatous diseases eg. Tuberculosis or sarcoidosis

.anagement

3mptomatic with transfusion of blood products

3plenic si9e ma be reduced b chemotherap or splenicirradiation

edian survival is !)* ears. 2/F transform to acute meloid

leu#emia

Chro%i* Myeloid Le')e!ia

Case History

A !2)ear)old man presents with a left upper abdominal mass for 1 month, but has noother smptoms.

=b. 1$./ g;dlE platelets normalE >@0 "!4 1/ ;lE

>@0 differential: "$F E 2F LE -F oE (F @asoE !$F meloctesE "Fmetameloctes

LA& score: 2-

De,i%itio%: A clonal stem cell disorder characteri9ed b increased granuloctic

proliferation at all stages of maturation.

=ematological features:

1. Leucoctosis

2. 5ull spectrum differential with pea#s at melocte and matureneutrophil


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!. osinophilia and basophilia

". LA& score low

8istinguish from leu#emoid reaction b:1. o clinical histor of infection or inflammation etc.

2. The presence of significant splenomegal

!. The low LA& score". The wbc differential

$. The presence of &hi chromosome

Cyto$e%eti* ,eat're

&hiladelphia chromosome: mutual translocation with e4change of genetic

material between chr and chr 22. This results in he formation of an abnormal hbrid

gene %@cr)Abl' that results in increased cell proliferationote: The &hiladelphia chromosome is %ot specific for 0L. &resent in $F of patients

with 0L, also found in some cases of ALL

Role o, +hi i% &atho$e%esis o, CML

6enetic seuence on 0hr 22 % bcr ' are fused with seuences translocated from chr abl' . This fusion gene codes for an abnormal protein with Tyrosi%e 1i%aseactivit. This

Trosine


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!.3plenic irradiation ma be used for palliation of massive splenomegal

2. 3pecific treatment1. 0hoice of therap depends on the age of the patient, phase of disease and the

availabilit of a matched bone marrow donor.

2. 0hronic phasea. Treatment of choice used to be bone marrow transplant if patient is

less than "$ ears old, and a matched donor is available for allogeneic

bone marrow transplant. Onl 2$F of patients are eligible.

". +f bone marrow transplant is not possible 7 ) interferon will

effectivel lower the cell count. +nterferon is administered

subcutaneousl. ain side effect is fever ; malgia. E#&e%si3e+nterferon is not used if @T is planned 7 worsens outcome

*. 6livec % imatinib' inhibits the trosine #inase activit of the protein

produced b the fused gene on the &hi chr. ow approved for first line

treatment. Ad3a%ta$e ( oral ad!i%istratio%4 also a*ts at as tar$etedthera&y to &re3e%t &rod'*tio% o, the !ali$%a%t *lo%e. This has

%o2 re&la*ed "o%e !arro2 tra%s&la%t as treat!e%t o, ,irst *hoi*e.

+rod'*es *li%i*al5 hae!atolo$i*al a%d *yto$e%eti* re!issio%s i% a

hi$h &er*e%ta$e o, &atie%ts i% the *hro%i* &hase.

d. =dro4urea: 6iven orall $oomg 7 ! 6m dail. 5reuent monitoring

of >@0 is necessar because the rate of fall is unpredictable. 0ounts

recover uic#l after cessation or lowering of dose. a be used in

pregnanc. Not *ar*i%o$e%i*

e. @usulfan: 6iven orall as dail low dose or pulse high dose.&redictable rates of fall of >@0 so freuent monitoring of counts notnecessar. Low counts do not recover promptl after cessation. a

cause prolonged marrow aplasia. 0ontraindicated in pregnanc. Bsed

in older patients when freuent clinic visits are inconvenient. 3ideeffects include pulmonar fibrosis

!. Accelerated phase

a. 0toto4ic therap used in higher doses, or switch agents.b. 0ombination of agents 7 add ctosar to oral agent

". @last phase

a. Lmphoid : vincristine and prednisone will induce remissions in somepatients % bac# to chronic phase' E remissions are of short duration

b. eloid : ctosar and adriamcin , remissions are harder to induce

than in de)novo AL.


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non neoplastic wbc disorders

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