This document discusses several non-neoplastic and neoplastic disorders of white blood cells. It describes leukopenia, neutropenia, agranulocytosis, and reactive leukocytosis as non-neoplastic disorders. It then summarizes several types of lymphoid neoplasms including acute lymphoblastic leukemia/lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma. Key features such as pathogenesis, clinical presentation, and distinguishing characteristics are highlighted for each condition.

1. White Cell Disorders
Dr Maria Idrees; PT
Ms NMPT (RIU)
DPT (TUF)

2. NONNEOPLASTIC DISORDERS OF
WHITE CELLS
Leukopenia
• Leukopenia results most commonly from a
decrease in granulocytes, the most numerous
circulating white cells.
• Lymphopenia is much less common; it is
associated with rare congenital
immunodeficiency diseases, advanced human
immunodeficiency virus (HIV) infection, and
treatment with high doses of corticosteroids.

3. Neutropenia/Agranulocytosis
• A reduction in the number of granulocytes in
blood is known as neutropenia or, when
severe, agranulocytosis.
• Neutropenic persons are susceptible to
severe, potentially fatal bacterial and fungal
infections. The risk of infection rises sharply as
the neutrophil count falls below 500 cells/μL.

4. Pathogenesis
• The mechanisms underlying neutropenia can be
divided into two broad categories:
• Decreased granulocyte production. Clinically important
reductions in granulopoiesis are most often caused by
marrow hypoplasia (as occurs transiently with cancer
chemotherapy and chronically with aplastic anemia) or
extensive replacement of the marrow by tumor (such
as with leukemia).
• Alternatively, neutrophil production may be
suppressed while other blood lineages are unaffected.
This is most often caused by certain drugs or by
neoplastic proliferations of cytotoxic T cells and natural
killer (NK) cells (so-called “large granular lymphocytic
leukemia”).

5. • Increased granulocyte destruction. This can be
encountered with immune-mediated injury
(triggered in some cases by drugs) or in
overwhelming bacterial, fungal, or rickettsial
infections resulting from increased peripheral
use. Splenomegaly also can lead to the
sequestration and accelerated removal of
neutrophils.

6. Clinical Features
• They commonly take the form of ulcerating,
necrotizing lesions of the gingiva, floor of the
mouth, buccal mucosa, pharynx, or other sites
within the oral cavity (agranulocytic angina).
• In addition to local inflammation, systemic
symptoms usually are present consisting of
malaise, chills, and fever. Because of the danger
of sepsis, patients are started on broadspectrum
antibiotics covering both bacterial and fungal
infections at the first sign of infection.

7. Reactive Leukocytosis
• An increase in the number of white cells in the
blood is common in a variety of inflammatory
states caused by microbial and nonmicrobial
stimuli.

8. Causes of Leukocytosis

9. Infectious Mononucleosis
• Infectious mononucleosis is an acute, self-
limited disease of adolescents and young
adults that is caused by Epstein- Barr virus
(EBV), a member of the herpesvirus family.
• The infection is characterized by (1) fever, sore
throat, and generalized lymphadenitis and (2)
a lymphocytosis of activated, CD8+ T cells.

10. Pathogenesis
• Transmission to a seronegative “kissing cousin”
usually involves direct oral contact. It is
hypothesized that the virus initially infects
oropharyngeal epithelial cells and then spreads to
underlying lymphoid tissue (tonsils and
adenoids), where mature B cells are infected.
• The infection of B cells takes one of two forms. In
a minority of cells, the infection is lytic, leading to
viral replication and release of virions. More
commonly, the infection is nonproductive and the
virus persists in latent form as an
extrachromosomal episome.

11. Clinical Features.
• Infectious mononucleosis classically manifests
with fever, sore throat, and lymphadenitis, but
atypical presentations are not unusual.
• Ultimately, the diagnosis depends on the
following, in increasing order of specificity:
• (1) the presence of atypical lymphocytes in the
peripheral blood;
• (2) a positive heterophil reaction (Monospot
test);
• and (3) a rising titer of antibodies specific for EBV
antigens.

12. • In most patients, mononucleosis resolves within 4
to 6 weeks, but sometimes the fatigue lasts
longer. Occasionally, one or more complications
supervene.
• Perhaps the most common of these is hepatic
dysfunction, associated with jaundice, elevated
liver enzyme levels, disturbed appetite, and,
rarely, even liver failure. Other complications
involve the nervous system, kidneys, bone
marrow, lungs, eyes, heart, and spleen (including
fatal splenic rupture).

13. Reactive Lymphadenitis
• Infections and nonmicrobial inflammatory
stimuli often activate immune cells residing in
lymph nodes, which act as defensive barriers.
Any immune response against foreign antigens
can lead to lymph node enlargement
(lymphadenopathy).
• Infections causing lymphadenitis are varied
and numerous, and may be acute or chronic.

14. Acute Nonspecific Lymphadenitis
• This form of lymphadenitis may be isolated to
a group of nodes draining a local infection, or
be generalized, as in systemic infectious and
inflammatory conditions.
Chronic Nonspecific Lymphadenitis
• Depending on the causative agent, chronic
nonspecific lymphadenitis can assume one of
three patterns: follicular hyperplasia,
paracortical hyperplasia, or sinus histiocytosis.

15. Cat-Scratch Disease
• Cat-scratch disease is a self-limited lymphadenitis
caused by the bacterium Bartonella henselae. It is
primarily a disease of childhood; 90% of the patients
are younger than 18 years of age. It manifests with
regional lymphadenopathy, most frequently in the
axilla and the neck.
• The nodal enlargement appears approximately 2 weeks
after a feline scratch or, less commonly, after a splinter
or thorn injury.
• In most patients the lymph node enlargement
regresses during a period of 2 to 4 months. Rarely,
encephalitis, osteomyelitis, or thrombocytopenia may
develop in patients.

16. Hemophagocytic Lymphohistiocytosis
(HLH)
• HLH is an uncommon disorder in which a viral
infection or other proinflammatory exposures
trigger activation of macrophages throughout
the body, leading to phagocytosis of blood
cells and their precursors, cytopenias, and
symptoms related to systemic inflammation
and organ dysfunction.

17. • The involved genes and proteins are diverse, but
they share a common feature in that they are
required for the cytolytic function of CD8+ T cells
and NK cells.
• Owing to this defect in “killer lymphocytes,”
cytotoxic lymphocytes are unable to kill their
targets (e.g. virus infected cells) and remain
engaged with targeted cells for longer than
normal periods of time, leading to excessive
release of cytokines, such as interferon gamma,
that activate macrophages.

18. NEOPLASTIC PROLIFERATIONS OF
WHITE CELLS
• We will organize our discussion by dividing the
white cell neoplasms into four broad categories
based on the origin and differentiation state of
the tumor cells, as follows:
• Lymphoid neoplasms, which include certain
leukemias and the non-Hodgkin and Hodgkin
lymphomas. In many instances these tumors are
composed of cells resembling some normal stage
of lymphocyte differentiation, a feature that
serves as one of the bases for their classification.

19. • Myeloid neoplasms, which include certain
leukemias, myelodysplastic syndromes
(MDSs), and myeloproliferative neoplasms.
These tumors have in common an origin from
a hematopoietic stem cell or some other very
early hematopoietic progenitor, and they
typically involve the bone marrow.
• Histiocytic neoplasms, which include
proliferative lesions of macrophages and
dendritic cells. Of special interest is a
spectrum of proliferations of Langerhans cells
(Langerhans cell histiocytoses).

20. Lymphoid Neoplasms
• The numerous lymphoid neoplasms vary widely in their
clinical presentation and behavior, and thus present
challenges to students and clinicians alike.
• Some characteristically manifest as leukemias, with
involvement of the bone marrow and the peripheral
blood.
• Plasma cell tumors usually arise within the bones and
manifest as discrete masses, causing systemic
symptoms related to the production of a complete or
partial monoclonal immunoglobulin.
• Two groups of lymphomas are recognized: Hodgkin
lymphomas and non-Hodgkin lymphomas.

21. • As background for the subsequent discussion of
this classification, certain important principles
warrant consideration:
• B and T cell tumors often are composed of cells
that are arrested at or derived from a specific
stage of normal lymphocyte differentiation.
• Class switching and somatic hypermutation are
mistake-prone forms of regulated genomic
instability that place germinal center B cells at
relatively high risk for potentially transforming
mutations.

23. We will focus our discussion on a subset that are
particularly clinically important or pathogenically
illustrative:
• Precursor B and T cell lymphoblastic lymphoma/
• leukemia—commonly called acute lymphoblastic
leukemia (ALL)
• Chronic lymphocytic leukemia/small lymphocytic
lymphoma
• Follicular lymphoma
• Mantle cell lymphoma
• Burkitt lymphoma
• Multiple myeloma and related entities
• Hodgkin lymphoma

24. Precursor B and T Cell Neoplasms
Acute Lymphoblastic Leukemia/Lymphoma
• Acute lymphoblastic leukemia/lymphomas
(ALLs) are neoplasms composed of immature
B (pre-B) or T (pre-T) cells, which are referred
to as lymphoblasts. About 85% are B-ALLs,
which typically manifest as childhood acute
“leukemias.” The less common T-ALLs tend to
present in adolescent males as thymic
“lymphomas.”

25. Pathogenesis
• Many chromosomal aberrations seen in ALL
dysregulate the expression and function of
transcription factors that are required for the
normal differentiation of B and T cell
progenitors.

26. Clinical Features
ALL is an aggressive disease, and most patients
present within a few weeks of the onset of
symptoms. Among the most important signs
and symptoms are the following:
• Symptoms related to depression of marrow
function, including fatigue resulting from
anemia; fever, reflecting infections secondary
to neutropenia; and bleeding due to
thrombocytopenia.

27. • Mass effects caused by neoplastic infiltration,
including bone pain resulting from marrow
expansion and infiltration of the
subperiosteum; generalized
lymphadenopathy, splenomegaly, and
hepatomegaly; and in T-ALL, complications
related to compression of large vessels and
airways in the mediastinum
• Central nervous system manifestations
resulting from meningeal spread, such as
headache, vomiting, and nerve palsies

28. Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma
• Chronic lymphocytic leukemia (CLL) and small
lymphocytic lymphoma (SLL) are essentially
identical, differing only in the extent of peripheral
blood involvement.
• Somewhat arbitrarily, if the peripheral blood
lymphocyte count exceeds 5000 cells/μL, the
patient is diagnosed with CLL. Most cases fit the
diagnostic criteria for CLL, which is the most
common leukemia of adults in the Western
world. By contrast, SLL constitutes only 4% of
NHLs.

29. Follicular Lymphoma
• This relatively common tumor constitutes 40%
of the adult NHLs in the United States. Like
CLL/SLL, it occurs much less frequently in
Asian populations.
Pathogenesis
• Greater than 85% of follicular lymphomas
have a characteristic (14;18) translocation that
fuses the BCL2 gene on chromosome 18 to the
IgH locus on chromosome 14.