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WHITE CELL DISORDERS
Disorders of white cells include deficiencies (leukopenias) and proliferations, which may be
reactive or neoplastic. Reactive proliferation in response to an underlying primary, often
microbial, disease is fairly common. Neoplastic disorders, though less common, are more
ominous.
NON-NEOPLASTIC DISORDERS OF WHITE CELLS
Leukopeniais most commonly the result of a decrease in neutrophils (the most prevalent
circulating white cells).
Neutropenia
Neutropenia: a reduction below normal of the number of neutrophils in peripheral blood; when
severe, it is referred to as agranulocytosis,where affected persons are extremely susceptible to
bacterial and fungal infections, which can lead to death.
Etiology and Pathogenesis
The mechanisms that cause neutropenia can be broadly divided into two categories:
1. Inadequate or ineffective granulopoiesis, which is a manifestation of:
A. Generalized marrow failure as in:
- Aplastic anemia
- A variety of leukemias
- Megaloblastic anemia
B.Isolated neutropenia; there is involvement of neutrophilic precursors only as is seen with
- Congenital
- Idiopathic benign (racial or familial e.g. Africans and in the Middle East)
- Cyclical neutropenia syndrome (with 3-4 weeks periodicity)
2. Accelerated removal or destruction of neutrophils:
- Acquired: drug-induced (immune-mediated or direct toxicity)
- Overwhelming
bacterial
(typhoid,
miliary
tuberculosis),
viral
(hepatitis,
influenza,HIV), fungal infections
- Splenomegaly that leads to sequestration and accelerated removal of neutrophils
Pathologic features
The changes in the bone marrow (BM) depend on the underlying mechanism.
Hypercellular marrow; is seen when the neutropenia results from excessive destruction of
the mature neutrophils or from ineffective granulopoiesis, as occurs in megaloblastic anemia.
Marked decrease in maturing granulocytic precursors in the marrow; as associated with the
use of certain drugs that suppress granulopoiesis.
All marrow elements are suppressed;seen after treatment with most myelotoxic drugs but
erythropoiesis and megakaryopoiesis can be normal if the responsible agent specifically
affects the granulocytes.
The main problem with neutropenia is infection. They commonly take the form of ulcerating,
necrotizing lesions of the mouth, pharynx, or other sites within the oral cavity. These lesions
often show a massive growth of microorganisms.
Lymphopenia: a reduction below normal of the number of lymphocytes in peripheral blood and
are associated with:
1. Congenital immunodeficiency diseases
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2. Acquired:
Advanced HIV infection
Treatment with corticosteroids and other immunosuppressive therapy
Hodgkin disease
Widespread irradiation
Reactive Leukocytosis
An increase in the number of white cells is common in a variety of reactive inflammatory states
caused by microbial and non-microbial stimuli. Leukocytosis is relatively non-specific and can
be classified on the basis of the particular white cell series affected.
Neutrophilic Leukocytosis (Neutrophilia)
a. Acute bacterial infections (especially pyogenic)
b. Sterile inflammation caused by tissue necrosis (myocardial infarction, burns)
c. Metabolic disorders (uremia, eclampsia, acidosis, gout)
d. Neoplasms of all types
e. Acute hemorrhage or hemolysis
f. Treatment with myeloid growth factors (G-CSF, GM-CSF)
Eosinophilic Leukocytosis (Eosinophilia)
a. Allergic disorders such as asthma, hay fever, allergic skin diseases
b. Parasitic infestations
c. Drug sensitivity
d. Collagen vascular disorders (polyarteritisnodosa, vasculitis)
e. Certain malignancies (e.g., Hodgkin disease and some non-Hodgkin lymphomas)
f. Treatment with GM-CSF
g. Idiopathic (Hypereosinophilic syndrome)
h. Neoplastic; as seen in myeloproliferative neoplasms, and chronic eosinophilic leukemia
Basophilic Leukocytosis (Basophilia):often indicative of myeloproliferativeneoplasms (e.g.,
chronic myeloid leukemia). Reactive modest increase is seen in ulcerative colitis, myxoedema,
drug allergies and smallpox or chickenpox infections.
Monocytosis
a. Chronic bacterial infections (e.g., tuberculosis, brucellosis, endocarditis, typhoid)
b. Collagen vascular diseases (systemic lupus erythematosus, rheumatoid arthritis)
c. Rickettsiosis
d. Malaria
e. Hodgkin disease, acute myeloid leukemia and other malignancies
f. Myelodysplastic syndrome
g. Inflammatory bowel diseases (e.g., ulcerative colitis)
Lymphocytosis
a. Acute infections: infectious mononucleosis (Epstein-Barr virus), rubella, mumps,
infectious hepatitis, cytomegalovirus, HIV, herpes, B. pertussis
b. Chronic infections: brucellosis,typhoid fever, syphilis, healingTB,toxoplasmosis
c. Chronic lymphoid leukemias
d. Acute lymphoblastic leukemia
e. Non-Hodgkin lymphoma (some)
f. Thyrotoxicosis
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NEOPLASTIC PROLIFERATIONS OF WHITE CELLS
A. Lymphoid neoplasms, which include Hodgkin and non-Hodgkin lymphomas, acute and
chronic lymphoidleukemias, and plasma cell dyscrasias&related disorders.
B. Myeloid neoplasms arise from stem cells that normally give rise to the formed elements of the
blood: granulocytes (neutrophils, eosinophils and basophils), red cells and platelets. The myeloid
neoplasms fall into three fairly distinct subcategories:
1. Acute myeloidleukemias: immature progenitor cells accumulate in the BM
2. Chronic myeloproliferativeneoplasms: in which inappropriately increased production of
formed blood elements leads to elevated blood cell counts
3. Myelodysplastic syndromes, which are characteristically associated with ineffective
hematopoiesis and cytopenias.
ACUTE LEUKEMIAS (AL)
There are two major types of AL; acute lymphoblastic (ALL) and acute myeloblastic (AML).
The pathophysiology, laboratory findings, and clinical features of one closely resemble those of
the other.
Acute leukemia is usually an aggressive clonal malignant transformation involving the
hematopoietic stem cells or early progenitors and characterized by uncontrolled proliferation of
blasts in the BM with spillage into the peripheral blood and variable infiltration of other organs.
Etiology of AL
Several factors have been linked to the occurrence of AL including:
I.Environmental Agents
A.Ionizing Radiation
Exposure to atomic bomb explosions is associated with increased incidence of AL; younger
age and those who are closer to the hypocenterare at particularly high risk. The predominant
type is AML though ALL is reported in younger individuals. Exposure to diagnostic X-rays or
radioisotopes at diagnostic levels (low dose) does not increase the risk. Infants whose mothers
were exposed to X-rays during pregnancy are at higher risk.
B.Chemicals
Exposure to the following has been noted to be associated with a higher incidence
Benzene
a. Benzene and other petroleum derivatives
b. Shoe makers and plastic glues
c. Handling buses and trucks
Alkylating agents: (cytotoxic drugs used in the treatment of certain malignancies)
II. Host susceptibility to AL is determined by
A. Genetic factors
If one identical twin is affected, the other twin has a 20% chance of developing ALL.
Those with Down's syndrome have 10-30 fold ↑ risk (> 3y; lymphoid, < 3y; myeloid).
Patients with Blooms syndrome, Fanconi anemia and Ataxia telangiectasia are associated
with increased risk.
B. Acquired factors; AL show increased incidence in association with the following
Myelodysplasia (myelodysplastic syndrome).
After chemotherapy + radiotherapy
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Chronic myeloproliferativeneoplasms.
Aplastic anemia.
Paroxysmal nocturnal hemoglobinuria.
III. Oncogenic viruses: there is no good evidence except for HTLV-1, which may cause adult
T-cell leukemia/lymphoma.
IV. Others: there is a significant correlation between infants with AL and alcohol intake,
smoking and exposure to benzene and petroleum derivatives of their mothers during pregnancy.
Pathophysiology of Acute Leukemias
In AL there is a block in differentiationwhich leads to the accumulation of immature
leukemic blasts in the BM, which suppress the function of normal hematopoietic stem cells
by physical displacement and other poorly understood mechanisms.
Eventually BM failure results, which accounts for the major clinical manifestations of AL.
The acute leukemias have the following clinical characteristics:
Variable age of onset: childhood AL (age <15 years) is usually ALL (80%) whereas adult
AL (age ≥15 years) is usually AML (80%).
Abrupt onset especially in children
Symptoms related to depression of normal marrow function. These include:
a. Fatigue (due mainly to anemia)
b. Fever (reflecting mainly infections resulting from neutropenia)
c. Bleeding such aspetechiae, ecchymoses, epistaxis, gum bleeding (secondary to
thrombocytopenia).
Symptoms related to organ or tissue infiltration.
Generalized
lymphadenopathy,
splenomegaly,
hepatomegalyand
testicular
involvementthese are more pronounced in ALL than in AML.Central nervous system
manifestationsthese include headache, vomiting, and nerve palsies resulting from meningeal
spread; these features are more common in children than in adults and are also more
common in ALL than AML. Gum infiltration is more common in AML.Arthralgia, bone
pain and tenderness.
Laboratory diagnosis of Acute Leukemias
The diagnosis of AL is based on the presence of > 20 % blasts in the BM and/or peripheral
blood. However; it can be diagnosed with even < 20 % blasts ifspecific leukemia-associated
cytogenetic or molecular genetic abnormalities are present.
It is of great practical importance to distinguish ALL from AML. The nuclei of lymphoblasts
have somewhat coarse and clumped chromatin and one or two nucleoli; myeloblasts tend to have
finer chromatin with multiple nucleoli and more cytoplasm, which may contain granules or Auer
rods.
Blood film:
a. RBCs: anemia is almost always present.
b. WBCs: total WBC count may show high count (where blasts are self-evident), or low
count (blasts may be present or absent).
Neutropenia is also a common finding in the peripheral blood.
c. Plateletcount is reducedin most cases (i.e.<150,000/μL or <150 × 10
9
/L).
BM aspirate is necessary to confirm the diagnosis (especially when low counts).
BM trephine biopsy is only essential when:
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1. BM aspirate is inadequate; this is commonly due toBM fibrosis.
2. To distinguish whether a poor aspirate is due to hypocellularity or persistent leukemia.
Investigations
Hematological: BF and BM findings are already mentioned.
Biochemical tests may reveal increased S. uric acid, S. LDH, and hypercalcemia.
Liver and Renal Function Tests are performed as a baseline before treatment begins.
Radiological Examination may reveal lytic bone lesions, mediastinal widening caused by
enlargement of the thymus and/or mediastinal lymphadenopathy.
CSF examination may show blast cells, indicating CNS involvement.
Cytochemistryis useful if the leukemia is not obviously myeloid.
Immunophenotypingis indicated in all patients in whom the leukemia is not obviously myeloid.
Cytogenetic analysisis essential in all patients, best performed on BM aspirate.
Classification of acute leukemia is based on:
1. Morphology of blasts
2. Cytochemistry through the use of special stains like; SBB, PAS, MPO, Estrases…etc
3. Immunophenotyping (cell surface marker analysis by flow cytometry).
4. Cytogenetic analysis
5. Molecular genetic analysis
Morphological classification
I. French American British (FAB) classification (1976)
A. Acute Lymphoid Leukemia (ALL) is classified into three subtypes:
ALL- L1: Monomorphic blasts, majority are small, high nucleo-cytoplasmic (N/C) ratio,
and scanty cytoplasm with small or inconspicuous nucleoli.
ALL- L2: Heterogeneous blasts, variable sizes and N/C ratios, more prominent nucleoli
with nuclear membrane irregularities.
ALL- L3: Monomorphic large blasts with prominent nucleoli and strongly basophilic,
vacuolated cytoplasm.
B. Acute Myeloid Leukemia (AML) is classified into eight subtypes:
M0: AML with minimal evidence of myeloid differentiation
M1: AML without maturation
M2: AML with maturation
M3: Acute promyelocytic leukemia
M4: Acute myelomonocytic leukemia
M5: Acute monoblastic(M5a), acute monocytic(M5b) leukemia
M6: Acute erythroleukemia
M7: Acute megakaryoblastic leukemia
II. WHO classification (2000 & 2002)
There was a consensus that FAB L1, L2 and L3 of ALL are no longer relevant, since L1 and
L2 morphology do not predict immunophenotype, genetic abnormalities, or clinical
behavior. ALL-L3 is generally equivalent to Burkitt lymphoma in leukemic phase and
should be diagnosed as such.
The WHO classification of AML had reduced the blast threshold for diagnosis from 30% (in
FAB classification) to 20% in the peripheral blood and/or BM. In addition, patients with
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certain clonal, recurrent cytogenetic abnormalities should be considered to have AML
regardless the blast percentage.
Cytochemistry of AL
ALL is negative for Myeloperoxidase, Sudan Black B, and Non-specific estrases. Periodic
Acid Schiff is positive in many cases.
AML is positive for Myeloperoxidase, Sudan Black B, and Non-specific estrases. PAS is
positive in AML-M6
Immunophenotypingof AL
This is very useful in typing and subtyping of AL.The specific marker for B-cells is CD79a;CD3
for T-cells. The most specific myeloid marker is anti-MPO.
Karyotyping of AL
ALL
: the most common karyotypic abnormalities in pre-B-cell tumors is hyperploidy (>50
chromosomes/cell) which is associated with t(12: 21) chromosomal translocation. The presence
of these aberrations correlates with a good prognosis. Poor outcomes are observed with pre-B-
cell tumors that have translocations involving chromosome 11q23 or the Philadelphia (Ph
+
)
chromosome.
AML
: good outcome correlates with t(8:21) and t(15:17). Conversely, poor outcome correlates
with Ph
+
, t(6:9) and hyperploidy.
Course and Prognosis of AL
If untreated, patients will only survive for few months, and they will usually die either of severe
infection or bleeding due to progressive BM replacement by blast cells. ALL in general carries a
better prognosis than AML.Children 2 to 10 years of age have the best prognosis; most can be
cured. Other groups of patients do less well.
THE CHRONIC LYMPHOID LEUKEMIA
A
number of disorders are included in this group characterized by accumulation in the blood of
mature lymphocytes of either B- or T- cell type. In general the diseases are incurable but tend to
run a chronic and fluctuating course.
Diagnosis
This group is characterized by a chronic persistent lymphocytosis. Subtypes are distinguished by:
1. Morphology. 2.Immunophenotype. 3.Cytogenetics
4. DNA analysis may be useful in showing a monoclonal rearrangement of either
immunoglobulin (Ig) gene(for B-cells) or T- cell receptor (TCR) gene (for T-cells).
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
CLLis a low grade clonal lymphoproliferative disorder characterized by progressive
accumulation of usually well-differentiated CD5
+
lymphocytes in the BM with an accompanying
peripheral lymphocytosis. Involvement of lymph nodes (LN), spleen and liver invariably occurs
sometimes during the disease course. The etiology is unknown. There is seven-fold increased
risk of CLL in the close relatives of the patient. CLL is the most common of the chronic
lymphoid leukemia, accounting for 60% of cases, andit is the most common in the
Westrepresentingabout 25% of all leukemias in adults > 50 years. CLL is rare in the Far East.
Clinical features of CLL
1. The majority of patients are over 50 years.
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2. Most cases are diagnosed when routine blood test is performed.
3. Lymphadenopathy: Symmetrical enlargement of cervical, axillary or inguinal LNs is usually
discrete and non-tender.
4. Splenomegaly and less commonly hepatomegaly are common in intermediate stage.
5. Features of anemia and thrombocytopenia present in advanced disease.
6. Early bacterial infections predominate but with advanced disease viral and fungal infections
such as herpes zoster are also seen.This is due to immunosuppression which is a significant
problem resulting fromhypogammaglobulinemia and cellular immune dysfunction.
Laboratory findings
Lymphocytosis; the absolute lymphocyte count is > 5 × 10
9
/L (up to 300 × 10
9
/L or more).
The predominant cells are small lymphocytes with compact dark-staining round nuclei,
scanty cytoplasm, and little variation in size. The CLL lymphocytes are fragile and are
frequently disrupted during the preparation of smears, which produces characteristic smudge
cells. Variable numbers of larger activated lymphocytes are also usually present in the blood
smear.
Anemiaand Thrombocytopeniaare seen in later stages due to BM failure,hypersplenism or
autoimmune process.
BM examination shows lymphocyte infiltration >30 % of all nucleated marrow cells. BM
biopsy reveals early interstitial, nodular, mixed (nodular & interstitial) and late diffusepattern
of involvement.
Immunophenotypeshows pan-B-cell markers (CD19
+
& CD22
+
) with CD5
+
, CD23
+
and
weak expression of SmIg (surface membrane immunoglobulinfor IgM or IgD)with weak or
negative FMC7 and CD79b.
Serum Ig reduction becomes more marked with advanced disease.
Karyotype.The most common cytogeneticabnormalities are:deletion of 13q14 (15-20%)
which is associated with good prognosis. Triosomy 12 (10-15%), deletion at 11q23 (20%)
and structural abnormalities of 17p involving the p53 gene (all carry bad prognosis).
Staging of CLL
It is useful to stage patients at presentation both for prognosis and for deciding on therapy. The
stage is determined by several variables such as peripheral lymphocyte count, BM lymphocyte
percentage, presence or absence of lymphadenopathy, hepatosplenomegaly.The presence of
anemia<10 gm/dLand/or thrombocytopenia<100,000 /µL indicates advanced disease stage.
Course and prognosis
Many patients,in early stage, never need therapy.Survival ranges from 12years for early stage to
< 3 years for advanced stage.Cure is rare. CLL may transform to:
CLL/PL or frank prolymphocytic leukemia (PLL) that is resistant to treatment
Richter's transformation (Immunoblastic lymphoma, localized high grade NHL)
PROLYMPHOCYTIC LEUKEMIA
The prolymphocyte is around twice the size of a CLL lymphocyte and has a larger central
nucleolus. PLL typically presents with splenomegaly without lymphadenopathy and with a high
and rapidly rising lymphocyte count. Diagnosis is made by appearance of >55% prolymphocytes
in blood film.Anemia is a poor prognostic feature Response to treatment is poor.
HAIRY CELL LEUKEMIA
HCL patients typically present with infections, anemia or splenomegaly. Lymphadenopathy is
very uncommon.Lymphocyte count is rarely >20 × 10
9
/L. The peripheral blood shows
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pancytopenia andmonocytopeniawith variable number of unusually large lymphocytes with
villous cytoplasmic projections. BM biopsy; shows a characteristic appearance of mild fibrosis
and a loose diffuse cellular infiltrate. Patients can expect long-term remission with treatment.
CLASSIC CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPN)
This term covers a group of clonal disorders of the hemopoietic stem cells that lead to effective
proliferation of one or more hematopoietic component in the BM, and in many cases, in the liver
and spleen leading to elevated blood levelsof one or more myeloid cell lineages
(i.e.erythrocytosis, leukocytosis, and thrombocytosis). The classic MPNs include:
1. Chronic myeloid leukemia (CML - Ph
+ve
)
2. Polycythemia vera (PV)
3. Essential thrombocythemia (ET)
4. Primary myelofibrosis (MF)
These disorders are closely related to each other and transitional forms and evolution from one
entity into another occurs during the course of the disease.
Karyotype and Molecular Features
The vast majority of CML show thePhiladelphia chromosome, in(90-95%) and M-BCR-
ABL p210 in (99% of patients).Ph chromosome is a minute chromosome 22 from which the
long arms are deleted (22q-). It is part of reciprocal translocation between chromosome 9 &
22 t(9; 22) in which part of 22 is clearly visible on 9 but the part of 9 on 22 is too small to be
distinguished cytogenetically. This translocation is detected by PCR or FISH techniques.
Almost all PV patients and about 50% of ET and MF cases show Janus-Associated Kinase 2
(JAK2) mutation that occurs in the BM and in the peripheral blood granulocytes. This
mutation is not found in secondary polycythemia, or reactive thrombocytosis. JAK2plays a
major role in normal myeloid development.
POLYCYTHEMIA
Polycythemia (erythrocytosis): is an increase in the hemoglobin (Hb) concentration above the
upper limit of normal for the patient's age and sex in specific population. It is classified
according to its pathophysiology:
A. Absolute
1. Primary
o Polycythemia vera
o Familial (congenital) Polycythemia.
2. Secondary
Caused by compensatory erythropoietin increase in:
High altitudes
Pulmonary disease and alveolar hypoventilation (sleep apnoea)
Cardiovascular disease, especially congenital with cyanosis.
Increased affinity hemoglobin (familial Polycythemia).
Heavy cigarette smoking
Caused by inappropriate erythropoietin increase in:
Renal diseases (e.g. hydronephrosis, vascular impairment, cysts,carcinoma)
Tumors (such as uterine leimyoma, renal cell carcinoma, hepatocellular carcinoma,
cerebellar hemangioblastoma).
B. Relative (Stress or pseudopolycythemia):
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a. Cigarette smoking
b. Dehydration: water deprivation, vomiting.
c. Plasma loss: burns, enteropathy.
POLYCYTHEMIA VERA (PV)
PV is an insidious clonal MPN characterized by generalized hyperplasia of all marrow elements,
but dominated by expansion of the red blood cell volume>25% above mean normal predicted
value orHb>18.5 g/dl for men and>16.5 g/dl for women.In 50% of patients, there is also
neutrophiliaand thrombocytosis.There is endogenous erythroid colony growth despite subnormal
serum erythropoietin level. The clinical features include headache, dyspnea, blurred vision, night
sweats, pruritus(characteristically after hot bath)and plethoric appearance.Splenomegaly occurs
in 75% of patients. Hypertension occurs in one-third of patients. The course may be complicated
by hemorrhage, thrombosis, gout and peptic ulceration.Typically, the prognosis is good with a
median survival of 10-16 years. Thrombosis and hemorrhage are the major clinical problems.
Transition from PV to MF and AL may occur.
ESSENTIAL THROMBOCYTHEMIA (ET)
ETis characterized by a sustained increase in platelet count> 400 × 10
9
/L (400,000 /µL), because
of megakaryocytic proliferation and overproduction of platelets. There is endogenous
megakaryocyte growth independent of thrombopoietin. Other causes of raised platelet count need
to be fully excluded before the diagnosis can be made. Many cases are symptomless and
diagnosed on routine blood counts. Thrombosis in about 25% of the patientsmay occur in venous
or arterial systems. Hemorrhage as a result of abnormal platelet function may cause either
chronic or acute bleeding. Erythromelalgia is a characteristic symptom (it is a burning sensation
felt in hands or feet and relieved by aspirin). Up to 40% of patients will have palpable
splenomegaly, whereas in others there may be splenic atrophy because of infarction. Abnormal
large platelets and megakaryocyte fragments may be seen on blood film. BM typically shows an
excess proliferation of abnormal large and mature megakaryocyte, and no or little granulocyte or
erythroid proliferation.Often the disease is stationary for 10-20 years or more and has a lesser
risk to transform to MF, AL and PV.
MYELOFIBROSIS (MF)
MF is a clonal MPN of the pluripotent hematopoietic stem cell, characterized by proliferation of
multiple cell lineages and accompanied by progressive BM fibrosis, with development of
hematopoiesis in the spleen and liver. The onset is insidious with symptoms of anemia. About
≥⅓ of the patients have previous history of PV. Massive splenomegaly is the main physical sign.
Laboratory findings:
1. Anemia is usual.
2. The WBC and platelet counts are frequently high at presentation but with advanced disease,
leucopenia and thrombocytopenia are common.
3. A leukoerythroblastic blood film is found and the red cell morphology shows characteristic
'tear-drop' poikilocytes.
4. BM is usually unobtainable by aspiration (dry tap). Trephine biopsy shows hypercellular
marrow; granulocytic proliferation and increased numbers of atypical megakaryocytes are
frequently seen with often decreased erythropoiesis inpre-fibrotic phasewith extensive
marrow fibrosisin fibrotic phase.
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5. In 10% of cases there is increased bone formation with increased bone density on X-ray
(osteomyelosclerosis).
6. Neutrophil alkaline phosphotase (NAP) score is usually increased.
MF has the poorest prognosis of the MPNs; the median survival is 3-5 years (range 1-15 years).
Causes of death include: heart failure, infection and in 10-20% of cases transformation to AML.
CHRONIC MYELOID LEUKEMIA (CML)
CML is a clonal genetic change in a pluripotential hematopoietic stem cell, which proliferates
and generates a population of differentiated cells that gradually replaces normal hematopoiesis
and leads to a greatly expanded total myeloid mass. CML represents about 15 % of leukemia.
CML usually passes into 3 phases during its course:
A. Chronic Phase (CP), B. Accelerated Phase (AP), C.Blastic Phase (BP).
The Chronic phase (CP)usually lasts 2-7 years and in 50% of cases it is transformed to blastic
phase directly. In up to 50% of cases the diagnosis is made incidentally from a routine blood
count (asymptomatic). There may be features of anemia and of abnormal platelet function
(bruising, epistaxis, menorrhagia, etc). Splenomegaly is nearly always present and is frequently
massive. Gout and renal impairment (caused by hyperuricemia) may occur.
Laboratory findings
Anemia; usually normochromic normocytic.
Leukocytosis: usually in the range of 20-200 ×10
9
/L, occasional patients may present with
leukocytosis >200 ×10
9
/L causing features of hyperviscosity.
Blood film shows a full spectrum of granulocytic cells, ranging from blast forms (usually
<10%) to mature neutrophils, with myelocytes and neutrophils predominating.
The percentages of eosinophils and basophils are usually increased.
Platelet numbers are usually ↑ in the range of 300-600 × 10
9
/L, but may be normal or ↓.
NAP score is decreased or absent.
BM Aspirate:
Markedly hypercellular marrow
Blast cells < 10% of all nucleated cells (ANC).
Eosinophilsand basophils are usually prominent.
Megakaryocytes are small, hypolobed and increased in numbers.
BM Biopsy shows complete loss of fat spaces due to dense hypercellularity.
The Advanced disease (AP & BP);the clinical features are quite variable
Asymptomatic
Patients may develop fever, excessive sweating, anorexia and weight loss or bone pain.
Occasionally, patients present with generalized lymphadenopathy; LN biopsy shows nodal
infiltration with blast cells that may be myeloid or lymphoid.
Localized skin infiltrates may be seen. Discrete masses of blast cells may develop at almost
any site; these are referred to as "Myeloid Sarcomas."
Laboratory findings
In AP:Blasts range (10-19%) in BF and/or BM, basophils ≥20%, platelet count <100 × 10
9
/L
or persistently >1000 × 10
9
/L, increasing spleen size and WBCs unresponsive to therapy. There
may be megakaryocytic proliferation in sizable sheets and clusters, associated with marked
fibrosis, and/or severe granulocytic dysplasia.
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In BP:Blasts >20%, or extramedullary blast proliferation (LN, skin, elsewhere), or detection of
large foci or clusters of blats in BM biopsy.
Course and prognosis
Patients with CML-CP usually show an excellent response to treatment with imatinib.
Those who respondhave prolonged survival andmay never relapse.
Transformation to ALends with death within 2-6 months.
Death usually occurs from blastic transformation or intercurrent hemorrhage or infection.
MYELODYSPLASTIC SYNDROME (MDS)
MDS is a group of clonal disorders of multipotent hematopoietic stem cells which are
characterized by increasing BM failure with quantitative and qualitative abnormalities of
megakaryocytes, erythroid and granulocytic cells. MDS is either primary or it is secondary to
chemotherapy ± radiotherapy.
Pathogenesis
MDS starts following genetic damage to multipotent hematopoietic progenitor cell, leading to
increased stem cell proliferation but ineffective differentiation and maturation, resulting in a
hypercellular BM with peripheral blood pancytopenia; this is the hallmark of the disease.
Neutrophils, monocytes and platelets are often functionally impaired.
Clinically;the evolution of disease is often slow. The patients may be asymptomatic or present
with anemia (transfusion-dependent), recurrent infections and easy bruising or bleeding.
Laboratory findings
A. Peripheral Blood:
Pancytopenia is frequent
Anemia
Granulocytes are often decreased in number and frequently lack granulation
Pelger anomaly (neutrophil with single or bilobednucleus) is often present
Platelets may be improperly large or small and are usually decreased in number
Blasts in variable numbers are present in poor prognosis cases
B. Bone Marrow:
Usually hypercellular
Multinucleate normoblasts are seen
Ring sideroblasts may be seen (>4 perinuclear iron granules/normoblast& covering ≥ ⅓
of the nuclear circumference)
Granulocyte precursors show defective granulation
Megakaryocytes are abnormal (micronuclear, small binuclear or polynuclear)
At least 10% of the cells in a lineage should be dysplastic to consider the diagnosis of MDS.
PLASMA CELL DYSCRASIAS
PCDs originate from a clone of B cells that differentiates into plasma cells and secretes a single
complete and/or partial immunoglobulin (Ig). These disorders are also called monoclonal
gammopathies, due to the presence of usually excessive amounts of serumIgs, referred to
asparaproteinor M-protein.
The plasma cell dyscrasias can be divided into many variants:
1. Multiple Myeloma (MM)
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MMis the most common of the malignant plasma cell dyscrasias. It is a neoplastic proliferation
characterized by accumulation ofclonal plasma cellin the BM,the presence of paraprotein in the
serum and/or urine and related tissue damagethat is usually associated with multifocal lytic
lesions throughout the skeletal system.The etiology of the disease is unknown;dysregulation or
increased expression of cyclin D1 and D3 is an early unifying event andIL 6 is a potent growth
factor for myeloma cells and is often active by autocrine mechanism.
Hyperploidy is present in about half of cases whereas non-hyperploid cases have a high
incidence of translocations involving the Ig heavy-chain gene (IGH) on chromosome
14.Monoallelic loss of 13q is frequent in both categories.All these genetic abnormalities are also
seen in monoclonal gammopathy of undetermined significance (MGUS).
The most common paraprotein is IgG (60%), followed by IgA (20% to 25%). In the remaining
15% to 20% of cases, the plasma cells produce only κ or λ light chains. Because of their low
molecular weight, the free light chains are rapidly excreted in the urine, where they are termed
Bence-Jones proteins (BJP). Even more commonly, malignant plasma cells produce both serum
paraproteinand BJP in urine. The excess light chains have adverse effects on renal function.
Gross pathologic features
Multiple myeloma presents most often as multifocal destructive bone lesions throughout the
skeletal system. The affected bones are; vertebral column (65%), ribs (45%), skull (40%),
pelvis (30%), and femur(25%).There are often pathological fracturesand vertebral collapse.
These focal lesions generally begin in the medullary cavity, erode the cancellous bone, and
progressively destroy the cortical bone. The osteolytic lesions are caused by osteoclast
activation resulting from high serum level of RANKL (receptor activator of nuclear factor-
κB ligand), produced by plasma cells and BM stroma, which binds to RANK receptors on the
osteoclast surface, which promotes the differentiation and activation of osteoclasts.
Microscopic features
BM examination reveals an increased number of plasma cells (10 - 90%) of the cellularity.
The neoplastic cells can resemble normal mature plasma cells, but they more often show
abnormal features, such as prominent nucleoli or abnormal cytoplasmic inclusions containing
immunoglobulin.
Plasma cell infiltrations of soft tissues (plasmacytomas) can be encountered in the spleen,
liver, kidneys, lungs, and lymph nodes early or with disease progression.
Terminally, a leukemic picture may emerge (plasma cell leukemia or acute leukemia).
Metastatic calcification stemming from boneresorption and hypercalcemia.
Myeloma nephrosisrefers to renal involvement; it is a distinctive feature of MM.
a. Proteinaceous casts are prominent in the distal convoluted tubules and collecting ducts.
Most of these casts are made up of BJPs.
b. Some casts have tinctorial properties of amyloid.
c. Multinucleate giant cells created by the fusion of infiltrating macrophages usually
surround the casts.
d. Very often the epithelial cells lining the cast-filled tubules become necrotic or atrophic
because of the toxic actions of the Bence-Jones proteins.
e. Pyelonephritis can also occur as a result of the increased susceptibility to bacterial
infections. Less commonly, interstitial infiltrates of abnormal plasma cells are seen.
The clinical manifestations:
1. Bone pain,especially backache is extremely common resulting from plasma cell infiltration,
vertebral collapse and pathologic fractures.
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2. Features of anemiaresults from BM replacement andinhibition of hematopoiesis.
3. Recurrent bacterial infections result from severe suppression of normal Ig secretion, abnormal
cell-mediated immunity and neutropenia.
4. Features of renal failure and/or hypercalcemia.Renal insufficiency occurs in as many as 50%
of patients as a result ofproteinaceous deposit from heavy BJ proteinuria, hypercalcemia, uric
acid, amyloid and pyelonephritis.
5. Bleeding tendency. Paraproteins may interfere with platelet function and coagulation factors;
thrombocytopenia occurs in advanced disease.
6. Amyloidosisdevelops in 5% to 10% of patientswith features such as macroglossia, carpal
tunnel syndrome and diarrhea.
7. Hyperviscosity syndrome may occur in 2% of MM cases due to excessive production and
aggregation of myeloma paraproteins. Purpura, hemorrhages, visual failure, CNS symptoms,
neuropathies and heart failuremay be present.
Diagnosis of multiple myeloma depends on three principal findings:
1. Paraprotein in serum and/or urine.
2. Presence ofclonal plasma cells in the BMoften with abnormal forms or plasmacytoma.The
characteristic clonal immunophenotype is CD38
high
, CD138
high
and CD45
low
.
3. Complications related to organ damage or tissue impairment such as bone disease, renal
impairment, anemia, hypercalcemia, hyperviscosity, amyloidosis or recurrent infection.
Investigations in MM:
Electrophoresis of the serum and urine is an important diagnostic tool. In 97% of cases a
monoclonal spike of complete Ig or Ig light chain can be detected in the serum and/or urine.
Anemia is usually normochromic normocytic or macrocytic. Rouleaux formation is marked.
Neutropenia and thrombocytopenia occur in advanced disease.
Few plasma cells appear in the blood film in 15% of cases.
High ESR and C-reactive protein.
BM plasma cells are increased (usually >10% of ANC).
Radiological; the diagnosis is strongly suspected when the characteristic focal,
osteolyticpunched-out lesions in the bone are present (in 60% of cases)especially when located
in the vertebrae or calvarium. Generalized osteoporosis (20%) can also be seen and no bone
lesions in (20%). In addition, pathological fractures or vertebral collapse are common.
S. Calcium increased in 45% of patients. Typically, the serum alkaline phosphatase is normal
(except following pathological fractures).
S. Creatinine is raised in 20% of cases.
S. Albumin decreases with advanced disease.
S. β
2
-microglobulin is often raised (level < 4 mg/L imply a relatively good prognosis).
Prognosis
Multiple myeloma is a progressive disease.Patients with serum β
2
-microglobulin > 5.5 mg/ L and
serum albumin level < 35 g/L have poor survival as do those with frequent circulating plasma
cells. The median survival with non-intensive chemotherapy is 3 - 4 years.
2. Monoclonal Gammopathy of Undetermined Significance (MGUS)
A serum paraprotein may sometimes be detected in asymptomatic individuals without any
evidence of MM (related organ damage or tissue impairment) and is termed MGUS. It has a high
prevalence (3.2% and 5.8% in individuals over 50 and 70 years of age, respectively), making this
the most common plasma cell dyscrasia.There are no bone lesions, no BJP in urine and the
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percentage of plasma cells in the BM is normal (<4%) or only slightly increased (<10%).
Serumparaproteins are <30 g/L and serum light chains are ↑ in ⅓ of patients. Patients with
MGUS develop a well-defined plasma cell dyscrasia (MM, LPL, or amyloidosis) at a rate of 1%
per year. Moreover, MGUS cells often contain the same chromosomal translocations that are
found in full-blown MM. Thus, the diagnosis of MGUS should be made with caution and only
after careful exclusion of all other forms of monoclonal gammopathies, particularly MM.
3. Localized Plasmacytomas(solitary plasmacytoma)
These are isolated plasma cell tumors involving the skeleton or the soft tissues. Extraosseous
lesions occur mainly in mucosa of the upper respiratory tract (sinuses, nasopharynx, and larynx),
GIT or the skin. The associated paraprotein disappears following radiotherapy to the primary
lesion. Most of those with solitary skeletal plasmacytomas develop full-blown MM over a period
of 5 to 10 years.
4. Plasma cell leukemia
PCL occurs either as a late complication of MM or as a primary disease characterized by the
presence of ≥ 20% plasma cells in the peripheral blood. There is pancytopenia, organomegaly,
hypercalcemia, renal involvement and bone disease. The outlook is poor.
5. Lymphoplasmacytic Lymphoma (LPL) /Waldenströmmacroglobulinemia (WM)
Itis an indolent B-cell lymphoma with an IgMparaprotein that often behaves as cryoglobulin
causing Raynaud’s phenomenon. Anemia, hepatosplenomegaly, lymphadenopathy and mucosal
bleeding are common. Hyperviscosity syndrome is evident in 70% of patients especially with
IgM levels >30 g/L, where plasmapheresis is a dramatically effective treatment. Bone lesions are
rare, as is renal failure. Peripheral blood lymphocytosis is usually a feature of late disease. BM
showsa pleomorphic, diffuse infiltrate of lymphocytes, plasmacytoid lymphocytes and plasma
cells>30% of cells. The M-protein light chain is lambda λ in 75% of patients and 70% have BJP.
Median survival is approximately 6 years.