LEUKEMIA
Leukemia Introduction Stem cells (sc)
•Myeloid Stem cells. •Proerythroblast -> …… -> reticulocytes -> erytherocytes •Megakaryoblast -> megakaryocyte -> platelets •Myeloblast: •Monoblast -> promonocyte -> monocyte -> macrophages •N. promyelocyte -> myelocyte myelocyte ->metamyelocyte -> band ->neutrophil •B. promyelocyte -> basophil •E. promyelocyte -> eosinophil •Lymphoid Stem cells. •Lymphoblast •B-cells •T-cells •Natural killer (NK) cells ★N.B
in normal bone marrow, there is 2-4 % of blast cells.
Acute Leukemia Definition:
•Clonal proliferation of hematopoietic progenitors with decreased ability to differentiate into mature elements. •Decreased RBCs, platelets, and neutrophils production •More blast cells in bone marrow and prepherally •≥ 20% of bone marrow cells are blast cells (myeloblasts (myeloblasts or lymphoblasts) Epidemiology : •AML: median age is 65 year old of age, > 80% of adult cases of acute leukemia •ALL: median age is 10 year old of age (i.e more common in children), bimodal with second peak in elderly. Risk Factors:
•Radiation •Chemotherapy •Chemotherapy (alkylating ( alkylating agents, topoisomerase II inhibitor) •Benzene •Smoking ★N.B:
any cancer is a multistep hypothesis
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LEUKEMIA
Associated diseases as a risk factors:
•Acquired hematopoietic diseases: •Myelodysplastic syndrome, myeloproliferative disorder (specially CML), aplastic anemia, paroxysmal nocturnal haemoglobinuria. •Inherited diseases: •Down syndrome, Klinefelter’s syndrome, fanconi anemia, ataxia telangiectasia. Classifications:
•Many classifications depends on different things, for example, there are morphic and cytochemical classification, Immunophenotypic classification, cytogenetic classification and finally molecular classification. AML classifications:
•Until the year 2000 the Dx of AML was based on FAB(French- American –British) classification, which include presence of ≥30 of myeloblast in B.M, and further classification based on morphology and cytochemistry (major subtype M0M7 ), then the WHO modified the FAB schema by reducing the number of blasts required for Dx and incorporating cytogenetic, morphologic and clinical features in defining disease entities. The FAB classification (M0 M7): M0: minimal differentiated leukemia. M1:myeloplastic leukemia. M2: myeloplastic leukemia with maturation. M3:promyelocytic leukemia (APL = Acute promyelocytic leukemia ) M4:myelomonocytic leukemia. M5:monocytic leukemia. M6:erythroleukemia (Di Guglielmo disease) M7:megakaryoblastic leukemia. The WHO classification ( І, ІІ, ІІІ,IV) І
:AML with recurrent genetic abnormalities.
ІІ:
AML with myelodyslasia related changes.
ІІІ: therapy
related eg: alkylating agents or topo
ІІ
inhibitors.
IV: not otherwise specified . ALL classification: Depends on immunohistochemistry like the presence of TDT,CD, WHO immunophenotype classification of ALL: •Precursor B-cell. •Precursor T-cell. •Burkitt’s lymphpma (-ve TDT) NB. Burkitt’s lymphoma can present as acute leukemia
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LEUKEMIA
Clinical Manifestations:
AML (more common in AML)
ALL (more common in ALL)
Pancytopenia Anemia: sympt ms e.g. fatigue. Thrombocyto enia: Bleeding. Neutropenia: Re urrent infections. N.B. Infections happen in areas where n ormal flora habits. Examples for infections : URTI an pneumonia. Gastr enteritis. A scess. •Also in Monocytic AML (M5). •Hepatomegaly. •Lymphadenopathy. •Myeloblast are larger and less likely to cause •Hence lymphoblast are small cells and have these things. adherent molecules: they can cross the BBB (blood brain barrier): •Hence myeloblast are larger cells, leukostasis: CNS involvement: •Hyperviscosity syndrome: •Cranial nerve palsy. Headache, blurred vision, tinnitus •Seizures. Hyperviscosity retinopathy (e.g. •Nausea, vomiting, headache. Engorgement of retinal veins, hemorrhage, •Also, can cause Testicular mass: U/S is exudate..). indicated. • Thrombi in brain, lung, heart. •Anterior mediastinal mass (especially in T-cell). •Leukemic infiltration in the skin: (This is in M4 "myelomonocytic" and M5 "monocytic"). •Gum hypertrophy. •Subcutaneous Nodules: Chloroma. •DIC: in M3 "promyeloblast" (APL= Acute promyeloblastic leukemia). •Promyelocyte are larger, granular cells and have creased nucleus : •May release tissue factors which may cause DIC and massive bleeding. Investigations:
N.B; we will mention 2 emergencies in the investigations 1.CBC WBC •↑(leukocytosis) •Rarely, Normal, aleukemic
Leukemia (in ALL only) •Low leukocyte (Febrile Neutropenia)
*The 1st Emergency*
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!
Neutrophil ! Monocyte ! Basophil ! Eosinophil ! Lymphocyte: ! The lab won't differ between lymphocyte and lymphoblast but it will show this sign " [Flagging System] but on blood film: it will appear as blast cells.
LEUKEMIA
Febrile Neutropenia Definition: •Fever: single oral temp. 38.3 Or 38 1h •Neutropenia: neutrophils <500 cells /l or <0.5 ★They
are more caused by gram negative Rods especially pseudomonas aeruginosa, they are more likely to cause septic shock. ★Septic
screen will be 50% -ve
Treatment: •Aggressive hydration •Abx (each hospital has its own protocol): •1st : "which cover Gr -ve" : Cefepime or Tazocin or Meropenem •2nd : (if still fever >24h): cover gram +ve •3rd : (if still fever): cover fungal
-continue the investigations2.Blood film : Blast cell •
Myeloblast Lymphoblast
•Then you will do : 3.Bone marrow aspiration or bone marrow biopsy ( take 5 sample ) :
I.Morphology ( under microscope ) : 20% or more blast cell " remember the definition " . Others : Aure rod ( eosinophilic needle shape inclusions ) Granules
DxforAML
• •
ve=AML
II.Cytochemistry
-ve=ALL +vemyeloperoxidaseand\ornon specificestrase=AML
+veTDT(terminaldeoxynucleo5dyltransferase) foundin9%ofALL "notinburki+'slymphoma".
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LEUKEMIA
III.Flowcytometry : •Determine the immunophenotype :
Myeloid
LymphoidBorT
(m0–m7)
Infiltra5ve
cellprecursor orburki's Breast prostate
N.BifCD4is–ve=itisinfiltravenotB.Minorigin
IV. Cytogenetic lab : It is for : 1-Dx 2-Prognosis 3-Rx 4-Follow up i.e. for risk stratification : low \ intermediate \ high . •Examples : For Dx. : •t ( 15: 17 ) = diagnostic for m3 AML = APL . •t ( 8 : 21 ) or t ( 16 : 16 ) = Dx for AML . For prognosis : •Philadelphia chromosome (ph) t( 9: 22 ) = very bad prognosis for ALL . •N.B ph chromosome is also found in CML . V.Molecular analysis ( PCR ) : •Look for oncogen.
4.Urea and Electrolyte : •As a base line . •Look for " Tumor lysis syndrome " = the 2nd emergency . •Because of the rapid cell turnover : •↑ urate, ↑ LDH,↑ k , ↑ phosphate . • but LOW Ca . ★It can cause an obstructive nephropathy = acute renal failure . N.B tumor lysis syndrome can occur de novo .
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Thyroid GI
LEUKEMIA
Chronic Myelogenous Leukemia (CML) Definition: It is one of the myeloproliferative disorder with clonal overproduction of myeloid stem cell
N.B: Myeloproliferative disorder : •polycythemia vera •CML •Essential Thrombocytosis •Mylofibrosis
•Philadelphia chromosome (ph)= t(9:22) •BCR-ABC genes fusion →
↑ tyrosine kinase activity
•Dx: presence of BCR-ABL fusion. •Prognosis: worse if (ph chromosome) not present. Epidemiology and Risk factor:
•Median age is 50 years •Increased risk with radiation Clinical manifestations:
•Triphasic clinical course: (history of the disease) Chronic phase ( <10% of blasts in B.M)
-Asymptomatic general symptoms ,fatigue ,fever. -Weight lose, Night sweets, abdominal discomfort (splenomegaly). Accelerated phase (10-20% blasts in B.M) -Worsening symptoms and refractory luckocytosis -Bleeding (↓platelets) ,infection (neutropenia) -Progressive increase in spleen size -Features of gout (↑purine breakdown) -Pruritis (basophilia) Blastic phase (>20% of blasts in B.M). -This is acute leukemia. •Signs:1-Splenomegaly (>75%) often massive – very important sign N.B massivesplenomegaly means spleen below umbilicus •Causes of massive splenomegaly :1- hematological (CML – Myelofibrosis). 2- infections (chronic malaria – schistosomiasis – kala azar). 3- others (tropical spleenomegaly – gaucher’s disease “rarely”). 2-Hepatomegaly. 3-Anemia. 4-Bruising.
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LEUKEMIA
Investigations :-CBC :- ↑ WBC, lift shifted with all stages of myeloid maturation , ↑basophils , anemia , thrombocytosis. -Bone marrow :- hypercellular with ↑ myloid to erythroid ratio. -NAP score (neutropiil alkaline phosphatase): low N.B this will be high in polycythemia rubra vera. -↑uric acid level , ↑B12 level. -Cytogenetics: Philadelphia chromosome Treatment:
Tyrosine kinase inhibitors: imatinib, dasatanib, nilotinib
•
Allogenic bone marrow transplantation.
•
CLL (chronic lymphocytic leukemia) Definition: monoclonal accumulation of mature B-cells, which is functionally incompetent, as they escape programmed cell death. Epidemiology : most common adult leukemia, median age is 65. Clinical:
Often asymptomatic (present with ↑ lymphocytic count)
•
Lymphoma B symptoms: fatigue,night sweats, weight loss.
•
Signs: lymphadenopathy (80%), hepatosplenomegaly(50%)
•
Complications: •Autoimmune hemolytic anemia (AIHA), and ITP (idiopathic thrombocytopenic purpura) •Hypogammaglobulinemia : neutropenia: ↑ infections •Bone marrow failure •Aggressive transformation: Richter’s syndrome = transformation into a high grade lymphoma. •Monoclonal gammopathy CLL Staging(just for reading)
Rai system Stage
Description
0
Lymphocytosis alone
I
+ Lymphadenopathy
II
+ Hepatosplenomegaly
III
+ Anemia (not AIHA)
IV
+ Thrombocytopenia (not ITP)
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Median survival
> 10 y y
1-2 y
Binet system Description
Stage
< 3 node areas
A
no e areas Anemia or Thrombocytopenia
C
LEUKEMIA
Investigation:
-CBC: - ↑ Lymphocyte , ↓ Hb , ↓ Neutrophils , ↓ Platelets. -Bone marrow: infiltration with B-lymphocytes. -Blood film: smudge cells ( damage to abnormal lymphocyte while making the smear ). -Lymph node biopsy: infiltrated with lymphocyte. - FlowCytometry & Cytogenetics: see acute leukemias. Treatment: - Indications for Rx: - Rai stage III II , Binet stage C. - Symptomatic. - Recurrent infections. - AIHA or ITP. - progressive disease , Resistant to steroid.
-Rx options: - Fludarabine ( purine analog ) + cyclophosphamide. - Chlorambucil for elderly. - Monoclonal Ab against CD20 (Rituximab) or CD52 (Alemtuzumab) - Radiotherapy: for lymphadenopathy or splenomegaly. -Supportive: Steroid → AIHA or ITP , Recurrent infections→ I.V immunoglobulin , transfusion. -Hypersplenism → splenectomy.
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