Introduction
White blood cell disorders as a topic, requires undivided attention as their signs overlap on some occasions. Quality attention creates a room for better decision making in diagnosis and scheduling treatment.
These white cell disorders usually originate from hematopoietic cells of either common myeloid or common lymphoid progenitors in bone marrows. White cell disorders may often develop in other lymphoid tissues like thymus, spleen, lymph nodes and other sites.
How then do we differentiate leukemia from lymphoma? Leukemia is the spead of neoplastic cells within bone marrow and the blood. On the other hand, lymphoma is the development of tumors within lymph nodes, which may infiltrate blood causing leukemia.
Origin of hematopoietic cells
The origin of blood cells are the hematopoietic stem cells (HSCs). They differentiate into: Common lymphoid progenitors & common myeloid progenitors.
The common lymphoid progenitors differentiate into: B-lymphocytes; T-lymphocytes; NK cells.
Common myeloid progenitors differentiate into immature progenitors: myeloblast; monoblast; eosinophiloblast; basophiloblast; proerythroblast; megakaryoblasts.
Immature progenitors differentiate accordingly into mature forms: neutrophil; monocyte; eosinophil; basophil; erythrocyte; platelets.
As the blood cell precursors differentiate, they begin to express receptors for lineage-specific growth factors. This is essential to ensure brief growth, survival and supply of blood cells when need arises (e.g. cell replacement & infection),
Special growth factors essential for hematopoiesis include: Stem cell factor (c-KIT ligand); FLT3 ligand; granulocyte colony stimulating factor (G-CSF); macrophage colony stimulating factor (M-CSF); granulocyte-macrophage colony stimulating factor (GM-CSF); IL-5; thrombopoietin; erythropoietin.
Blood cell neoplasms arise either from mutations that inhibit precursor cells from maturing, or prevent their reliance on growth factors. In order to diagnose blood cell tumors and evaluate their morphology, fine needle aspirate of bone marrow is essential. For blast forms, further analysis including lineage-specific antibodies & histochemical markers are essential.
To get a better view of marrow activity, it is best to do needle biopsy. In a normal bone marrow interstitial, there are equal amounts of fat and blood cells. Conditions including aplastic anemia increase fat cells, while granulomatous diseases, blood cell malignancies decrease fat cells.
Overview of hematopoiesis during fetal development
The yolk sac begins early hematopoiesis during the 3rd week of embryogenesis through the early erythroid progenitors.
Several weeks later into embryogenesis, the HSCs become in charge of definitive hematopoiesis in the aorta/gonad/mesonephros/ region.
In the 3rd month of gestation, HSCs migrate to the liver, which serves as another site of definitive hematopoiesis until birth. Around the 4th month of gestation, HSCs move to the bone marrow, which becomes haematopoietically functional by birth.
After delivery until puberty, bone marrow throughout the skeleton becomes main sites of hematopoiesis. After puberty, hematopoiesis becomes only active on the axial skeleton.
There are three categories of white cell disorders: neoplastic proliferation; reactive proliferation (e.g. in infections); leukopenia. Next, we shall discuss various examples of white blood cell disorders.
Neutropenia, agranulocytosis
Neutropenia is the reduction in the number of neutrophils. Agranulocytosis is the great reduction in neutrophil number with much more clinical outcomes.
The causes include: exposure to toxic drugs (aminopyrine, thiouracil, chloramphenicol, sulfonamides, chlorpromazine, phenylbutazone); aplastic anemia; megaloblastic anemia; tumors; granulomatous disease; myelodysplastic syndromes; over whelming infections; splenomegaly; Kostmann syndrome (inherited defect affecting granulocytic differentiation).
Clinical manifestations: fever; chills; malaise; necrotizing ulcers of oral cavity; invasive bacterial and fungal infections in lungs, urinary tract & kidneys.
Leukocytosis
This is an increase in the number of white blood cells in the blood. Special terms are given to white cells involved: neutrophilia, basophilia, eosinophilia, monocytosis, & lymphocytosis. In Leukemoid reaction, a special type of leukocytosis, large numbers of immature granulocytes appear in blood during severe infections.
Causes of leukocytosis include: Acute bacterial infections; allergic reactions; parasitic infections; Churg Strauss disease; tuberculosis; ulcerative colitis; viral infections (hepatitis A, cytomegalovirus, Epstein Bar virus); Bordetella pertussis.
Lymphadenitis
Refers to the enlargement of lymph nodes, in which primary follicles and paracortical T-cell zone undergo hyperplasia due to infection. It may be acute or chronic.
Acute lymphadenitis causes painful, occasionally suppurative swelling on lymph nodes around cervical, axillary, inguinal, mesenteric regions. Chronic lymphadenitis causes nontender swelling usually on lymph nodes around the axillary and inguinal regions.
Acute lymphoblastic leukemia/Lymphomas (ALLs)
These are tumors of immature lymphocytes (lymphoblasts) affecting both B-cells and T-cells. They affect children under 15 years of age, with prevalence in boys and whites. Cytologically, lymphoblasts present as small agranular cytoplasm, with larger, condensed nuclei. Two known types are: B-cell ALLs; T-Cell ALLs.
The causes of B-cell ALLs are: loss of function mutation involving PAX5 gene (encodes transcription factor Pax5); balanced translocation t (12p;21q) forming fusion gene transcript, TEL/AMLI; balanced translocation t (9q;22q) forming fusion gene transcript BCR/ABL (shows bad prognosis). The peak incidence for B-ALLs is 3 years.
Main cause of T-cell ALLs is the gain of function mutation of NOTCH1 gene (encodes Notch1, a transmembrane protein). Peak incidence for T-ALLs is 15 years and presents as thymic masses (thymic lymphoma) at this age.
Except for BCR/ABL transcript, the rest of the chromosomal changes affecting ALLs, dysregulate transcription factors that cause maturation arrest. The BCR/ABL gene transcript encodes BCR-ABL tyrosine kinase that drives unregulated growth.
Clinical manifestations: neutropenia; thrombocytopenia; anemia; hepatosplenomegaly; generalized lymphadenopathy; testicular enlargement; compression of large vessels & airways in mediastinum; headache; vomiting; nerve palsies.
Diagnosis: Immunophenotyping and histochemical staining. In histochemical staining, lymphoblasts stain positive with periodic acid-Schiff stain that show cytoplasmic materials.
In immunophenotyping, there is usually an expression of special DNA polymerase (Terminal deoxynucleotidyl-transferase) by lymphoblasts. Other common markers include: CD19, CD10, Pax5 (for B-cell); CD1, CD2, CD5, CD7 (for T-cell).
Besides factors including age (<2 yrs, >10yrs) and chromosomal changes (BCR; ABL), overall prognosis is good with aggressive chemotherapy. Remission rate is 95%, while cure rate is about 80%.
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
These are neoplasms of actively dividing mature naive or memory B-cells of the lymph nodes, that inflitrate the blood. The site of active division is the proliferation center, which consitutes a mixture of actively dividing immature pro-lymphocytic B-cells with mature B-cells.
Within the lymph nodes, this proliferation center contains stromal cells that promote growth and survival of tumor cells.
Cytologically, they are small, round cells (6-12μm) with scant cytoplasm. They affect people over 60 years and there is high prevalence among men.
The causes include: production of growth factors by stromal cells in the proliferation centers that stimulate transcription factor, NF-κB; chromosomal deletions in 13q, 11q, 17p.
Diagnosis: Requires immunophenotyping and peripheral blood smears. In immunophenotyping, there is surface expression of CD19, CD20; low level surface IgM/D or both. In peripheral blood smears, smudge cells (disrupted tumor cells) are present.
Clinical manifestations: fatigue; weight loss; generalized lymphadenopathy; anorexia; leukopenia (in SLL); lymphocytosis >4000/μl or leukocytosis >200,000/ μl (in CLL); hepatosplenomegaly; hemolytic anemia; thrombocytopenia; hypogammaglobulinemia.
Prognosis: On average, 4 to 6 years survival period. Tumor may transform into prolymphocytic forms or diffuse large B-cell lymphoma (Richter syndrome).
B-cell prolymphocytic leukemia/lymphoma (B-cell PLL)
This is a rare aggressive form of CLL/SLL affecting mature B-cells. There is increase in appearance of prolymphocytes (large cells with single nucleolus) in tissue samples.
Clinical manifestations: cytopenia; splenomegaly.
Diffuse large B-cell lymphoma
These are large, diffusing neoplastic mature B-cells with diameter of 36-72μm & are the most common form of Non-Hodgkins Lymphoma (NHL). Cytologically, they are large cells with multilobulated or cleaved nuclei. They usually affect people over 60 years, and occasionally children and young adults. It is prevalent in men.
The cause include: mutation of BCL6 on chromosome 3q27. Overexpression of Bcl6 protein inhibits germinal center B-cell differentiation & promotes growth.
Diagnosis: immunophenotyping shows markers: CD19, CD20, BCL6 (germinal center B-cell markers)
Clinical manifestations: enlarging mass in lymph nodes, adenoids, tonsils. Other extranodal sites include: enlarging mass in liver, spleen, G.I tract, bone (rare), other tissues.
Follicular lymphoma
This is a tumor that affects peripheral mature B-cells in their follicular germinal centers. It equally affects both male and female and presents in middle age (40 to 70 yrs).
Cytologically, they present as small cells with irregular, cleaved nucleus and scant cytoplasm (centrocytes) or large cells with multiple nucleoli & modest cytoplasm (centroblasts).
The common cause include: chromosomal translocation t (14q:18q) causing a fusion transcript of IgH/BCL2. This fusion causes an overexpression of Bcl2 protein that inhibits apoptosis.
Clinical manifestations: generalized lymphadenopathy; extranodal masses (rare) in G.I tract, CNS, testis. It is incurable & average survival years is 7-9. Predominant diagnostic marker is BCL2.
Burkitt lymphoma
This is an aggressive tumor of mature B-cells that are intermediate in size of 10 to 25μm in diameter. Cytologically, they are intermediate-sized cells with round nuclei, multiple nucleoli and moderate cytoplasm.
Three subtypes: African endemic, sporadic non-endemic & HIV associated Burkitt lymphoma. African endemic, sporadic non-endemic forms usually affect children & young adults.
Histologic samples show tumors with high mitotic activity and many apoptotic debris. Macrophages surround apoptotic areas, and their cytoplasms have a “starry sky” appearance that is pale.
The most common cause includes: chromosomal translocation t (8q:14q) which creates a fusion transcript IgH/c-MYC. Overexpression of MYC protein drives uncontrolled cell proliferation and growth.
Clinical manifestations: African, endemic forms present as enlarging mass in mandibles (usually), adrenal glands, kidneys, ovaries. Sporadic, non-endemic forms often present as enlarging mass in ileocecum & peritoneum.
Prognosis: With intensive chemotherapy, cure rate among children and young adults is high.