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What is leukemia ????

Leukemia is cancer that starts in the blood-forming cells of the bone marrow. When one of these cells changes and becomes a leukemia cell, it no longer matures the way it should and grows out of control. it divides to make new cells faster than normal.

Leukemia cells also don't die when they should. This allows them to build up in the bone marrow, crowding out normal cells.At some point, leukemia cells leave the bone marrow and

spill into the bloodstream.

This increases the number of white blood cells in the blood. Once in the blood, leukemia cells can spread to other organs, where they can prevent other cells in the body from functioning normally.Leukemia is different from other types of cancer thatstart in organs like the lungs, colon, or breast and thenspread to the bone marrow.Cancers that start elsewhere and then spread to thebone marrow are not leukemia.Leukemia is myeloid or lymphocytic dependingon which bone marrow cells the cancer starts in.

Myeloid neoplasmAcutemyeloidleukemia ChronicmyeloidLeukemia

Pluripotent hematopoietic stem cells

(HSC) in the marrow differentiate into

all of the different circulating blood

cells.

• HSCs commit to the myeloid or

lymphoid lineage under the

influence of cytokines & growth

factors, generating myeloid or

lymphoid stem cells. Mature

myeloid cells include neutrophils,

basophils, eosinophils, and

monocytes.

• Red blood cells (RBC) and

platelets are also derived from a

common myeloid progenitor but

diverge soon thereafter. This

process of hematopoiesis is

illustrated in the following diagram.

MyeloidNeoplasm• Arise from hematopoietic stem cells and typically give rise to

monoclonal proliferations that replace normal bone marrowcells .

• In Acute Myeloid Leukemias, the neoplastic cells are blocked at some early stage of myeloid cell development .

• Immature myeloid cells called blasts which can exhibit evidence of granulocytic , erythroid , monocytic or megakaryocytic differentiation , accumulate in the bone marrow replacing normal elements and frequently circulate in peripheral blood . .

Ideally the diagnosis and classification of AML are based on the results of morphologic, histochemical , immunophenotypic , and karyotypic studies.

•Fab classification : ( French-American-British)•A cute myeloid leukemia (AML) is divided into 8 categories ( MO-M7)

•From MO-M3 : depending upon the degree of maturation

•From M4-M7 : depending on the lineage of the leukemic blasts .

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•The disease affects older adults, with the median age being 50 years , also affects children ,constituting 20% of childhood leukemia . Symptoms & signs are related to :

A- Bone marrow failure : caused by replacement of the normal hematopoietic elements by malignant blasts.This includes :1- Features of anemia as weakness , pallor& low Hb level. 2- Infections caused by neutropenia .3 Bleeding diathesis like purpura, GIT bleeding hematuria

gum bleeding due to thrombocytopenia .4 Renal impairment due to hyperuricemia & gout .

B- Infiltration of organs: like hepatosplenomegaly,lymph nodes involvement , brain &

other organs may be involved .

With bone pains & tenderness.

But, rarely, AML presents as a discrete tissue mass , which is called granulocytic sarcoma .

Figure 73 : Gum hypertrophy & bleeding a common feature in acute monocytic leukemia .

• Most AML harbor mutations in genes encoding transcription factorsthat are required for normal myeloid cell differentiation .

• These mutations interfere with the differentiation of early myeloidcells , leading to accumulation of myeloid precursors ( blasts) in themarrow .

• Of particular importance is the (15/17 ) translocation in acute promyelocytic leukemia , which results in fusion of retinoid acid receptor α (RARA) gene on chromosome 17 & the PML gene on chromosome 15 .

• The chimeric gene produces a PML/RARA fusion protein which blocks the myeloid differentiation at the promyelocytic stage , by inhibiting the function of the normal retinoic acid receptor .

Therapeutically the use of (all-trans retinoic acid) (ATRA) , analogus to vitamin A , overcome this block , and enhance the promyelocytes to differentiate into mature neutrophils , thus treating the leukemia .

This is an important example of a highly effective therapy targeted at a tumor-specific molecular defect .

Bone Marrow :In AML myeloid blasts make up more than 20% 0r 30% of the bone marrow cellularity.Myeloblasts are precursors of granulocytes have delicate nuclear chromatin; three tofive nucleoli; and fine, azurophilic granules in the cytoplasm.Distinctive red-staining rod-like structures known as Auer rods may be present inmyeloblasts or more differentiated

cells like promyelocytes ; they are particularly prevalent in acute promyelocytic leukemia.Auer rods are found only in neoplastic myeloblasts and are thus a helpful diagnostic clue when present .In other subtypes of AML , monoblasts , erythroblasts, or megakaryocytes predominate .

Figure 74 : Bone marrow biopsy appearance in acute leukemia .

Figure 75 : Bone Marrow smear showing involvement by Acute Myeloid Leukemia , showing myeloblasts acute myelocytic leukemia minimally differentiated (Mo).

Peripheral Blood :• The number of leukemic cells in peripheral blood is

highly variable being more than 100 000 cell/c.mm,but in 50% of patients being under 10 000 cell/c.mm .

• Occasionally the peripheral blood smear may not contain any blast thus it is called aleukemic leukemia

•For this reason bone marrow examination is essential to exclude leukemia in patients with pancytopenia .

• Because of different responses to therapy, it is of great practicalimportance to distinguish ALL from AML .

• The nuclei of lymphoblasts in Wright-Giemsa-stained preparationshave somewhat coarse and clumped chromatin and fewer nucleolithan myeloblasts. Their cytoplasm often contains large aggregatesof periodic acid-Schiff-positive material .

• The myeloblasts tend to have finer chromatin & contains 3-5 nucleoli . They contain more cytoplasm, which may contain fine azurophilic granules which are often peroxidase positive.

• A distinctive red –staining rod-like structure called Auer rods may be present in myeloblasts .

• Auer rods are found only in neoplastic myeloblasts

Figure 76 : A: Lymphoblasts , the nuclei show coarse and clumped chromatin and fewer nucleoli .B: Myeloblasts , AML (Mo) the nuclei have finer chromatin & contains 3-5 nucleoli .They contain more toplasm.

Figure 77 : Myeloblasts in acute myeloid leukemia (AML) .

Figure 78 : Myeloperoxidase positive stain in myeloblasts of acute myeloid leukemia .

Figure 79 : Myeloperoxidase stain positive in myeloblasts .

Figure 80 : Bone marrow aspirate showing PAS positive lymphoblasts in ALL .

Figure 81 : Lymphoblasts : Positive PAS cytoplasmic stain.

Mo : Minimally differentiated : constitute 2% - 3% of AML. Blasts lack auer rods,stain negative with myeloperoxidase & positive with myeloid- associated antigens such as CD13, CD14, CD15, CD64, or CD117 .

M1 : AML without maturation :Constitute 20% . Some blasts about 3% are myeloperoxidase positive & may show auer rods . Very little maturation beyond myeloblasts .

M2 : AML with maturation :Constitutes 30%-40% .

More than 20% of marrow cells are myeloblasts , but many

cells are at later stages of granulocytes differentiation.

Stain positive with myeloperoxidase .

Show Auer rods , often associated with t(8:21) .

M3 : Acute promyelocytic leukemia :Constitutes 5%- 10% of AML .

Consisting of abnormal promyelocytes with numerous auer rods and associated with t( 15:17) .With high incidence of DIC .

Figure 82 : Blood film in AML , without maturation ( M1 )

Figure 83 : Acute Myeloid Leukemia with maturation (M2) : showing intracytoplasmic Auer rods.

Figure 84 : Microscopic view of myeloblasts in M1 & M2 AML

Figure 85 : Myeloblast in AML promyelocytic leukemia ( M3) showing cytoplasmic Auer rods (arrow).

Figure 86 : Bone marrow aspirate in AML (M3) the acute promyelocytic leukemia showing Auer bodies & cytoplasmic granules .

Figure 87 : Promyelocytic Leukemia (M3) promyeloblasts show Auer rods & fine cytoplasmic granules

Figure 88 : M3 : Acute promyelocytic L. M4 : Acute myelomonocytic Leukemia .

M4 : Acute myelomonocytic leukemia :Constitutes 15%- 20% , myelocytes show monocytic differentiation ,

cells stain positive with lysosomal non-specific esterase .

Show occasional Auer rods. Associated with inverted chromosome ,i.e.

inv.(16) .

There is an increased production of immature neutrophil, white blood cells and immature monocyte in the bone marrow. These immature cancerous cells are called blasts.

Criteria for AMML is confirmed if the myleoblastsand promonocytes in the bone marrow are greater than 20 percent. With high number of monopcytes in peripheral blood.

M5 : Acute monocytic leukemia : Constitutes 10% of AML.

is a type of acute myeloid leukemia. In AML-M5 >80% of the leukemic cells are of monocytic lineage.

This cancer is characterized by a dominance of monocytes in the bone marrow.

There is an overproduction of monocytes that the body does not need in the periphery.

Monoblasts & immature monocytes seen .

Auer rods are absent .

Cells stain positive with lysosomal non-specific esterase & negative with myeloperoxidase stain .

Also stains with CD 68 .

Figure 89 : Myelomonocytic leukemia (M4).

Figure 90 : Acute Myelomonocytic leukemia (M4)

Figure 91 : AML M5 & a positive non-specific esterase stain .

Figure 92 : Peripheral blood showing ,acute monocytic leukemia (M5) .

Figure 93 : Monocytic leukemia. (M5) non-specific esterase stain .

Figure 94 : Monocytic leukemia , cells stain positive with CD68 antibody .

M6 : Acute erythroleukemia : Constitutes 5% of AML.

Most commonly associated with abundant dysplastic erythroid progenitors usually occurs in advanced age or following chemotherapy.

M7 : Acute megakaryocytic leukemia : Constitutes 1% of AML.

Blasts of megakaryocytes predominate ,stains positive with platelet-associated antigen .

Auer rods are abscent .

Increased reticulin in bone marrow called myelofibrosis is common .

Figure 95 : M6 (AML) erythroleukemia .

Figure 96 : Blood film showing acute erythroleukemia (M6) the malignant cells are precursors or erythrocytes .

Figure 97 : AML ( M7) Acute megakaryocytic leukemia .

Figure 98 : Megakaryocytic leukemia (M7) , the malignant cells are the precursors of thrombocytes .

•Cases with granulocytic differentiation are typically positive for the enzyme myeloperoxidase, which is detected by incubation of cells with peroxidase substrates.

•Auer rods are intensely peroxidase positive , which can help bring out their presence when they are rare.

•Monocytic differentiation is demonstrated by staining for lysosomal nonspecific esterases.

The expression of immunologic markers is heterogeneous in AML

Most express some combination of myeloid-associated antigens , such as CD13, CD14, CD15, CD64, or CD117.

CD33 is expressed on pluripotent stem cells but is retained on myeloid progenitor cells.

Monoblasts stain positive for CD68 antigen .Such markers are helpful in distinguishing AML and identifying

primitive AMLs (e.g., the M0 subtype) from ALL.

In addition, monoclonal antibodies reactive with platelet-associated antigens are very helpful in the diagnosis of the M7 subtype, acute megakaryocytic leukemia .

90% of patients with AML have chromosomal abnormalities .

Most AMLs are associated with acquired mutations in transcription factors that inhibit normal myeloid differentiation, leading to the accumulation of cells at earlier stages of development.

Of particular interest is the t (15;17) translocation in acute promyelocytic leukemia .

AML associated with a (8-21) chromosomal translocation or inversion of chromosome 16 have a favorable prognosis .

Where as those associated with t( 9:22) called Philadelphia chromosome have a poor outcome .

Prognosis of AML Age

Younger adults, usually those younger than 60 years of age, have a more favourable prognosis than older adults.

This may be because chromosomal abnormalities can happen as a person gets older. Older people may also

have other health conditions that make it difficult for them to cope with the side effects of treatments for AML.

White blood cell count

A white blood cell (WBC) count of more than 100,000 at the time of diagnosis is linked with a less favourable

prognosis.

Response to chemotherapy

People who reach complete remission after induction chemotherapy have a more favourable prognosis than

those who have refractory disease that does not respond to treatment.

Early relapseAn early relapse means that the leukemia returns soon after treatment. It is linked with a less favourable prognosis.

Previous blood disordersPeople who already had a blood disorder, such as a myelodysplastic syndrome (MDS), usually have a less favourableprognosis.

Previous treatment for cancerAML that develops after treatment for another cancer usually has a less favourable prognosis.

InfectionA serious, uncontrolled infection at the time of diagnosis is a less favourable prognostic factor.

Leukemia cells in the central nervous systemSpread of AML to the brain and spinal cord (called the central nervous system, or CNS) is a poor prognostic factor.

Principally affects adults between 25 and 60 years of age and accounts for 15% to 20% of all cases of leukemia.

The peak incidence is in the fourth and fifth decades .

•95% of CML is uniformly associated with the presence of an acquired, genetic abnormality BCR-ABL fusion gene .The BCR-ABL fusion gene is the product of a (9;22) translocation that moves the ABL gene from chromosome 9 to a position on chromosome 22 adjacent

to the BCR gene.The derivative chromosome 22 is often referred to as the Philadelphia (Ph)

chromosome, because it was discovered in Philadelphia.In patients with CML the BCR-ABL fusion gene is present in granulocytes,

erythyroid , megakaryocytes and in B- cell precurssors and some T-cell precursors as well .

Figure 120 : Chromosomal study of CML showing philadelphia chromosome t9:22 translocation ( small arrows) .

Figure 121 : Chromosomal study showing t9-22 with Bcr-Abl fusion gene .

The Philadelphia chromosome is only

found in the affected blood cells.

Because of the damage to the DNA,

the Philadelphia chromosome results

in the production of an abnormal enzyme

called a tyrosine kinase.

Along with other abnormalities, this

enzyme causes the cancer cell to grow

uncontrollably.

This finding is firm evidence for the origin of CML from a pluripotent stem cell .Normal myeloid proginators depend on signals generated by growth factors & their receptors

for growth & survival . But CML proginators have much decreased requirments .

This altered growth factor dependence is due to the presence of BCR-ABL fusion gene which

produce protein that simulate tyrosine kinase which generates signals that mimic the effect of

growth factor receptor activation . The drug Cleevec interferes with that protein .

Although the BCR- ABL fusion gene are present in multiple lineages, for unknown reason

granulocytes are most affected

As evidenced by markedly elevated number of granulocytes in the B.M. & peripheral blood

, the proliferation of CML proginators retain the capacity for terminal differentiation .

Although the Ph chromosome is highly characteristic of CML, it should be remembered that

it is also present in 25% of adults with ALL and rare cases of adults with AML .

Mutations of the Philadelphia chromosome transform stem cells into white blood cells. This

genetic mutation does not run in families, but it may increase the risk of chronic myeloid

leukemia.

• The peripheral blood findings are highly characteristic .

• The leukocyte count is elevated, often exceeding 100,000 cells/μL .

• The circulating cells are predominantly neutrophils, metamyelocytes , and myelocytes but basophils and eosinophils are also prominent .

• A small proportion of myeloblasts, usually less than 5% ,can be seen in the peripheral blood.

• An increased number of platelets (thrombocytosis) is also typical .

• The bone marrow is hypercellular as a result of a hyperplasia of granulocytic andmegakaryocytic precursors .

• Myeloblasts are usually only slightly increased .

Figure 122 : Chronic Myeloid Leukemia : Peripheral Blood , showing mature granulocytic cells .

In this set of images, you can see myeloid precursors presence in peripheral blood smear of a patient diagnosed with chronic myeloid leukemia (CML). We

described each image by following numbers:

1- Blast cell (probably basophilic normoblast)

2- Band cell

3- Band cells going to be segmented

4- Dysplastic cell

5- Metamyelocyte

6- Basophil

7- Eosinophilic myelocyte

8- Late metamyelocyte

Figure 124 : Blood film in Chronic myeloid Leukemia : showing mature neutrophils, myelocyte & metamyelocyte .

:• The onset of CML is usually slow, and the initial symptoms are

often nonspecific (e.g., easy fatigability weakness, and weightloss).

• Extreme splenomegaly that is characteristic of this condition. Splenic infarct is common .

• The red pulp of the enlarged spleen has an appearance thatresembles bone marrow because of the extensiveextramedullary hematopoiesis . .

• The course of CML is one of slow progression.

• Even without treatment, the median survival is 3 years .

•After a variable period, approximately 50% of individuals with CML enter an accelerated phase, during which there is a• gradual failure in the response to treatment ;

increasing anemia and new thrombocytopenia• the appearance of additional cytogenetic

abnormalities ;• and finally transformation into a picture

resembling acute leukemia called blast crisis .

• On occasions it may be necessary to distinguish CML from a "leukemoid reaction," a dramatic elevation of the granulocyte count in response to infection, stress, chronic inflammation, neoplasms .

• The presence of the Philadelphia (Ph) chromosome definitive way of distinguishing CML from leukemoid reactions

• Measurement of leukocyte alkaline phosphatase can also be helpful, because the granulocytes in CML are almost completely devoid of this enzyme, whereas it is increased in leukemoid reactions and other myeloproliferative disorders (such as Poly cythemia Vera ) .

What are the Phases of CML? As a disease of the bone marrow, CML does not form tumors, so it can’t be

staged like most types of cancer. Rather, CML is categorized based on the

three general phases of the disease. These phases are defined based on the

amount of immature white blood cells, called blasts, in the bone marrow or

blood. According to definitions established by the World Health Organization,

the three phases of CML are as follows:

1.Chronic phase: Patients in this phase usually have less than 10% blasts in

their bone marrow or blood samples.

2.Accelerated phase: During this phase, blood and bone marrow samples

usually have 15% or more blasts, but less than 30%. Platelet counts are generally

very low, and new chromosome changes in the leukemia cells are typically

exhibited.

3.Blast phase: Samples of blood and/or bone marrow usually have 20% or more

blasts, and large clusters of blasts are present in the bone marrow. These blast

cells have spread to other organs and tissues. When fever, fatigue, and an

enlarged spleen are present, it is categorized as a blast crisis.

What are the symptoms of CML in children? Children and young adult presented with accelerated phase and blast crises more

frequently

The most common signs of chronic myeloid leukemia in children include: Anemia: This condition occurs when a healthy amount of normal red blood cells cannot be produced

because the bone marrow is overcrowded by leukemia cells. A blood test will reveal low hemoglobin

levels. Children with anemia may feel very tired, appear pale, and experience a racing heart rate.

Swollen lymph nodes: Leukemia cells often collect in the lymph nodes, causing swelling under the

arms, in the neck, in the chest and groin.

Bleeding and/or bruising: Bleeding can result from a very low level of platelets, which are cells that

help the body form blood clots. This happens because the bone marrow cannot produce a sufficient

number of platelets.

Bone and joint pain: When the bone marrow becomes overcrowded with blasts, pain in the bones and

joints may occur.

Recurrent infections and/or fever: Although a child with CML may have a very high number of white

blood cells, these cells cannot function properly to fight infection. Consequently, it may be difficult for

the child to recover from ordinary childhood infections.

Trouble breathing: Leukemia cells may clump together in the thymus gland, located beneath the

sternum and around the throat. This clump of cells can affect breathing, making children wheeze,

cough, or experience painful breathing.

Abdominal pain: When leukemia cells accumulate in the liver, kidneys, and spleen, they can cause

these organs to enlarge, leading to abdominal pain.

Prognostic and predictive factors for CMLThe following are prognostic and predictive factors for CML. Age

People 60 years of age or older have a less favourable prognosis.

Phase

CML that is in the accelerated or blast phase at the time of diagnosis has a less favourable

prognosis.

Number of blasts

Having a high number of blast cells (blasts) in the blood or bone marrow at diagnosis is a

less favourable prognostic factor.

Enlarged spleen

If the spleen is larger than normal at diagnosis, the prognosis is less favourable.

Platelet count

A very low or very high platelet count at diagnosis is a less favourable prognostic factor.

Number of eosinophils and basophils

Eosinophils and basophils are types of granulocytes (white blood cells) that release

chemicals to fight some types of infection and during allergic reactions. Higher numbers of

eosinophils and basophils in the blood means a less favourable prognosis.

Chromosome changes

Chromosome changes, or abnormalities, are a prognostic factor for

CML.

The Philadelphia chromosome

The most acommon chromosomal abnormality in people with CML is the

Philadelphia (Ph) chromosome. The Ph chromosome is a translocation,

or rearrangement, of chromosomes 9 and 22. This translocation creates

the BCR-ABL fusion gene, which leads to the development of CML.

About 95% of adults with CML have leukemia cells with the Ph

chromosome. When the Ph chromosome is present, CML is described

as Ph-positive, or Ph+, CML. When the Ph chromosome isn’t present, it

is described as Ph-negative, or Ph–, CML.

People with Ph+ CML have a more favourable prognosis than those with

Ph– CML.

• (ALL) :

• A malignant proliferation of immature pre-B or pre-T lymphocytes referred to as lymphoblasts .

• Highly aggressive tumors that present with symptoms of bone marrow failure, or as rapidly growing masses .

• Tumor cells contain genetic lesions that block differentiation, leading to the accumulation of immature blasts that cannot function as immune cells, which accounts for the major clinical manifestations of acute leukemia.

• Most ALL occur in individuals younger than 15 years of age , slightly more frequent in boys than girls .

• The peak incidence is 4 years of age .

• It does occur in adults but less frequently .

• 85 % of ALL are the pre-B cell tumors that typically manifest as childhood acute leukemia with extensive bone marrow & peripheral blood involvement .

• The less frequent pre-T ALL tend to present in adolescent males as lymphoma with thymic involvement in 50%-70% of cases , also presenting as lymphadenopathy & hepatosplenomegally .

•There is a stormy onset of symptoms including fatigue (due mainly to anemia), fever (reflecting infections resulting from the absence of mature leukocytes), and bleeding (petechiae, ecchymosis, epistaxis, gum bleeding) secondary to thrombocytopenia .

•Bone pain and tenderness ,these result from marrow expansion and infiltration of the sub periosteum .

• lymphadenopathy, splenomegaly, and hepatomegaly caused by dissemination of the leukemic cells .

•Central nervous system manifestations which

include headache, vomiting, and nerve palsies resulting from meningeal spread .

•Testicular involvement is common in ALL.

•These features are more common in children than in adults and are more common in ALL than AML .

• Both pre-B & pre-T All cells have the same morphologic pattern .

• The lymphoblasts have scant agranular cytoplasm with a large nucleus showing delicate finely stippled chromatin , and abscent or inconspicuous nucleoli .

• In some cases the nuclear membrane show a convoluted or lobulated appearance .

• The cytoplasm stains positive with PAS- stain but lacks the peroxidase positive granules which are seen in myeloblasts .

Figure 125 : Acute Lymphoblastic Leukemia : Bone marrow

Figure 126 : Blood Film : Acute Lymphoblastic leukemia

•With Terminal deoxy Transferase ( TdT) a specialized DNA polymerase that is expressed only by pre-T or pre-B lymphoblasts is positive in up to 95% of cases .

•Further subtyping of ALL into pre-B- and pre-T-celltypes relies on stains for lineage-specific markers,such as CD19 (B cell) and CD3 (T cell).

Figure 127 : Terminal Deoxyneucleotidyl transferase (Tdt ) stain in lymphoblastic lymphoma.

• Approximately 90% of patients with lymphoblastic

leukemia/lymphoma have nonrandom karyotypic abnormalities.

•Most common in pre-B-cell tumors is hyperdiploidy (>50

chromosomes/cell), which is associated with the presence of a

cryptic (12;21) chromosomal translocation involving EL1 and

AML1 genes.

• The presence of these aberrations correlates with a good outcome.•Poor outcomes are observed with pre-B-cell tumors that have

translocations involving the gene on chromosome 11q23 or

Philadelphia (Ph) chromosome.

With aggressive chemotherapy & prophylactic treatment of CNS more than 90% of children with ALL achieve complete remission & about 2/3 are considered cured .

1-Age under 2 years .

2-Presentation in adolescence or adulthood .

3-Presence of t-9-22 translocation( Philadelphia chromosome ) which is seen in 3% of childhood ALL % 25% of adulthood ALL

Allogenic bone marrow transplantation offer a hope for those of poor prognosis category .

• It is the most common leukemia in adults .

• This type of leukemia is indistinguishable from small cell lymphoma only in the degree of peripheral blood involvement.

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• Contains increased number of small lymphocytes with scant cytoplasm . These cells are fragile & frequently disrupted during preparation of the blood smear producing smudge cells .

• The total leukocytes count may reach 200 000 cells /c.mm

• Involvement is seen in all cases of CLL taking the form of interstitial aggregates of small lymphocytes .

•Splenic involvement show both red & white pulps enlargement caused by leukemic cells infiltration.

•Hepatic portal tracts are also infiltrated by leukemic cells .

•Leukemic cells express pan B cell markers (CD10-20),& T cell markers (CD5) .

Figure 128 : Microscopic view of bone marrow biopsy showing paratrabecular mononuclear cells infiltrate in CLL .

Figure 129 : Blood film : Chronic lymphatic leukemia showing smudge lymphocytic cells.

• Most patients are over 50 years .

• Male to female ratio is 2:1 .• Usually asymptomatic , symptomes when present include

fatigability , weight loss & anorexia .

• Generalized lymphadenopathy & hepatosplenomegaly seen in

50%-60% of cases .

• In 10%-15% of cases have auto-antibodies to red cells & platelets

causing auto-immune hemolytic anemia & thrombocytopenia .

:•Extremely variable overall median survival is 4-6 years , but some

cases may live for 10 years.

• Occurs in 15%-30% of patients with CLL .

• The prolymphocytic transformation is characterized by theappearance of prolymphocytes in peripheral blood , thesecells with large nucleus and a centrally placed nucleolus .

• Or the transformation into diffuse large B-cell lymphoma occurs in 10% of cases called Richter’s syndrome .

• This transformation have a very bad prognosis & most patients survive less than one year.

• In this type of leukemia the cancer cells are a lot like normal cells called prolymphocytes.

• These are immature forms of B lymphocytes (B-PLL) or T lymphocytes (T-PLL). Both B-PLL and T-PLL tend to grow and spread faster than the usual type of CLL.

• Most people with it will respond to some form of treatment, but over time they tend to relapse (the cancer comes back).

• PLL may develop in someone who already has CLL (in whichcase it tends to be more aggressive), but it can also occur inpeople who have never had CLL.

•

•This is rare cancer of the lymphocytes that tends to progress slowly.

•The cancer cells are a type of B lymphocyte but they're different from those seen in CLL.

• There are also important differences in symptoms and treatment.

•This type of leukemia gets its name from the way the cells look under the microscope --they have fine projections on their surface that make them look "hairy." Treatment for HCL can work very well.

•Hairy cell leukemia affects more men than women, and it occurs most commonly in middle-aged or older adults.

Hairy cell

leukemia:

abnormal B cells

look "hairy" under

a microscope

because of radial

projections from

their surface.

•Hairy cell leukemia is considered a chronic disease because it may never completely disappear, although treatment can lead to a remission for years.

•Some people have no signs or symptoms of hairy cell leukemia, but a blood test for another disease or condition may inadvertently reveal hairy cell leukemia.

•Other times people with hairy cell leukemia experience signs and symptoms common to a number of diseases and conditions, such as:

•A feeling of fullness in your abdomen that may make it uncomfortable to eat more than a little at a time

•Fatigue

•Easy bruising

•Recurring infections

•Weakness

•Weight loss

• Hairy cell leukemia progresses very slowly and sometimes remains stable for many years. For this reason, few complications of the disease occur.

• Untreated hairy cell leukemia that progresses may crowd out healthy blood cells in the bone marrow, leading to serious complications, such as:

• Infections. Reduced numbers of healthy white blood cells put you at risk of infections that your body might otherwise fight off.

• Bleeding. Low platelet counts make it hard for your body to stop bleeding once it starts. If you have a mildly low platelet count, you might notice that you bruise more easily. Very low platelet counts can cause spontaneous bleeding from the nose or gums.

• Anemia. A low red blood cell count means fewer cells are available to carry oxygen throughout your body. This is called anemia. Anemia causes fatigue.

Diagnosis On physical exam, 80–90% of patients have an enlarged

spleen, which can be massive.

Peripheral lymphadenopathy (enlarged lymph nodes) is uncommon (less

than 5% of patients),

abdominal lymphadenopathy is a relatively common finding on

computed tomography (CT) scans.

A complete blood count (CBC) will often show pancytopenia,

There are usually very few circulating hairy cells. When a bone

marrow examination is performed, typically, the marrow is reported

as “inaspirable”, a “dry tap”, or difficult to aspirate.

A bone marrow biopsy is usually diagnostic, showing a diffuse or

patchy infiltrate with a “fried egg” appearance, cells with a moderate

amount of cytoplasm neatly spaced one from another.

The most important lab finding is the presence of hairy cells in the bloodstream.Hairy cells are

abnormal white blood cells with hair-like projections of cytoplasm; they can be seen by examining

a blood smear or bone marrow biopsy specimen.

Flow cytometry studies on the peripheral blood (if sufficient cells are present in the

peripheral blood) and/or bone marrow demonstrate monoclonal B cells, which are

negative for CD5 and CD10 and are positive for CD11c, CD25, and CD103 (the hairy cell-

associated antigens).

The blood film examination is done by staining the blood cells with Wright's stain and

looking at them under a microscope.Hairy cells are visible in this test in about 85% of

cases.

Before the advent of acceptable flow cytometry, the diagnosis of hairy cell leukemia was

based on cytochemical staining with the hairy cells showing positive staining for acid

phosphatase in the presence of tartrate, tartrate-resistant acid phosphatase (TRAP)

positivity.

are a groupof cancers in which immature blood cells in the bonemarrow do not mature and therefore do not becomehealthy blood cells.Early on, there are typically no symptoms.Latersymptoms may include feeling tired, shortness ofbreath, easy bleeding, or frequent infections.Some types may develop into acute myeloid leukemia.The types of MDS are based on specific changes in theblood cells and bone marrow

previous chemotherapy or radiation therapy, exposureto certain chemicals such as tobacco smoke, pesticides,and benzene, and exposure to

heavy metals such as mercury or lead.

Problems with blood cell formation result in some combination of low red blood cells, low platelets, and low white blood cells.

Some types have an increase in immature blood cells, called blasts, in the bone marrow or blood.

:

Refractory anemia (RA) characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursorsRefractory anemia with ring sideroblasts (RARS)lso characterized by less than 5%

myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater of red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts"Refractory anemia with excess blasts (RAEB) characterized by 5-19% myeloblasts

in the marrowRefractory anemia with excess blasts in transformation (RAEB-T)characterized by

5%-19% myeloblasts in the marrow (>20% blasts is defined as acute myeloid leukemia)Chronic myelomonocytic leukemia (CMML), not to be confused with chronic

myelogenous leukemia or CMLcharacterized by less than 20% myeloblasts in the bone marrow and greater than 1*109/L monocytes (a type of white blood cell) circulating in the peripheral blood.

Anemia

Infection due to Neutropenia

Thrombocytopenia

Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count.Splenomegaly or rarely hepatomegalyAbnormal granules in cells, abnormal nuclear shape and

size

Chromosome abnormality, including chromosomal

translocations and abnormal chromosome number

The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome

Full blood count and examination of blood film

Blood tests to eliminate other common causes of cytopenias, such as lupus, hepatitis, B12, folate, or other vitamin deficiencies, kidneyfailure or heart failure, HIV, hemolytic anemia, monoclonal gammopathy

Bone marrow examination by a hematopathologist: This is required to establish the diagnosis

Cytogenetics or chromosomal studies

Virtual karyotyping

Flow cytometry is helpful to identify blasts, abnormal myeloid maturation

The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to AML.

Treatments may include supportive care, drug therapy, and stem cell transplantation.

Supportive care may include bloodtransfusions, medications to increase the making of red blood cells, and antibiotics.

BONE MARROW: THERAPY-

RELATED MYELODYSPLASTIC

SYNDROME Blood smear from an adult female with a

myelodysplastic syndrome related to

radiotherapy and chemotherapy for

Hodgkin disease. A hypogranular neutrophil with a with a

pseudo-Pelger-Huet nucleus is shown.neutrophils with bilobed nuclei which are composed of two nuclear masses connected with a thin filament of chromatin.

The red blood cells show markedpoikilocytosis, in part related to post-splenectomy status. (Wright-Giemsa stain)

Bone marrow aspirate: ring

sideroblasts

Refractory anemia with ring

sideroblasts is a type

of myelodysplastic syndrome.

RARS is characterized by 5% or

less myeloblasts in bone marrow.

RARS is having 15% or

more ringed sideroblasts among

the erythroid precursors in the

bone marrow. are nucleated erythroblasts (precursor

s to mature red blood cells) withgranules of iron accumulated in the mitochondria surroundingthe nucleus

Case study Please answer cases cases in Live session ?Q1: 65 year-old healthy man recently suffered from increasing fatigue and shortness of

breath with minimal exercise with some abdominal discomfort over the past month. On

physical examination he has non-tender cervical lymphadenopathy.

Hepatosplenomegaly ,the spleen is palpated 3 cm below left costal margin on inspiration.

A CBC shows WBC count 30,100/microliter with 15 segs, 3 bands, 78 lymphs, and 4

monos, Hgb 10.5 g/dL, Hct 35%, MCV 91, and platelet count 250,300/microliter. Direct

Coombs test is positive ???? What does that mean??. Which of the following is the most

likely diagnosis?Discuss !

A- Leukemoid reaction

B- Chronic myelogenous leukemia

C- Acute myelogenous leukemia

D - Acute lymphocytic leukemia

E- Chronic lymphocytic leukemia

F- Systemic lupus erythematosus

Q:What does coombs test refer to ? Why it is Positive ??

Case study 2

Q2:55-year-old man has had increasing fatigue and tiredneee over the past 4 months.

On physical examination he has massive splenomegaly but no lymphadenopathy.

Laboratory studies show a Hgb of 10.5 g/dL, Hct 31.3%, MCV 93 fL, WBC count

1800/microliter, and platelet count 45,000/microliter. Examination of his peripheral

blood smear shows increased numbers of peripheral blood lymphocytes containing

tartrate-resistant acid phosphatase. Which of the following is the most likely diagnosis?

A- Chronic lymphocytic leukemia

B- HTLV-1 infection with leukemia

C - Hairy cell leukemia

D- Gaucher disease

E - Myelodysplasia

THANK YOU & GOOD LUCK