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N5315 Advanced Pathophysiology

Disorders of Leukocytes

Quantitative Alterations of Leukocytes

You will want to be familiar with the meaning of these basic terms. They are commonly
used to describe abnormally high or low white blood cell counts. The ones which end in
the suffixes -osis or -philia tend to refer to an elevated count. The suffix –penia refers to a
low count. The beginning of the word is the cell type. For instance, Leuko refers to all
white blood cells. Neutro refers to neutrophils. Make sure you are familiar with the terms
and what causes them.
• Leukocytosis refers to an increase in the number of total WBC.
• Leukopenia is a decrease in the number of total WBC.
• Neutrophilia is an elevated neutrophil count which is commonly seen in
bacterial infections, inflammation and necrotic tissue.
• Neutropenia is a decrease in the number of neutrophils and is commonly
seen in liver disease, viral infections, and drugs.
• Eosinophilia is an increase in the number of eosinophils and is commonly
seen in allergic reactions and parasitic infections.
• Eosinopenia is a decrease in the number of eosinophils and is seen with
pancytopenia and steroid use.
• Basophilia is an increase in the number of basophils and is seen with
allergic reactions.
• Monocytosis is an increase in the number of monocytes and is seen when
someone is recovering from an infection or with a TB infection.
• Monocytopenia is a decrease in the number of monocytes and can be seen
with steroid use and HIV infection.
• Lymphocytosis is an increase in the number of lymphocytes which is seen
in viral infections, lymphoma and leukemia.
• Lymphocytopenia is a decrease in the number of lymphocytes and is seen
with AIDS, chemotherapy and steroid use.

Leukemia Types
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Leukemia is a malignant disorder of the blood and blood forming organs. This results in
an overproduction of leukocytes by the bone marrow. The overproduction causes an
overcrowding in the bone marrow by the leukemic cells thus preventing the production of
normal blood cells. These cells are ejected into the blood and accumulate in the liver,
spleen, lymph nodes and other organs in the body.

Leukemia may be classified as acute or chronic. Acute leukemias are abrupt in onset, are
aggressive diseases and are characterized by the production and accumulation of
immature cells such as blast cells. Chronic leukemias are characterized by the production
of cells that appear mature but do not function appropriately and they accumulate. The
onset of chronic leukemia is gradual in nature, and it is far less aggressive than acute
leukemia. Leukemias may be classified as myelogenous versus lymphocytic.
Myelogenous means that there is an excessive production of granulocytes, whereas in
lymphocytic leukemias, the excessive production is with the lymphocytes. In all forms of
leukemia, men tend to be more commonly affected as are Americans of European
descent. Caucasian children are more commonly affected than other children. ALL is the
least common type but is the most common type in children. CLL and AML are most
common in adults.

Make sure you are familiar with the various characteristics of the types of leukemias
presented in this chart. Also review the table in your textbook titled: Clinical
Manifestations and Related Physiology in Leukemia.

Type Pathology Age of Signs & Symptoms Prognosis

Onset

Marked by > 30% of Most Fever, pallor, bleeding,

lymphoblasts in the common in fatigue,
Acute Lymphocytic
blood or bone children but lymphadenopathy,
Leukemia (ALL)
marrow. The is seen in infection, joint pain,
proliferation of blast adults. splenomegaly,
cells is related to hepatomegaly, night Survival rate
genetic/chromosomal sweats, weight loss, decreases with
abnormalities. anemia, age.
thrombocytopenia,
petechiae and
ecchymosis.
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CNS may be affected:

headache, vomiting,
papilledema, facial
palsy, meningeal
irritation.

Acute Myelogenous Is marked by a Most

proliferation of common
Leukemia (AML) As above Remission rates
immature myeloid adult
are inversely
cells, decreased leukemia.
related to age.
apoptosis and a lack Incidence
of cellular increases
differentiation. There with age.
are many
chromosomal
abnormalities
associated with the
disorder. It is
aggressive and fast
growing.

Chronic Lymphocytic Malignant Incidence is Suppression of humoral

transformation of B- increased in immunity, increased
Leukemia (CLL) Longer life span
lymphocytes. They persons older infections with
expected than in
do not prevent the than 40. encapsulated bacteria.
acute leukemias.
growth of normal Most are asymptomatic
Survival time is
blood cells as much at the time of diagnosis.
ten or more years.
as an acute leukemia
Neutropenia
does. B-cells have
decreased apoptosis.
Infiltrates lymph
nodes, liver, spleen
and salivary glands.
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Chronic Myelogenous Characterized by the Incidence is Splenomegaly most Bone marrow

presence of the increased in common finding. transplant may be
Leukemia (CML)
Philadelphia persons older Hepatomegaly, curative.
chromosome than 40. hyperuricemia,
infection, fever, wt loss

Pathophysiology overview of leukemia:

All leukemias share some of the same pathologic characteristics. Most leukemias arise
from the B-cell and T-cell differentiation pathways. The majority of leukemias arise from
the B-cell differentiation pathway. Leukemia blast cells are immature WBCs which fill
the bone marrow and spill into the blood. They crowd out the bone marrow and trigger
the cessation of the production of other blood cells. This leads to a pancytopenia.

The Philadelphia chromosome is mainly located in CML but may be found in some
persons with AML and ALL. This chromosome is a result of a translocation between
chromosomes 9 and 22. The translocation causes a fusion of the BCR 1 gene region on
chromosome 22 and the proto-oncogene ABL1 on chromosome 9. This results in the
expression of an oncoprotein called the BCR-ABL1. This protein promotes cell
proliferation, which is needed for cells to become leukemic cells. This protein not only
increases cellular proliferation, but it decreases sensitivity to apoptosis.

African Americans tend to have lower mortality rates than Caucasians from acute
leukemias. Acute leukemias tend to run in families and show an increased incidence with
other hereditary abnormalities such as Down’s Syndrome, Faconi aplastic anemia, and
some immune deficiencies. Increased risk for acute leukemias in adults include smoking,
benzene, ionizing radiation, HIV infection, Hepatitis C infection and drugs which
suppress the bone marrow. AML may occur after chemotherapy for lymphomas, multiple
myeloma, ovarian cancer, breast cancer. Acute leukemia may occur from CML, CLL,
polycythemia vera, myelofibrosis, lymphoma, multiple myeloma, ovarian cancer and
sideroblastic anemia.

CLL progresses slowly, the etiology is not known and there is a familial tendency. CML
occurs mainly in adults but it may occur in children and adolescents. Persons with
chronic leukemia tend to have a longer life expectancy than those with acute leukemias.
Chronic leukemias as a whole progress slowly.

CML progresses in three stages:

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• Chronic phase which lasts 2-5 years. During this time the patient may be
asymptomatic.
• Accelerated phase which lasts 6-18 months during which symptoms develop.
• Terminal blast phase which is marked by excessive proliferation of the leukemic
cells. Survival at this point is only 3-6 months.

Lymphomas
Lymphomas are the proliferation of malignant lymphocytes and they are the most
common blood cancer in the United States. They are usually caused by a viral infection
or genetic mutations. The two main types are Hodgkin’s lymphoma and non-Hodgkin’s
lymphoma.

Hodgkin’s Lymphoma is a malignant neoplasm of the B lymphocyte cells. These

abnormal cells are called Reed-Sternberg cells and are characteristic of Hodgkin’s
lymphoma. The etiology is not known but it is thought to be linked to the Epstein Barr
Virus. It occurs most commonly in persons between the ages of 15-34 and in persons
over 50. It tends to be more common in men and Caucasians. The pathogenesis is not
well understood, but it is characterized by the development of the Reed-Sternberg cells.
There are several subtypes, but you do not have to know the specific subtypes. They
develop in one area of the lymphatic system and secrete cytokines, trigger inflammation,
and cause necrosis of the area. This can spread throughout the lymphatic system, but on
initial diagnosis it is usually a localized disease. Clinical Manifestations include:
• A locally enlarged painless mass, lump or swelling is the presenting sign, most
commonly in the neck. They may have an asymptomatic mediastinal mass seen
on CXR. Fever, weight loss, night sweats, pruritis (itching), adenopathy,
thrombocytosis, leukocytosis, abdominal mass, eosinophilia may also be present.
Overall it has a better prognosis than Non-Hodgkin’s lymphoma.
• Other laboratory findings include elevated ESR, elevated alkaline phosphatase,
and paraneoplastic syndromes.

Non- Hodgkin’s Lymphoma is the malignant transformation of lymphocytes (B-cells, T-

cells, NK cells). The malignant immune cells originate from chromosomal translocations
which activate oncogenes and/or inactivate tumor suppressor loci. The cause is not
known. There are NO Reed-Sternberg Cells. This is commonly seen in persons who are
immunosuppressed such as those with AIDS, hepatitis C, EBV, and post transplantation
patients (secondary to immune suppression). H. Pylori infection increases the risk of
gastric lymphoma. The median age of diagnosis is 67. This highest incidence is seen in
North America, Europe, Oceania and in Africa. Risk factors for NHL include a family
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history, exposure to certain chemicals, irradiation, infection with EBV, human

herpesvirus-8, HTLV virus), and immune suppression. These patients will have
generalized lymphadenopathy, and the disease is usually widespread throughout the
lymphatic system. The cervical, axillary, inguinal, and femoral lymph node chains are
usually the most commonly involved sites. This is a painless lymphadenopathy. The
disease may cause tumors in the nasopharynx, GI tract, nose, thyroid, testes, and soft
tissue. Usually persons affected do not experience fever, night sweats, or weight loss in
the early stages, but they will experience these symptoms in the later stages of the
disease. NHL is classified as low, intermediate or high grade. Low grade NHL
progresses slowly and persons may have spontaneous regression of malignant nodes.
These people tend to present with painless adenopathy and do not display weight loss or
fever. Cytopenias may be observed in this stage. Intermittent and high-grade NHLs are
more aggressive and have a varied presentation. Night sweats, fever, weight loss and
fatigue are common in these persons.

Multiple Myeloma (Plasma Cell Myeloma)

Multiple Myeloma is the proliferation of malignant plasma cells. It affects African
Americans more commonly, presents around the sixth decade of life and is slightly more
common in men. Risk factors for the development of multiple myeloma include radiation
exposure, pesticide exposure and a history of monoclonal gammopathy of undetermined
significance.

The disease is typically associated with a chromosomal abnormality such as a deletion or

translocation which leads to the production of malignant plasma cells. The plasma cells
secrete hepatocyte growth factor and parathyroid hormone related peptide which attaches
to stromal cells which then triggers the release of several cytokines. IL-6 stimulates
osteoclastic activating factor which in turn stimulates osteoclasts to break down bone.
This process results in bone lesions and hypercalemia. The malignant plasma cells (B-
cells) also secrete antibodies which infiltrate the organs, mainly the bones, and cause
malignant tumors in these areas. They can infiltrate the kidneys and cause renal failure.

The most commonly affected bones are the vertebrae, ribs, skull, and pelvis. This is a
progressive disease with a median lifespan of three years. Clinical manifestations depend
upon the area or organ affected by the neoplasm but may include hypercalcemia
(confusion, lethargy, weakness), recurrent infections, bone pain, pathological fractures,
elevated alkaline phosphatase, and renal failure. The person may experience weakness,
fatigue, weight loss, anorexia, easy bleeding or bruising and dyspnea. Normocytic anemia
will be present.