WHITE BLOOD CELL DISORDERS

Can be broadly divided into proliferative disorders and leukopenias.

Proliferative can be reactive or neoplastic

LEUKOPENIA

Deacreased levels of white blood cells (usually from reduced numbers of

neutrophils)

Lymphocytopenia is less common (seen in HIV, infection, autoimmune disease

etc.)- it is actually due to lymphocytes sequestration to different parts of the
body that results in less peripheral lymphocytes.

NEUTROPENIA- can be caused by 1)inadequate granulopiesis 2)increased

destruction of neutrophils in the periphery

Type 1 is seen in :

-suppresion of HSC (aplastic anemia) (bone marrow disorders)

-suppresion of commited granulocyte precursors due to drugs
-ineffective hematopoiesis due to disease ( megaloblastic anemia ,
myelodysplastic syndromes)
-congenital conditions

Type 2 is seen in:

-immune mediated injury (lupus or drug induced)

-splenomegaly
-increased peripheral utilization as in the case of infection

THE MOST COMMON CAUSE OF NEUTROPENIA IS DRUG INDUCED

cancer treatment drugs

clinical features: the patients symptoms are related to infection,

malaise , fever and chills

treatment: broad spectrum antibiotic

neutropenia following chemo G-CSF

REACTIVE PROLIFERATIONS OF WHITE CELLS AND LYMPH NODES

Leukocytosis is an increase in the WBC count

During infection there is a rapid extravasation of leukocytes from the BM, this is
due to IL-1 and TNF.

If the IL-1 and TNF release is prolonged then macrophages and other cells
produce growth factors which stimulate the proliferation of the commited
granulocyte progenitor cells.

Some growth factors act preferentially on some leukocytes, i.e. G-CSF

(neutrophils) IL-5 (eosinophil)

Usually it is easy to distinguish between reactive proliferations and neoplastic

proliferations, but sometimes during acute infection it might be difficult.

NEOPLASTIC PROLIFERATION OF WHITE CELLS

-LYMPHOID NEOPLASMS :B-cell , T-cell and NK cell

-MYELOID NEOPLASMS: arise from early hematopoietic progenitors, three
categories are recognized. 1)acute myeloid leukemias 2)myelodysplastic
syndromes 3)chronic myeloproliferative disorders
-HISTOCYTOSES uncommon proliferation of the macrophages and dendritic
cells.

Chromosomal abnormalities most commonly translocations are responsible for

many white cell neoplasms

The genes that are affected usually play a crucial role in the development,
growth and survival of the normal cell.

Many oncoproteins cause an arrest in the differentiation , often at an early

stage when cells are proliferating rapidly as in the case of acute leukemias.

Other mutations seem to directly enhance the self renewal of the tumor cells,
giving these cells stem cell like properties. (usually activate thyrosine kinase,
which in turn activate RAS etc)

Also mutations that prevent apoptosis are present in some conditions.

Alot of mutations occur during gene re-arrangements of B cells.

After antigen stimulation the B cells enter germinal centers and upregulate
expression of AID (activation induced cytosine deaminase) which is important
for class switching and somatic hypermutation.
Some protooncogenes like MYC gene are activated by translocations to the
active Ig locus.

Another type of protooncogene is BLC6, activated by AID mistargeted breaks in

the chromosome

In B and especially T cells there can be activation in protooncogenes due to the

VDJ recombination action.

Some causes of white cell neoplasia are also inherited diseases as fanconi
anemia or bloom syndrome.

Viruses are also involved in the development of cancer, such as in EBV, human
T cell leukemia virus and kaposi sarcoma virus.

Chronic inflammation also predisposes to lymphoid neoplasia. (h.pylori and

gastric B-cell lymphomas)

Iatrogenic factors include chemotherapy and medication

Smoking also induces myeloid leukemia

LYMPHOID NEOPLASMS

2/3 of NHL and all hodgkin lymphomas present as enlarged non tender lymph
nodes.

Lymphoid neoplasms are categorized into 5:

1. Pre B cell leukemia/lymphoma

2. Peripheral B cell leukemia/lymphoma
3. Pre T cell leukemia/lymphoma
4. Peripheral T / NK cell
5. Hodgkin lymphoma

The majority of neoplasms are of B cell origin (80%) the rest being T cell, very
rarely they are NK cell tumors.

LYMPHOID NEOPLASMS ARE ASSOCIATED WITH IMMUNE ABNORMALITIES:

decreased immunity or autoimmunity

The neoplastic B and T cell will home to usual tissues as the normal
counterpart. Since they can travel through lymphatics usually at the time of
diagnosis the tumor would have spread to distant sites, exeptiions being
hodgkin lymphomas and marginal zone B cell lymphomas.
PRECURSOR B CELL AND T CELL NEOPLASMS

ACUTE LYMPHOBLASTIC LEUKEMIA AND LYMPHOMA: composed of immature B

cells and T cells (lymphoblasts)

Most the B-ALL tend to manifest in children whilst the T-ALL in adolescents as
thymic lymphomas.

ALL is the most common type of cancer in children. Younger than 15

Peak incidence at about 3 years
Peak incidence of T-ALL is in adolescence at the age when the thymus reaches
the maximum size.

B-ALL and T-ALL occur less frequently in adults and when they occur it has a
worse prognosis as they are more aggressive and less receptive to treatment.

PATHOGENESIS:

-70% OF T-ALL HAVE GAIN IN FUNCTION IN NOTCH1

-B-ALL HAVE LOSS OF FUNCTION MUTATIONS IN GENES REQUIRED FOR B CELL
DEVELOPMENT PAX5,EBF,E2A OR GENE TRANSLOCATIONS.

These mutations disturb the differentiation and arrest the maturation of the
cells, and in diong so promote increased self renewal giving stem cell like
properties.

Abbarations that drive cell growth like tyrosine kinase are common.

Most common in ALL is hyperploidy (more than 50 chromosomes) (seen only in

B-ALL)
Also alot of chromosome translocations are seen.

Immunophenotyping TdT positive, myeloperoxidase negative , acid schiff

positive.

To distinguish B from T cell precursors we need to look at the cell markers.

Characteristic features of ALL:

stormy onset
symptoms related to depressed marrow function (anemia, thrombocytopenia,
fever, infections)

mass effect by neoplastic infiltration: bone pain, testicular enlargement

invasion of CNS headaches etc

PROGNOSIS:

- Pediatric ALL has a good prognosis, with agressive chemo 95% have
remission
- ALL however is the leading cause of cancer deaths for children
- Worse prognosis if younger than 2
- Adult has worse pronosis
- High levels of peripheral WBC has bad prognosis

Good prognosis however if it is a trisomy of 4,7,10, or hyperploidy, or the

t(9,22)

The t(9,22) creates a fusion gene which keeps the tyrosine kinase on all the
time. (BCR-ABL tyrosine kinase)

Stronger tyrosine kinase activity than the one found in AML

Treatment for BCR-ABL positive ALL is treatment with BCR-ABL kinase inhibitors
with chemo

PERIPHERAL B CELL NEOPLASMS

CLL CHRONIC LYMPHOCYTIC LEUKEMIA AND SMALL LYMPHOCYTIC LEUKEMIA

DIFFER ONLY BY THE DEGREE OF PERIPHERAL LYMPHOCYTOSIS

CLL is the most common leukemi in adults in the western world

Age at diagnosis 60

2:1 male preponderance

PATHOGENESIS

Chromosomal translocations are rare.

Most common abnormality is deletions of 13q14,11q and 17p and trisomy 12q.

Some of the Ig genes of CLL are hypermutated whilst others are not suggesting
that the cell of origin can be either naive or post germinal centre B cell.

There are also gain of function mutations in the NOTCH1

CLL and SLL seem to be confined to proliferation centers where there are
stromal cells which express NF-kB which promotes cell growth and survival.
IMMUNOHISTOTYPE: CLL/SLL express pan B cell markers and CD19,20,23 and 5

CLINICAL FEATURES: patients are usually asymptomatic at diagnosis, when

symptoms appear they are non specific.

Lymphaenopathy and hepatosplenomegaly present in 50%

Some patients develop hemolytic anemia due to antibodies produced from non
neoplastic B cells.

Median survival is 4-6 years

Symptomatic patients are treated with gentle chemo, young patients can
benefit from stem cell transplantation.

BTK inhibitors also therapy

Sometimes the CLL can transform into diffuse large B-cell lymphoma which has
a poor prognosis.

FOLLICULAR LYMPHOMA

MOST COMMON FORM OF INDOLENT NHL

BCL2 CHROMOSOMAL TRANSLOCATIONS IN GERMINAL CENTER B CELLS.

14,18 translocation of BCL2 and IGH

BCL2 ANTAGONISES APOPTOSIS

MUTATIONS IN MLL2 IN 90% ASWELL. MLL2 IS RESPONSIBLE FOR EPIGENETIC

CHANGES

CLINICAL PRESENTATION

Painless generalized lymphadenopathy

Incurable,
survival is 7 years and is not improved by aggressive chemotherapy

30-50% transform into diffuse large B-cell lymphoma

DIFFUSE LARGE B CELL LYMPHOMA

is the most common form of NHL.

Mean age is 60

Dysregulation of the BCL6 gene.

It is hypothesised that this is due to somatic hypermutations.

BCL6 supresses the expression of factors which aid in b cell differentiation,

apoptosis and growth arrest

Immunohistotype: cd19, cd20. BCL6

CLINICAL PRESENTATION

Rapidly growing mass at nodal or extranodal site

Can arise anywhere in the body.

Primary or secondary involvement of the liver and spleen.

These are aggressive tumors which are fatal if not treated.

Intensive chemo will give about 60% remission

5% have also MYC translocation which makes it hard to distinguish from burkitt
lymphoma
need to give chemotherapy
this variant has worse prognosis

BURKITT LYMPHOMA

1-AFRICAN VARIANT (ENDEMIC)

2.SPORADIC
3.SUBSET OF AGRESSIVE LYMPHOMAS IN HIV INFECTED PATIENTS

all burkit lymphomas have a translocation of MYC gene which results in

increased MYC levels.
MYC gene is a master transcriptional regulator which increases the expression
of genes that are required for aerobic glycolysis, the so called warburg effect.
Warburg effect: In oncology, the Warburg effect is the observation that most
cancer cells predominantly produce energy by a high rate of glycolysis followed
by lactic acid fermentation in the cytosol, rather than by a comparatively low
rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most
normal cells.

The latter process is aerobic (uses oxygen). Malignant, rapidly growing tumor
cells typically have glycolytic rates up to 200 times higher than those of their
normal tissues of origin; this occurs even if oxygen is plentiful.
Otto Warburg postulated this change in metabolism is the fundamental cause
of cancer, a claim now known as the Warburg hypothesis. Today, mutations in
oncogenes and tumor suppressor genes are thought to be responsible for
malignant transformation, and the Warburg effect is considered to be a result
of these mutations rather than a cause.

Consequently the burkitts lymphoma is known to be the fastest growing human

tumor.

All endemic burkitt lymphomas are latently infected with EBV.

These are mature B cell tumors and express , IgM , CD19,CD20,CD10 and BCL6.

Endemic and sporadic burkitts lymphomas are mostly found in children or

young adults.
Accounts for 30% of children NHL

Endemic burkitts lymphoma shows as an enlargment in the mandible and

usually affects extranodal sites, kidneys, ovaries and the adrenal glands.

Even though this type of lymphoma is very aggressive it responds well to

aggressive chemotherapy.