WBC 2

Question 0

Chronic leukemias

Answer 0

Chronic lymphocytic leukemia (CLL)
Hairy cell leukemia
Chronic myelogenous leukemia (CML)

Question 1

Acute leukemias

Answer 1

Acute lymphoblastic leukemia (ALL)

Acute myeloid (myeloblastic) leukemia (AML)

Question 2

Myeloproliferative diseases

Answer 2

Polycythemia vera
Chronic idiopathic myelofibrosis (agnogenic myeloid metaplasia, myelofibrosis with myeloid metaplasia)
Essential thrombocythemia

Question 3

Plasma cell disorders

Answer 3

Multiple myeloma (plasma cell myeloma/plasmacytoma)
Waldenström macroglobulinemia
Benign monoclonal gammopathy (monoclonal gammopathy of undetermined significance, or MGUS)

Question 4

Lymphoid neoplasm

Answer 4

Hodgkin lymphoma (Hodgkin disease)

Non-Hodgkin lymphomas

Question 5

Leukemia

Answer 5

1. Leukemia is a general term for a group of malignancies of
   either lymphoid or hematopoietic cell origin.
    The number of circulating leukocytes is often greatly increased.

2.The bone marrow is diffusely infiltrated with leukemic cells,
3. Consequent failure of normal leukocyte, red cell, and platelet production can result in anemia, infection, or hemorrhage.
Infiltration of leukemic cells in the liver, spleen, lymph nodes, and other organs is common.

Question 6

Signs and symptoms of acute leukemias

Answer 6

Symptoms have usually been present for only days to weeks before diagnosis.

Disrupted hematopoiesis leads to the most common presenting symptoms (anemia, infection, easy bruising and bleeding).

Other presenting symptoms and signs are usually nonspecific (eg, pallor, fatigue, fever, malaise, weight loss, tachycardia, chest pain) and are attributable to anemia and a hypermetabolic state.

Bone marrow and periosteal infiltration may cause bone and joint pain, especially in children with ALL.

Initial CNS involvement or leukemic meningitis is uncommon.

Extramedullary infiltration by leukemic cells may cause lymphadenopathy, splenomegaly, hepatomegaly, and leukemia cutis (a raised, nonpruritic rash).

Question 7

Diagnosis of Acute Leukemias

Answer 7

1. CBC and peripheral blood smear (first tests)
2. Bone marrow examination
3. Histochemical studies, cytogenetics, immunophenotyping, and molecular biology studies

CBC : pancytopenia and peripheral blasts suggest acute leukemia.
(Lower than normal amounts of red cells and platelets)
 Although the diagnosis can usually be made from the peripheral smear, bone marrow examination (aspiration or needle biopsy) should always be done.
Blast cells in the bone marrow are between 20 and 95%.

DD: Aplastic anemia, viral infections such as infectious mononucleosis, and vitamin B12 and folate deficiency

Question 8

How to diagnose acute leukemia

Answer 8

Histochemical studies, cytogenetics, immunophenotyping, and molecular biology studies help distinguish the blasts of ALL from those of AML or other disease processes.
Specific B-cell, T-cell, and myeloid-antigen monoclonal antibodies, together with flow cytometry, are very helpful in classifying ALL vs AML, which is critical for treatment.

Other laboratory findings may include
hyperuricemia,
hyperphosphatemia,
hyperkalemia or hypokalemia,
elevated serum hepatic transaminases or LDH,
hypoglycemia, and hypoxia.
Lumbar puncture and head CT scan are done in patients with CNS symptoms, B-cell ALL, high WBC count, or high LDH.
Chest x-ray is done; if a mediastinal mass is present, CT may be done.
 CT, MRI, or abdominal ultrasonography may help assess splenomegaly or leukemia infiltration of other organs.

Question 9

Histological findings in acute leukemia

Answer 9

Blast cells are immature precursors of either lymphocytes (lymphoblasts), or granulocytes (myeloblasts). They do not normally appear in peripheral blood. When they do, they can be recognized by their large size, and primitive nuclei (ie the nuclei contain nucleoli), as in the picture. When present in the blood, they often signify ACUTE LEUKEMIA. This particular case demonstrates the presence of an Auer Rod, which is pathognomonic for Acute Myeloid Leukemia. Otherwise, special stains and surface marker techniques are needed to identify the lineage of the cells.

Question 10

Characteristics of acute leukemias

Answer 10

A predominance of blasts and closely related cells in the bone marrow and peripheral blood is characteristic.

The most common malignancies of the pediatric age group,

They exhibit a second incidence peak after 60 years of age.

Cytogenetic abnormalities are frequent. For example, the 9;22 translocation ,the Philadelphia chromosome (Ph1).
This abnormality, better known for its association with chronic myelogenous leukemia, is associated with a poorer prognosis when it occurs in acute leukemias.

Without therapeutic intervention, death occurs within 6 to 12 months.

Question 11

Acute Lymphoblastic leukemias (ALL)

Answer 11

ALL is the most common malignancy of children.

the 2nd most common cause of death in children < 15 yr.

A predominance of lymphoblasts in the circulating blood and in the bone marrow is characteristic.

ALL is the form of acute leukemia that is most responsive to therapy.

Further classification into a number of subgroups is based on
differences in morphology,
cytogenetic changes,
antigenic cellsurface markers,
or rearrangement of the immunoglobulin heavy-chain or T-cell receptor genes.

The form that is most common and most amenable to therapy is characterized by blast cells that are positive for the CD10 marker.

Question 12

Diagnosis and treatment of acute lymphoblastic leukemias

Answer 12

Examination of peripheral smear and bone marrow is usually diagnostic.

Treatment
Chemotherapy
Sometimes stem cell transplantation or radiation therapy

The 4 general phases of chemotherapy for ALL include

1. Remission induction
2. CNS prophylaxis: intrathecal chemotherapy
3. Postremission consolidation or intensification
4. Maintenanc : for 1 to 3 yr to avoid relapse.

Question 13

Prognosis of ALL

Answer 13

Favorable prognostic factors are
Age 3 to 7 yr
WBC count < 25,000/μL
French-American-British (FAB) L1 morphology
Leukemic cell karyotype with > 50 chromosomes and t(12;21)
No CNS disease at diagnosis
Unfavorable factors are
A leukemic cell karyotype with chromosomes that are normal in number but abnormal in morphology (pseudodiploid)
Presence of the Philadelphia (Ph) chromosome t(9;22)
Increased age in adults
B-cell immunophenotype with surface or cytoplasmic immunoglobulin

Question 14

FAB classification of ALL

Answer 14

Subtyping of the various forms of ALL used to be done according to the French-American-British (FAB) classification,
ALL-L1: small uniform cells
ALL-L2: large varied cells
ALL-L3: large varied cells with vacuoles (bubble-like features)
Each subtype is then further classified by determining the surface markers of the abnormal lymphocytes, called immunophenotyping. There are 2 main immunologic types:
1.pre-B cell
2. pre-T cell.
The mature B-cell ALL (L3) is now classified as Burkitt’s lymphoma/leukemia.

Subtyping helps determine the prognosis and most appropriate treatment in treating ALL.

Question 15

WHO proposed classification of ALL

Answer 15

The recent WHO International panel on ALL recommends that the FAB classification be abandoned, since the morphological classification has no clinical or prognostic relevance.

It instead advocates the use of the immunophenotypic classification mentioned below.
1- Acute lymphoblastic leukemia/lymphoma Synonyms:Former Fab L1/L2
i. Precursor B acute lymphoblastic leukemia/lymphoma. Cytogenetic subtypes:
t(12;21)(p12,q22) TEL/AML-1
t(1;19)(q23;p13) PBX/E2A
t(9;22)(q34;q11) ABL/BCR
T(V,11)(V;q23) V/MLL
ii. Precursor T acute lymphoblastic leukemia/lymphoma

2- Burkitt’s leukemia/lymphoma Synonyms:Former FAB L3

3- Biphenotypic acute leukemia

Question 16

Acute myeloid (myeloblastic) leukemia (AML

Answer 16

AML occurs most often in adults. The incidence of AML increases with age

AML may occur as a secondary cancer after chemotherapy or irradiation for a different type of cancer.

In AML, malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers of immature blood forms and replacement of normal marrow by malignant cells.

A predominance of myeloblasts and early promyelocytes is characteristic.
AML responds to current therapy more poorly than ALL.

Symptoms include fatigue, pallor, easy bruising and bleeding, fever, and infection;
Examination of peripheral smear and bone marrow is diagnostic.

Treatment includes induction chemotherapy to achieve remission and postremission chemotherapy (with or without stem cell transplantation) to avoid relapse.

Question 17

Classes of AML

Answer 17

AML has a number of subtypes that are distinguished from each other by morphology, immunophenotype, and cytochemistry.

 Five classes are described, based on predominant cell type, including

1. myeloid,
2. myeloid-monocytic,
3. monocytic,
4. erythroid,
5. megakaryocytic.

Acute promyelocytic leukemia (APL) is a particularly important subtype, representing 10 to 15% of all cases of AML, striking a younger age group (median age 31 yr) and particular ethnicity (Hispanics), in which the patient commonly presents with a coagulation disorder.

Question 18

Classification of AML

Answer 18

M0-Minimally differentiated AML-2-3%-Blasts lack Auer rods and myeloperoxidase but express myeloid lineage surface markers.

M1-AML without maturation-20%-M1–Some blasts (≥3%) are myeloperoxidase positive; few granules or Auer rods and very little maturation beyond the myeloblast stage of differentiation.

M2-AML with maturation-30-40%–>20% of marrow cells are myeloblasts, but many cells are seen at later stages of granulocyte differentiation; Auer rods are usually present; often associated with t(8;21).

M3-Acute promyelocytic leukemia–5-10%–Most cells are abnormal promyelocytes, often containing many Auer rods per cell; patients are younger on average (median age 35-40yr); high incidence of DIC; strongly associated with t(15;17).

M4-Acute myelomonocytic leukemia–15-20%–Myelocytic and monocytic differentiation evident by cytochemical stains; monoblasts are positive for nonspecific esterase; myeloid cells show a range of maturation; variable numbers of Auer rods; subset associated with inv(16).

M5-Acute monocytic leukemia-10%–Monoblasts and immature monocytic cells (myeloperoxidase negative, nonspecific esterase positive) predominate; Auer rods are usually absent; older patients; more likely to be associated with organomegaly, lymphadenopathy, and tissue infiltration; the M5b subtype is defined by the predominance of mature-appearing monocytes in the peripheral blood, whereas only immature cells are seen in the M5a subtype.

M6-Acute erythroleukemia-5%–Most commonly associated with abundant dysplastic erythroid progenitors; >20% of cells of the marrow nonerythroid cells are myeloblasts, which may contain Auer rods; usually occurs in advanced age or following exposure to mutagens (e.g., chemotherapy).

M7-Acute megakaryocytic leukemia-1%–Blasts of megakaryocytic lineage predominate, as judged by expression of platelet-specific antigens; myelofibrosis or increased marrow reticulin often present; Auer rods are absent.

Question 19

FAB classification of AML

Answer 19

M0-Acute myeloid leukemia with minimal evidence of
myeloid differentiation
M1-Acute myeloblastic leukemia without maturation
M2-Acute myeloblastic leukemia with maturation
M3-Acute promyelocytic leukemia
M4-Acute myelomonocytic leukemia
M5-Acute monocytic/monoblastic leukemia
M6-Acute erythroleukemia
M7-Acute megakaryoblastic leukemia

Question 20

Proposed WHO classification of AML

Answer 20

I. AML with Recurrent Chromosomal Translocations
AML with t(8;21)(q22;q22); CBFa/ETO fusion gene–Favorable
AML with inv(16)(p13;q22); CBFb/MYH11 fusion gene–Favorable
AML with t(15;17)(q22;q21.1); PML/RARa–Favorable prognosis
AML with t(11q23;variant)–Poor prognosis

II. AML with Multilineage Dysplasia
With prior myelodysplastic syndrome–Very poor prognosis
Without prior myelodysplastic syndrome–Poor prognosis

III. AML, Therapy-Related
Alkylating agent related–Very poor prognosis
Epipodophyllotoxin related–Very poor prognosis

IV. AML, Not Otherwise Classified
Subclasses defined by extent and type of differentiation (M0-M7)–intermediate prognosis

Question 21

Characteristics of chronic leukemia

Answer 21

These malignancies are characterized by proliferations of lymphoid or hematopoietic cells that are more mature than those of the acute leukemias.

The chronic forms have a longer, less devastating clinical course than the acute leukemias but are less responsive to therapeutic intervention.

Question 22

General consideration for CLL

Answer 22

CLL is characterized by proliferation of neoplastic lymphoid cells (almost always B cells) with widespread infiltration of the bone marrow, peripheral blood, lymph nodes, spleen, liver, and other organs.
 Leukemic cells of CLL are less capable of differentiating into antibody-producing plasma cells.
CLL most often occurs in persons older than 60 years of age and more frequently in men.

Question 23

Characteristics of CLL

Answer 23

The leukemic cells closely resemble normal mature peripheral blood lymphocytes and, like these cells, express surface immunoglobulin and pan–B-cell markers such as CD19 and CD20. They are also CD5 positive and CD10 negative.
The cells are susceptible to mechanical disruption and often appear on the peripheral blood smear as smudge cells.
The peripheral white blood cell count varies from 50,000/μL to 200,000/μL, with a preponderance of leukemic cells.
Leukemic cells diffusely infiltrate the bone marrow.

Question 24

Complications of CLL

Answer 24

Warm antibody autoimmune hemolytic anemia
Hypogammaglobulinemia and increased susceptibility to bacterial infection, often occurring early in the course of this Disorder

Question 25

Clinical features of CLL

Answer 25

The clinical course is usually described as indolent, often with few symptoms and minor disability for protracted periods.
Generalized lymphadenopathy and moderate hepatosplenomegaly are frequent features.
Mean survival is 3 to 7 years; treatment relieves symptoms but has little effect on overall survival.

Question 26

Diagnosis of CLL

Answer 26

1.CBC and peripheral smear
2.Bone marrow examination
3.Immunophenotyping
the hallmark is sustained, absolute peripheral lymphocytosis (> 5000/μL) and increased lymphocytes (> 30%) in the bone marrow

Question 27

Pathophysiology of CLL

Answer 27

In about 98% of cases, CD5+ B cells undergo malignant transformation, with lymphocytes initially accumulating in the bone marrow and then spreading to lymph nodes and other lymphoid tissues, eventually inducing splenomegaly and hepatomegaly.

As CLL progresses, abnormal hematopoiesis results in anemia, neutropenia, thrombocytopenia, and decreased immunoglobulin production.

Many patients develop hypogammaglobulinemia and impaired antibody response, perhaps related to increased T-suppressor cell activity.

Patients have increased susceptibility to autoimmune disease characterized by immunohemolytic anemias (usually Coombs’ test–positive) or thrombocytopenia and a modest increase in risk of developing other cancers.

Question 28

Treatment for CLL

Answer 28

Treatment
Symptom amelioration
Supportive care
Specific therapy includes
Chemotherapy
Corticosteroids
Monoclonal antibody therapy
Radiation therapy

Question 29

Hairy Cell Leukemia

Answer 29

Hairy cell leukemia is a
 B-cell disease
leukemic cells exhibit characteristic hair-like filamentous projections

The cells can be further identified by their positive staining for tartrate-resistant acid phosphatase (TRAP).

a) Hairy cell leukemia most often affects middle-aged men, who present with prominent splenomegaly and pancytopenia.
b) The disease has received major attention because of its dramatic response to several therapeutic agents, including α-interferon, 2-chlorodeoxyadenosine, and deoxycoformycin.

Question 30

CML

Answer 30

Chronic myelogenous leukemia (CML) is a neoplastic clonal proliferation of myeloid stem cells, the precursor cells of erythrocytes, granulocytes, monocytes, and platelets.

It is one of the myeloproliferative syndromes .

Question 31

Molecular changes in CML

Answer 31

The Philadelphia chromosome represents a remnant of chromosome 22 with the addition of a small segment of chromosome 9.
This cytogenetic change is found in all blood cell lineages (erythroblasts, granulocytes, monocytes, megakaryocytes, B- and Tcell progenitors), but not in the majority of circulating B or T lymphocytes

The c-abl proto-oncogene on chromosome 9 is transposed to an area on chromosome 22, adjacent to an oncogene referred to as bcr (for breakpoint cluster region), forming a new hybrid, or fusion, gene, bcr-abl.

 Bcr-abl codes for a protein (p210) with tyrosine kinase activity, which plays a critical role in the etiopathogenesis of CML.

Question 32

Characteristics of CML

Answer 32

Marked leukocytosis, with white blood cell counts varying from 50,000/μL to 200,000/μL

 Leukemic cells in the peripheral blood and bone marrow, mainly middle-to-late myeloid (granulocytic) precursor cells, including myelocytes, metamyelocytes, bands, and segmented forms

Small numbers of blasts and promyelocytes

The Philadelphia chromosome, found in granulocytic and erythroid precursor cells and in megakaryocytes

Marked reduction in leukocyte alkaline phosphatase activity in the leukemic leukocytes

Question 33

Clinical features of CML

Answer 33

Prominent splenomegaly and modestly enlarged liver and lymph nodes

Peak incidence in middle-age (35–50 years of age)

Terminates, in most cases, in an accelerated phase leading to so-called blast crisis marked by increased numbers of primitive blast cells and promyelocytes

Question 34

Phases of CML

Answer 34

Chronic Myelocytic Leukemia (CML) ,(Chronic Granulocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloid Leukemia).

CML has 3 phases:
1.Chronic phase: An initial indolent period that may last months to years

2. Accelerated myeloproliferative phase: Treatment failure, worsening anemia, and progressive thrombocytopenia
3. Terminal phase: Blast crisis; blast cell tumors possibly developing in extramedullary sites (eg, bone, CNS, lymph nodes, skin)

The terminal phase leads to fulminant complications resembling those of acute leukemia, including sepsis and bleeding.

Some patients progress directly from the chronic to the blast phase.

Question 35

Signs and symptoms of CML

Answer 35

Patients are often asymptomatic early on, with insidious onset of nonspecific symptoms (eg, fatigue, weakness, anorexia, weight loss, fever, night sweats, a sense of abdominal fullness), which may prompt evaluation.

Initially, pallor, bleeding, easy bruising, and lymphadenopathy are unusual, but moderate or occasionally extreme splenomegaly is common (60 to 70% of cases).

With disease progression, splenomegaly may increase, and pallor and bleeding occur. Fever, marked lymphadenopathy, and maculopapular skin involvement are ominous developments.

Question 36

Diagnosis of CML

Answer 36

Diagnosis
CBC and peripheral smear
Bone marrow examination
Cytogenetic studies (Ph chromosome)

CML is most frequently diagnosed by a CBC obtained incidentally or during evaluation of splenomegaly. Granulocyte count is elevated, usually < 50,000/μL in asymptomatic patients and 200,000/μL to 1,000,000/μL in symptomatic patients, and platelet count is normal or moderately increased. Hb level is usually > 10 g/dL.

Question 37

Treatment of CML

Answer 37

A tyrosine kinase inhibitor, sometimes with chemotherapy
Sometimes stem cell transplantation
Except when stem cell transplantation is successful, treatment is not curative; however, survival can be prolonged by treatment with imatinib

Question 38

Myeloproliferative diseases

Answer 38

This group of clonal proliferations of myeloid stem cells includes
chronic myelogenous leukemia,
polycythemia vera,
chronic idiopathic myelofibrosis (agnogenic myeloid metaplasia),
 essential thrombocythemia.

It is of great interest that most, if not all, patients with polycythemia rubra vera and a significant number of patients with agnogenic myeloid metaplasia and essential thrombocythemia have mutations in the gene for the Janus2 signaling protein and are JAK2V617F positive.

Common characteristics
 Peak incidence in middle-aged and elderly persons
Proliferation of one or more of the myeloid series (erythroid, granulocytic, and megakaryocytic) cell types
Increase in peripheral blood basophils and nucleated red cells
Increase in serum uric acid
Prominent splenomegaly

Question 39

Classification of myeloproliferative diseases

Answer 39

• Disorder. -Predominant Feature
  1. Polycythemia vera. 1. Erythrocytosis
  2. Primary myelofibrosis (or myelosclerosis) 2. Bone marrow fibrosis with extramedullary hematopoiesis
  3. Essential thrombocythemia. 3. Thrombocytosis
  4. Chronic myelocytic leukemia. 4.Granulocytosis

Question 40

Polycythemia Vera

Answer 40

Clinical characteristics
Marked erythrocytosis
Moderate increase in circulating granulocytes and platelets
Splenomegaly
Decreased erythropoietin

Other features
 Sludging of high hematocrit blood often leads to thrombotic or hemorrhagic phenomena.

Polycythemia vera often progresses to a late phase in which anemia supervenes. This phase is often marked by bone marrow fibrosis and extramedullary hematopoiesis and an increasing white blood cell count, and it can mimic CML.

Acute leukemia may supervene in approximately 3% of patients, most of whom have received antimitotic drugs or radiation therapy.

Question 41

Diagnosis and treatment of polycythemia Vera

Answer 41

Diagnosis
Polycythemia vera is marked by decreased erythropoietin, which distinguishes it from other forms of polycythemia, all of which are associated with increased erythropoietin.

 It must be distinguished from secondary polycythemia, which is associated with the following:
1.Chronic hypoxia, associated with pulmonary disease, congenital heart disease, residence at high altitudes, and heavy smoking

2.Inappropriate production of erythropoietin, associated with androgen therapy, adult polycystic kidney disease, and tumors, such as renal cell carcinoma, hepatocellular carcinoma, and cerebellar hemangioma

3.Endocrine abnormalities, prominently including pheochromocytoma and adrenal adenoma with Cushing syndrome
Treatment
Aspirin  therapy
Possibly phlebotomy
Possibly myelosuppressive therapy

Question 42

Chronic idiopathic myelofibrosis

agnogenic myeloid metaplasia, myelofibrosis with myeloid metaplasia

Answer 42

is characterized by
extensive extramedullary hematopoiesis involving the liver and spleen and sometimes the lymph nodes.
Additional manifestations include proliferation of non-neoplastic fibrous tissue within the bone marrow cavity (myelofibrosis).
Postulated pathogenetic factors
 Megakaryocytic proliferation may be the primary abnormality; the elaboration of platelet-derived growth factor and of transforming growth factor-β (TGF-β) by platelets and megakaryocytes may be the cause of the fibroblastic proliferation.
Megakaryocytes are spared in the marrow fibrotic process and increase in number, resulting in prominent bone marrow megakaryocytosis and peripheral blood thrombocytosis.

Clinical features
 Peripheral blood smear
1. Teardrop-shaped erythrocytes
2. Granulocytic precursor cells and nucleated red cell precursors in variable numbers
Anemia and massive splenomegaly