Pathology Diseases of White Blood Cells, Lymph Nodes, Spleen, & Thymus

AY 2018-2019 Dr. HA Saguil

1st Shifting Exam 03/23/2019

OUTLINE daughter cell

I. Development and Maintenance of Hematopoietic Tissues (p.1)
II. Disorders of White Blood Cells and Lymph Nodes (p.1)
III. Spleen (p.19)
IV. Thymus (p.21)
I. DEVELOPMENT AND MAINTENANCE OF
HEMATOPOEITIC TISSUES
Time Characteristics
• First appearance of blood cell
progenitors
• Long lived tissue macrophages
(e.g.microglial cells and Kupffer cells)-
derived from the yolk sac but
3rd week contribution of yolk sac to blood
embryogenesis formation is only transient
• Hematopoietic stem cells (HSCs)-
arise in the mesoderm of the
intraembryonic aorta/gonad/mesonephric
region weeks later
• HSCs migrate to the liver
- (becomes the chief site of blood cell
3rd month formation until before birth)
• HSC also reside at fetal placenta
4th month • HSC goes to bone marrow
• Marrow is haematopoietically active and
Birth
hepatic hematopoiesis dwindles
• Haematopoietically active marrow is
Puberty
found throughout the skeleton, then
restricts to axial skeleton
• About half of the marrow space is
Adults
haematopoietically active.
→ The newly committed cell lose the capacity for self renewal
and leads to terminal differentiation and death
→ As progenitors differentiate, they also proliferate more rapidly
in response to growth factors
→ Stem cell factor (KIT lgand) and FLT3-ligand-act through
receptors on very early committed cells
→ EPO, GM-CSF, G-CSF and Thrombopoeitin- act through
receptors expressed on committed progenitors
→ Feedback loops-tune marrow output for maintenance of
formed elements
• Many diseases alter the production of blood cells
→ Primary tumors-most important diseases that interfere with
marrow function
→ Genetic diseases, infections, toxins and nutritional
deficiencies as well as chronic inflammation can also
decrease blood cells in marrow.
• Tumors of hematopoietic origin are often associated with
mutations that block progenitor cell maturation or abrogate
their growth factor dependence
Net effect is an unregulated clonal expression of hematopoietic
elements replacing normal cells and spreads to other
hematopoietic tissues
II. DISORDERS OF WBC AND LYMPH NODES
A. LEUKOPENIA
• Usually results from reduced number of neutrophils
(neutropenia, granulocytopenia)
→ Lymphopenia- less common; most commonly observed in
advanced HIV; stems from lymphocyte redistribution rather
than decrease
→ Granulocytopenia- more common and often associated with
diminished granulocyte function
NEUTROPENIA / AGRANULOCYTOSIS

• Formed elements (red cells. Granulocytes, monocytes, platelets • Neutropenia can be caused by:
and lymphocytes)- have common origin from HSCs, pluripotent 1. inadequate or ineffective
cells that sit at the apex of a hierarchy of bone marrow granulopoiesis 2. increased destruction
progenitors. or sequestration of neutrophils in the
• HSCs give rise to several kinds of early progenitor cells with a periphery
restricted differentiation potential, such that they ultimately • Observed in:
produce mainly myeloid cells or lymphoid cells a. Suppression of hematopoietic
• Colony forming units (CFUs)- produce colonies composed of stem cells (anemia and infiltrative
specific kinds of mature cells when grown in culture marrow disorders)
• HSCs have two essential properties that are required for the b. Suppression of committed
maintenance of hematopoiesis: pluripotency and the capacity granulocytic precursors by
for self-renewal. exposure to certain drugs
c. Disease states assoc with
→ Pluripotency- ability of a single HSC to generate all mature
PATHOGENESIS ineffective hematopoiesis
blood cell
(megaloblastic anemia and
▪ When an HSC divides, at least one daughter cell must
myelodysplastic syndromes)
renew to avoid stem cell depletion
d. Rare congenital conditions (
→ Self-renewing divisions occur within a specialized marrow
Kostmann syndrome)
niche, in which stromal cells and secreted factors nurture and
• Occurs with
protect the HSCs
a. Immunologically mediated injury to
• The marrow response to short-term physiologic needs is
neutrophils (can be idiopathic,
regulated by hematopoietic growth factors through effects
immunologic and exposure to
on the committed progenitors
drugs)
→ Mature blood elements must continually be replenished b. Splenomegaly
→ Some HSCs give rise to multipotent progenitors-more c. Increased peripheral utilization
proliferative than HSCs but lesser self renewal capacity (bacterial, fungal, or rickettsial
→ Division of multipotent progenitors- give rise to at least one infection)

S4T2 Systemic Pathology Transers 1 of 24

 • Most common cause of
agranulocytosis is DRUG TOXICITY
• Signs and symptoms related to
infection includes malaise, chills and
fever followed by weakness and
CLINICAL
fatigability
• Agranulocytosis- infections are
FEATURES
overwhelming; may cause death
within hours/days
• Serious infections- neutrophil
count <500mm3
• Neutropenia - reduction in number of neutrophils in blood
• Agranulocytosis- clinically significant reduction in neutrophils
• Makes individual susceptible to bacterial and fungal infections
B. REACTIVE PROLIFERATION OF WBC AND LYMPH
NODES
LEUKOCYTOSIS
• Increase in the number of white cells in the blood
• Common reaction to a variety of inflammatory states
• Factors that influence Peripheral
Blood Leukocyte Count:
o Size of the myeloid and lymphoid
precursor and storage cell pools in
bone marrow, thymus, circulation
and peripheral tissues
o Rate of release of cells from
storage pools into circulation
o Proportion of cells that are
adherent to blood vessel walls at
any time (marginal pool)
o Rate of extravasation of cells from
the blood into tissues
• Leukocyte hemostasis is maintained
by:
o Cytokines
o Growth factors
o Adhesion molecules
o Through their effects on their
commitment, proliferation,
differentiation and extravasation of
leukocytes and their progenitors
• In sepsis or severe inflammatory
PATHOGENESIS
disorders (ex. Kawasaki disease),
leukocytosis is often accompanied by
morphologic changes in the
neutrophils, such as toxic granulations,
Döhle bodies, and cytoplasmic
vacuoles
o Toxic granules - coarser and
darker than the normal neutrophilic
granules, represent abnormal
azurophilic (primary) granules
o Döhle bodies are patches of
dilated endoplasmic reticulum that
appear as sky-blue cytoplasmic
“puddles.”
• Acute viral infections, particularly in
children, can cause the appearance of
large numbers of activated
lymphocytes that resemble neoplastic
lymphoid cells
• In severe infections, many immature
granulocytes appear in the blood,
mimicking a myeloid leukemia
(leukemoid reaction)
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
LYMPHADENITIS
• Following their initial development from precursors in the central
(primary) lymphoid organs, (the bone marrow for B cells) and
(the thymus for T cells), lymphocytes circulate through the blood
and, under the influence of specifc cytokines and chemokines,
home to lymph nodes, spleen, tonsils, adenoids, and
Peyer’s patches, which constitute the peripheral (secondary)
lymphoid tissues
• Lymph nodes
→ Most widely distributed and easily accessible lymphoid tissue
→ The activation of resident immune cells leads to morphologic
changes in lymph nodes
→ Within several days of antigenic stimulation, the primary
follicles enlarge and develop pale-staining germinal centers
• Germinal Centers
→ Highly dynamic structures in which B cells acquire the
capacity to make high-affinity antibodies against specific
antigens
• Paracortical T-cell zones
→ May also undergo hyperplasia
• The degree and pattern of the morphologic changes are
dependent on the inciting stimulus and the intensity of the
response
→ Trivial injuries - subtle changes
→ Significant infections -nodal enlargement and sometimes
leave residual scarring
• Lymph nodes in adults are almost never “normal” or “resting,”
and it is often necessary to distinguish morphologic changes
secondary to past experience from those related to present
disease
A. Acute Nonspecific Lymphadenitis
• Cervical region acute lympadenitis
→ Most often due to drainage of microbes or microbial
products from infections of the teeth or tonsils
• Axillary or Inguinal regions
→ Most often caused by infections in the extremities
• Mesenteric lymph nodes
→ Draining acute appendicitis
→ Other self-limited infections may also cause acute
mesenteric adenitis and induce symptoms mimicking acute
appendicitis, a differential diagnosis that plagues the surgeon
• Systemic viral infections (particularly in children) and
bacteremia often produce acute generalized lymphadenopathy
• The nodes are swollen, gray-red and
engorged
• Microscopically, there is prominence
of large reactive germinal centers
containing numerous mitotic figures
• With less severe reactions, scattered
neutrophils infiltrate about the follicles
and accumulate within the lymphoid
PATHOGENESIS sinuses
• Endothelial cells lining the sinuses
undergo hyperplasia
• Enlarged and painful nodes and the
overlying skin is red
• Sometimes, suppurative infections
can produce draining sinuses
• Healing of such lesions is associated
with scarring
B. Chronic Nonspecific Lymphadenitis
• Lymph nodes in chronic reactions are nontender, as nodal
enlargement occurs slowly over time and acute inflammation
with associated tissue damage is absent
2 of 24
(continuation of Chronic Nonspecific Lymphadenitis)
• Common in inguinal and axillary nodes, which drain relatively
large areas of the body and are frequently stimulated by
immune reactions to trivial injuries and infections of the
extremities
• Promote the appearance of organized collections of immune
cells in nonlymphoid tissues (tertiary lymphoid organs)
→ A classic example is that of chronic gastritis caused by
Helicobacter pylori, in which aggregates of mucosal
lymphocytes are seen that simulate the appearance of
Peyer patches
→ Rheumatoid arthritis, in which B- cell follicles often appear in
the inflamed synovium
→ Lymphotoxin, a cytokine required for the formation of normal
Peyer patches, is probably involved in the establishment of
these extranodal” inflammation-induced collections of
lymphoid cells
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
• Marked by cytopenias and s/sx of systemic inflammation related
to macrophage activation
• Also called Macrophage Activation Syndrome
• Some forms are familial and may appear early in life, even in
infants, while other forms are sporadic and may affect people of
any age.
• Systemic activation of macrophages and
CD8+ cytotoxic T cells
• The activated macrophages
phagocytose blood cell progenitors in
the marrow and formed elements in the
peripheral tissues, while the “stew” of
mediators released from macrophages
and lymphocytes suppress
hematopoiesis and produce symptoms
of systemic inflammation
• These effects lead to cytopenias and a
PATHOGENESIS
shock-like picture, sometimes referred to
as “cytokine storm” or the systemic
inflammatory response syndrome
• The most common trigger for HLH is
infection, particularly with Epstein-Barr
virus (EBV)
• Most patients present with an acute
febrile illness associated with
splenomegaly and hepatomegaly
• Hemophagocytosis is usually seen on
bone marrow examination, but is neither
suffcient nor required to make the
diagnosis
• Anemia, thrombocytopenia, and
CLINICAL very high levels of plasma ferritin and
FEATURES soluble IL-2 receptor,
both indicative of severe
inflammation, as well as elevated
liver function tests and triglyceride
levels, both related to hepatitis
• Coagulation studies may show
evidence of disseminated
intravascular coagulation which can
lead to death
• “Mild” chemotherapy
• Patients with germline mutations that
TREATMENT
cause HLH or who have
persistent/resistant disease are
candidates for hematopoietic stem
cell transplantation
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
C. NEOPLASTIC PROLIFERATIONS OF WBC
CATEGORY CHARACTERISTICS
• B-cell, T-cell, and NK-cell origin
• Phenotype of the neoplastic
LYMPHOID
cell closely resembles that of a
NEOPLASMS
particular stage of normal
lymphocyte maturation
• Arise from early hematopoietic
progenitors
1. Acute myeloid leukemias
• Immature progenitor cells
accumulate in the bone marrow
(↑ Immature cells in marrow)
2. Myelodysplastic syndromes
• Associated with ineffective
hematopoiesis and resultant
MYELOID peripheral blood cytopenias (↓
NEOPLASMS mature cells in blood)
3. Chronic myeloproliferative
disorders
• Increased production of one or
more terminally
differentiated myeloid elements
(e.g., granulocytes) usually
leads to elevated peripheral
blood counts (↑ mature cells in
blood)
• Uncommon proliferative lesions
of macrophages and dendritic
cells
HISTIOCYTOSES • Langehans Cell
Histiocytoses
o Langerhans cell (immature
dendritic cell) proliferation.
ETIOLOGIC & PATHOGENIC FACTORS IN WBC
NEOPLASIA
A. Chromosomal Translocations and other
Acquired Mutations
• Mutated or altered genes often play crucial roles in the
development, growth, or survival of the normal counterpart of
the malignant cell.
→ Certain mutations are strongly associated with specific tumor
types
→ Mutation produces a “dominant-negative” protein that
interferes with a normal function (a loss of function)
→ In others the result is an inappropriate increase in some
normal activity (a gain of function).
• Oncoproteins created by genomic aberrations often block
normal maturation, turn on pro-growth signaling pathways, or
protect cells from apoptotic cell death.
→ Many oncoproteins cause an arrest in differentiation, often at
a stage when cells are proliferating rapidly.
→ Example: In acute leukemias, dominant-negative oncogenic
mutations involving transcription factors are often present
that interfere with early stages of lymphoid or myeloid cell
differentiation.
→ Other mutations in transcriptional regulators seem to directly
enhance the self-renewal of tumors cells, giving such cells
stem-cell–like properties.
→ Mutations that inhibit apoptosis are prevalent in certain
hematologic malignancies
• Proto-oncogenes are often activated in lymphoid cells by errors
that occur during antigen receptor gene rearrangement and
diversification.
→ Oncogenic mutations occur most frequently in germinal
3 of 24
 center B cells during attempted antibody diversification • Due to exposure to carcinogens (i.e. benzene in tobacco
→ B cells enter upregulate the expression of activation-induced smoke)
cytosine deaminase (AID)
▪ A specialized DNA-modifying enzyme that is essential for
2 types of immunoglobulin (Ig) gene modifications: LYMPHOID NEOPLASMS
▪ Class switching: an intragenic recombination event in
which the IgM heavy-chain constant gene segment is A. Definitions and Classifications
replaced with a different constant segment (e.g., IgG3),
leading to a switch in the class (isotype) of antibody
• Leukemia
produced
→ Neoplasms that present with widespread involvement of the
▪ Somatic hypermutation: which creates point mutations
bone marrow and (usually, but not always) the peripheral
within Ig genes that may increase antibody affinity for
blood.
antigen
• Lymphoma
→ AID enzyme is also responsible for some oncoprotein
translocation resulting to activation of proto-oncogenes → Used for proliferations that arise as discrete tissue masses.
▪ c-MYC →activated in germinal center B-cell lymphomas → Hodgkin lymphoma
by chromosomal translocations → Non-hodgkin lymphomas (nhls).
▪ BCL6 → activated in germinal center B-cell lymphomas by • Plasma cell neoplasms
point mutations → Most often arise in the bone marrow and only infrequently
involve lymph nodes or the peripheral blood.
B. Inherited Gene Factors • Clinical presentation of lymphoid neoplasms is determined by
the anatomic distribution of disease.
→ Two thirds of nhls and virtually all hodgkin lymphomas
• Genetic diseases that promote genomic instability and
present as enlarged nontender lymph nodes (often > 2 cm).
predispose at increased risk of acute leukemia:
→ The remaining one third of nhls present with symptoms
→ Bloom syndrome
related to the involvement of extranodal sites (e.g., skin,
→ Fanconi anemia stomach, or brain).
→ Ataxia telangiectasia → Lymphocytic leukemias have signs and symptoms related to
→ Down syndrome (trisomy 21) the suppression of normal hematopoiesis by tumor cells in
→ Type I neurofibromatosisAll caps the bone marrow.
→ Multiple myeloma causes bony destruction of the skeleton
C. Viruses and often presents with pain due to pathologic fractures.
→ Plasma cell tumors are related to secretion of Igs
Lymphotopic → Hodgkin lymphoma is associated with release of
Associated Lymphoma inflammatory cytokines.
Viruses
Human T-cell • Adult T-cell leukemia/ lymphoma.
leukemia The WHO Classification of Lymphoid Neoplasms
virus-1 (HTLV-1) • Uses morphologic, immunophenotypic, genotypic, and
clinical features
Epstein-Barr virus • Burkitt lymphoma • Grouped lymphoid neoplasms into 5 broad categories,
(EBV) • Hodgkin lymphoma (HL) which are separated according to the cell of origin:
• B-cell lymphomas
• Rare NK-cell lymphomas 1. Precursor B-cell neoplasms (neoplasms of immature
Kaposi sarcoma • Unusual B-cell lymphoma B cells)
herpesvirus/human presenting as a malignant 2. Peripheral B-cell neoplasms (neoplasms of mature B
herpesvirus-8 effusion in the pleural cavity cells)
(KSHV/HHV-8) 3. Precursor T-cell neoplasms (neoplasms of immature
T cells)
4. Peripheral T-cell and NK-cell neoplasms
D. Chronic Inflammation (neoplasms of mature T cells and NK cells)
5. Hodgkin lymphoma (neoplasms of Reed-Sternberg
cells and variants)
Agents Associated Lymphoma
H. pylori infection Gastric B-cell lymphomas
Gluten-sensitive enteropathy Intestinal T-cell lymphomas,
HIV infection B-cell lymphomas that may
arise within any organ
Severe T-cell immunodeficiency B-cell lymphomas (particularly
those associated with EBV and
KSHV/HHV-8)

E. Iatrogenic Factors
• Ironically, radiation therapy and certain forms of chemotherapy
used to treat cancer increase the risk of subsequent myeloid
and lymphoid neoplasms.
• Due to the mutagenic effects of ionizing radiation and
chemotherapeutic drugs on hematolymphoid progenitor cells.

F. Smoking
• The incidence of acute myeloid leukemia is increased 1.3- to 2-
fold in smokers

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 4 of 24
 Figure 1. Origin of lymphoid neoplasms

Principles of Lymphoid Neoplasms

• Histologic examination of lymph nodes or other involved
tissues is required for diagnosis
• Antigen receptor gene rearrangement generally precedes
transformation of lymphoid cells; hence, all daughter cells
derived from the malignant progenitor share the same
antigen receptor gene configuration and sequence, and
synthesize identical antigen receptor proteins (either Igs or T-
cell receptors).
→ Analyses of antigen receptor genes and their protein
products can be used to distinguish reactive (polyclonal) and
malignant (monoclonal) lymphoid proliferations.
• Most lymphoid neoplasms resemble some recognizable
stage of B- or T-cell differentiation, a feature that is used in
their classification.
• The vast majority (85% to 90%) of lymphoid neoplasms are of
B-cell origin, with most of the remainder being T-cell tumors;
only rarely are tumors of NK cell origin encountered.

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 5 of 24
• Lymphoid neoplasms are often associated with immune
abnormalities.
o Loss of protective immunity (susceptibility to
infection) and a breakdown of tolerance • Morphology:
(autoimmunity) can be seen, sometimes in the same → In leukemic presentations, the marrow is hypercellular and
patient.
packed with lymphoblasts, which replace the normal
o Individuals with inherited or acquired
immunodeficiency are at high risk of developing marrow elements.
certain lymphoid neoplasms, particularly those → Mediastinal thymic masses (50% to 70% of T-ALLs) are
caused by oncogenic viruses (e.g., ebv). also more likely to be associated with lymphadenopathy and
• Neoplastic b and t cells tend to recapitulate the behavior of splenomegaly.
their normal counterparts. → Scant basophilic cytoplasm and nuclei somewhat larger than
→ Like normal lymphocytes, neoplastic b and t cells home to those of small lymphocytes
certain tissue sites, leading to characteristic patterns of → Nuclear chromatin is delicate and finely stippled, and nucleoli
involvement. are usually small and often demarcated by a rim of
→ For example, follicular lymphomas home to germinal centers condensed chromatin.
in lymph nodes, whereas cutaneous t-cell lymphomas home → Nuclear membrane is deeply subdivided, imparting a
to the skin. Like their normal counterparts, particular convoluted appearance.
adhesion molecules and chemokine receptors govern the → Interspersed macrophages ingesting apoptotic tumor cells
homing of the neoplastic lymphoid cells. imparts a “starry sky” appearance
→ Exceptions to this rule include: → Because of their different responses to chemotherapy, ALL
▪ Hodgkin lymphomas, which are sometimes restricted to must be distinguished from acute myeloid leukemia (AML)
one group of lymph nodes ▪ AML is a neoplasm of immature myeloid cells that can
▪ Marginal zone B-cell lymphomas, which are often cause identical signs and symptoms.
restricted to sites of chronic inflammation. ▪ Compared with myeloblasts, lymphoblasts have more
condensed chromatin, less conspicuous nucleoli, and
• Hodgkin lymphoma spreads in an orderly fashion, whereas smaller amounts of cytoplasm that usually lacks granules.
most forms of NHL spread widely early in their course in a ▪ Definitive diagnosis still relies on stains performed with
less predictable fashion. antibodies
→ Lymphoma staging is of most useful in guiding therapy in ▪ specific for B- and T-cell antigens
Hodgkin lymphoma. → Histochemical stains are also helpful, in that (in contrast to
myeloblasts) lymphoblasts are myeloperoxidasenegative and
B. PRECURSOR B- AND T- CELL NEOPLASMS often contain periodic acid-Schiff–positive cytoplasmic
material.
Diagnosis Cell of Genotype Salient
Origin Clinical • Pathogenesis
Features → Up to 70% of T-ALLs have gain-of-function mutations in
B-cell acute Bone Diverse Predominantly
NOTCH1, a gene that is essential for T-cell development.
lymphoblastic marrow chromosomal children;
leukemia/lym precursor translocations; symptoms → high fraction of B-ALLs have loss-of-function mutations in
phoma* B cell t(12;21) relating to genes that are required for B-cell development, such as
involving marrow PAX5, E2A, and EBF, or a balanced t(12;21) involving the
RUNX1 and replacement genes ETV6 and RUNX1, two genes that are needed in very
ETV6 and early hematopoietic precursors.
present in pancytopenia;
→ mutations disturb the differentiation of lymphoid precursors
25% aggressive
T-cell acute Precursor T Diverse Predominantly → promote maturation arrest→ induce increased self-
lymphoblastic cell (often chromosomal adolescent renewal, a stem cell–like phenotype.
leukemia/lym of thymic translocations, males; thymic → single mutations are not sufficient to produce ALL. (Early
phoma origin) NOTCH1 masses and returns suggest that fewer than 10 mutations are sufficient to
mutations variable bone produce full-blown ALL)
(50%-70%) marrow
→ Approximately 90% of ALLs have numerical or structural
involvement;
aggressive chromosomal changes.
→ Most common is hyperploidy (>50 chromosomes), but
Acute Lymphoblastic Leukemia/Lymphoma (ALL) hypoploidy and a variety of balanced chromosomal
translocations are also seen.
• Neoplasms composed of immature B (pre-B) or T (pre-T)
cells, which are referred to as lymphoblasts.
• Immunophenotype
• B-ALLs (85%): manifest as childhood acute “leukemias.”
→ Immunostaining for terminal deoxynucleotidyl-transferase
• T-ALLs (~15%) tend to present in adolescent males as thymic
(TdT) (specialized DNA polymerase expressed only in pre-B
“lymphomas.”
and pre-T cells)
• Most common cancer of children.
• 3 times more common in whites than black Markers
• More frequent in boys than girls B-ALLs Very immature B-ALLs
• Hispanic – highest incidence of any ethnic group • CD19, PAX5
• Less frequently in adults of all ages Mature “late pre-B” ALLs

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 6 of 24
 • CD10, CD19, CD20,
IgM heavy chain (μ • Prognosis
chain)
→ With aggressive chemotherapy about 95% of children with
T-ALLs More immature T-ALLs
• CD1, CD2, CD5, CD7 ALL obtain a complete remission, and 75% to 85% are
“Late” pre-T ALLs cured.
• CD3, CD4 CD8 → remains the leading cause of cancer deaths in children, and
only 35% to 40% of adults are cured.
• Clinical Features → Factors for worse prognosis:
→ Abrupt stormy onset within days to a few weeks of the first ▪ <2 years old (strong association of infantile ALL with
symptoms translocations involving MLL gene)
→ Symptoms related to depression of marrow function ▪ Presentation in adolescence or adulthood
▪ fatigue due to anemia ▪ Peripheral blood blast counts >100,000 (reflects high
▪ feversecondary to neutropenia tumor burden)
▪ bleeding due to thrombocytopenia → Factors for favorable prognosis:
→ Mass effects caused by neoplasticinfiltration ▪ 2-10 years old
▪ bone pain resulting from marrow expansion and infiltration ▪ Low white cell count
of the subperiosteum ▪ Hyperdiploidy
▪ generalized lymphadenopathy ▪ Trisomy of chromosomes 4, 7, 10
▪ splenomegaly ▪ Presence of t(12;21)
▪ hepatomegaly → Philadelphia chromosome T(9;22) creates a fusion gene →
▪ testicular enlargement constitutively active BCR-ABL tyrosine kinase (stronger
▪ In T-ALL, complications related to compression of large tyrosine activity in B-ALL than CML)
vessels and airways in the mediastinum ▪ Treatment: BCR-ABL kinase inhibitor + conventional
→ Central nervous system manifestations chemotherapy
▪ headache ▪ Older adults cannot tolerate very intensive chemotherapy
▪ vomiting that are curative in children
▪ nerve palsies resulting from meningeal spread
C. PERIPHERAL B-CELL NEOPLASMS

Chronic Lymphocytic Leukemia (CLL) and Small

Lymphocytic Lymphoma (SLL)
• Differ only in degree of peripheral blood lymphocytosis
• CLL: Absolute Lymphocyte count >5000cmm
→ MOST COMMON LEUKEMIA OF ADULTS IN THE
WESTERN WORLD
→ Median age of diagnosis: 60y/o
→ 2:1 Male predominance
• SLL:
→ 4% ONLY of all Non-Hodgkins’ Lymphoma

• Pathogenesis, Morphology, and Clinical Presentation

Figure 2. Acute lymphoblastic leukemia/lymphoma
→ Most common genetic anomalies are deletions of 13q14.3, 11q,
17p, and trisomy 12q
→ Proliferation Centers- PATHOGNOMONIC FOR CLL/SLL
→ SMUDGE CELLS- disruption of cells during smears
→ CLL/SLL disrupts normal immune function by uncertain
mechanisms (ie Hypogammaglobulinemia→predisposes to
bacterial infections)
→ Richter Syndrome-transformation to Diffuse Large B Cell
Lymphoma in 5-10% of patients

Follicular Lymphoma
• In the US, most common form of indolent NHL
• Usually presents in middle age
• Affects males and females equally
• LESS COMMON in Europe; RARE in Asian populations

• Pathogenesis, Morphology, and Clinical Presentation

→ Follicular Lymphoma likely arises from germinal center B cells,
Figure 3. Burkitt lymphoma.
and strongly associated with chromosomal translocations of
BCL2

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 7 of 24
→ In 90% of cases, there were mutations in the MLL2 gene
(encodes for histone methyltransferase, regulating gene
expression)
→ Two types of cells are present: Centrocytes (small cells with
cleaved nuclear contours and little cytoplasm) and
Centroblasts (larger cells with open nuclear chromatin, several
nucleolei, and modest amts of cytoplasm)
→ Centrocytes > Centroblasts
→ Bone marrow is involved in 85% of cases
→ 30-50% of cases transform to Diffuse Large B-Cell
Lymphoma
Diffuse Large B-Cell Lymphoma (DLBCL)
• Most common form of NHL
• Slight predominance in males
• Median age is 60y/0
• Expresses IgG, CD19 and CD20, with variable expression of
CD10 and BCL6
• Subtypes
→ Immunodeficiency-associated large B Cell Lymphoma- in T-
cell immunodeficiency (eg in HIV)
→ Primary Effusion Lymphoma- malignant pleural, or ascitic
effusion, mostly in HIV or elderly patients (HHV8 is involved)
• Pathogenesis, Morphology, and Clinical Presentation
→ Attributed to dysregulation of BCL6, a DNA-binding Zinc-finger
transcriptional repressor that is required for the formation of
normal germinal centers
→ 10-20% of tumors are associated with t(14;18)→overexpression
of the antiapoptotic BCL2 (as in Follicular lymphoma)
→ 5% of DLBCLs are associated with translocations involving
MYC (as in Burkitt’s Lymphoma), and are treated similarly as
Burkitt’s Lymphoma
→ Deep sequencing of DLBCL genomes identified mutations in
histone acetyltransferases such as p300 and CREBP.
→ Features: Large Cell Size, and diffuse pattern of growth
→ Presents as rapidly enlarging mass at a nodal or extranodal site
→ Waldeyer Ring (lymphatic tissue, including tonsils and
adenoids) is commonly involved
→ Involvement of liver or spleen → destructive masses
Burkitt Lymphoma
• Very aggressive tumor of mature B Cells that usually arises at
extranodal sites
• Fastest growing human tumor
• Strongly associated with translocations involving MYC gene
(regulates aerobic glycolysis, aka Warburg effect→ synthesis of
all building blocks, lipids, nucleotides, and proteins for growth
and cell division)
• Unlike other tumors of germinal center origin, BL mostly fails to
express antiapoptotic protein BCL2
• Subtypes
→ African (endemic) Burkitt Lymphoma
→ Sporadic (nonendemic) Burkitt Lymphoma
→ Subset of aggressive lymphomas occurring in HIV patients
• Pathogenesis, Morphology, and Clinical Presentation
→ All forms of Burkitt’s Lymphoma are highly associated with
translocations of MYC gene on chromosome 8→ Inc. MYC
protein levels
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
→ All endemic (AFRICAN) Burkitt Lymphomas are latently
infected with EBV (also present in 25% of HIV-associated
tumors, and 15-20% of sporadic cases
→ Tumor exhibits HIGH mitotic index with numerous apoptotic
cells
→ Starry Sky pattern- pathognomonic for these phagocytes due to
abundant cytoplasm
→ With bone marrow involvement: cells with royal blue
cytoplasm with clear cytoplasmic vacuoles
→ Both endemic and sporadic Burkitt lymphoma are found mainly
in children and young adults
→ Endemic BL often presents as a mass of the mandible, and
involves kidneys, ovaries, and adrenal glands
→ Sporadic BL often involves ileocecum and peritoneum
Plasma Cell Neoplasms and Related Disorders
• These B-Cell proliferations contain neoplastic plasma cells
which always secrete monoclonal Ig (M component;
myeloma) or Ig fragment, acting as tumor markers
• Dyscrasias- collective term for plasma cell neoplasm; accounts
for 15% of deaths by lymphoid neoplasms
• Multiple Myeloma- most common and deadly lymphoid
neoplasm
• Neoplastic cells often synthesize excess light chains along with
complete Igs, excreted in urine, termed Bence-Jones Proteins
• Clinicopathologic entities
→ Multiple Myeloma
→ Waldenstrom Macroglobulinemia’
→ Heavy Chain disease and Mediterranean lymphoma
→ Primary or immunocyte-associated amyloidosis
→ Monoclonal gammopathy of undetermined significance (MGUS)
• Multiple Myeloma
→ Plasma cell neoplasm commonly associated with lytic bone
lesions, hypercalcemia, renal failure, and acquired immune
abnormalities
→ Incidence higher in men and in those of African descent
→ Associated with frequent rearrangements involving IgH locus
and various proto-oncogenes
→ Factors produced by neoplastic plasma cells mediate bone
destruction (major pathologic feature)
→ Usually presents as destructive plasma cell tumors
(plasmacytomas) involving axial skeleton
→ Bone lesions appear as punched-out defects
→ Plasmablasts and bizarre, multinucleated cells may
predominate
→ Flame Cells- cells with red cytoplasms
→ Mott cells- with multiple grapelike cytoplasmic droplets, and
cells with a variety of other inclusions, including fibrils,
crystalline rods, and globules
→ Globular inclusions: Russell bodies (cytoplasmic) and
Dutcher bodies (nuclear)
→ Roleaux formation may be observed (RBCs in linear array)
→ May give rise to Plasma Cell leukemia
→ Myeloma kidney- due to Bence-Jones proteins
• Solitary Myeloma (Plasma Cytoma)
→ Solitary lesion of bone or soft tissue
→ Occur in the same locations
→ Extraosseous lesions are often located in the lungs,
oronasopharynx, or nasal sinuses.
8 of 24
 → Modest elevations of M proteins in the blood or urine may be
found in some patients.
→ Solitary osseous plasmacytoma almost inevitably progresses
to multiple myeloma, but this can take 10 to 20 years or
longer.
→ Extraosseous plasmacytomas, particularly those involving
the upper respiratory tract, are frequently cured by local
resection.
• Smoldering Myeloma
→ Defines a middle ground between multiple myeloma and
monoclonal gammopathy of uncertain significance.
→ Plasma cells make up 10% to 30% of the marrow cellularity,
and the serum M protein level is greater than 3 gm/dL, but
patients are asymptomatic.
→ About 75% of patients progress to multiple myeloma over a
15-year period
• Monoclonal Gammopathy of Uncertain Significance
→ Most common plasma cell dyscrasia, occurring in about 3%
of persons older than 50 years of age and in about 5% of
individuals older than 70 years of age.
→ Patients are asymptomatic and the serum M protein level is
less than 3 gm/dL.
→ Approximately 1% of patients with MGUS develop a
symptomatic plasma cell neoplasm, usually multiple
myeloma, per year.
→ Clonal plasma cells in MGUS contain many of the same
chromosomal translocations and deletions that are found in
fullblown multiple myeloma
• Lymphoplasmacytic Lymphoma
→ B-cell neoplasm of older adults that usually presents in the
sixth or seventh decade of life.
→ With superficial resemblance to CLL/SLL but differs in that a
substantial fraction of the tumor cells undergo terminal
differentiation to plasma cells.
→ Plasma cell component secretes monoclonal IgM, often in
amounts sufficient to cause a hyperviscosity syndrome
known as Waldenström macroglobulinemia.
→ Pathogenesis
▪ Associated with acquired mutations in MYD88 -
encodes an adaptor protein that participates in signaling
events that activate NF-κb and also augment signals
downstream of the B-cell receptor (Ig) complex, both of
which may promote the growth and survival of the tumor
cells.
→ Immunophenotype
▪ Lymphoid component expresses B-cell markers such as
CD20 and surface Ig
▪ Plasma cell component secretes the same Ig that is
expressed on the surface of the lymphoid cells. Usually
IgM but can also be IgG or IgA.
→ Clinical Features
▪ Weakness, fatigue, and weight loss
▪ Lymphadenopathy, hepatomegaly, and splenomegaly,
anemia
▪ Autoimmune hemolysis caused by cold agglutinins, igm
antibodies that bind to red cells at temperatures of less
than 37°c.
▪ Igm-secreting tumors greatly increases the viscosity
of the blood, giving rise to a hyperviscosity
syndrome.
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
▪ Visual impairment associated with venous congestion,
which is reflected by striking tortuosity and distention of
retinal veins; retinal hemorrhages
▪ Neurologic problems such as headaches, dizziness,
deafness, and stupor
▪ Bleeding related to the formation of complexes between
macroglobulins and clotting factors as well as interference
with platelet functions
▪ Cryoglobulinemia resulting from the precipitation of
macroglobulins at low temperatures, which produces
symptoms such as raynaud phenomenon and cold
urticaria
▪ Incurable progressive disease
▪ Tumor growth can be controlled for a time with low doses
of chemotherapeutic drugs and immunotherapy with anti-
CD20 antibody.
→ Morphology
▪ Marrow contains an infiltrate of lymphocytes, plasma
cells, and plasmacytoid lymphocytes in varying
proportions, often accompanied by mast cell hyperplasia
▪ Some tumors also contain a population of larger lymphoid
cells with more vesicular nuclear chromatin and prominent
nucleoli.
▪ Periodic acid-schiff-positive inclusions containing Ig are
frequently seen in the cytoplasm (Russell bodies) or the
nucleus (Dutcher bodies) of some of the plasma cells
Figure 4. Lymphoplasmacytic Lymphoma
Mantle Cell Lymphoma
• Usually presents in the fifth to sixth decades of life and shows a
male predominance.
• Tumor cells closely resemble the normal mantle zone B
cells that surround germinal centers.
• Pathogenesis
→ Usually presents in the fifth to sixth decades of life and
shows a male predominance.
→ Tumor cells closely resemble the normal mantle zone B cells
that surround germinal centers.
→ Have an (11;14) translocation involving the IgH locus on
chromosome 14 and the cyclin D1 locus on chromosome
11 that leads to overexpression of cyclin D1.
• Immunophenotype
→ Express high levels of cyclin D1
→ Most tumors are also express CD19, CD20, and
moderately high levels of surface Ig (usually IgM and IgD
with κ or λ light chain).
9 of 24
 → It is usually CD5+ and CD23−, which help to distinguish it
from CLL/SLL.
→ The IgH genes lack somatic hypermutation, supporting an
origin from a naive B cell.
• Clinical features
→ Most common presentation is painless
lymphadenopathy
→ Symptoms related to involvement of the spleen (present in
~50% of cases) and gut are also common.
→ Prognosis is poor; the median survival is only 3 to 4 years.
→ Not curable with conventional chemotherapy, and most
patients eventually succumb to organ dysfunction caused by
tumor infiltration.
→ Blastoid variant and a “proliferative” expression profiling
signature are associated with even shorter survivals.
→ Hematopoietic stem cell transplantation and proteasome
inhibitors are newer therapeutic approaches
• Morphology
→ Nodal tumor cells may surround reactive germinal centers to
produce a nodular appearance at low power, or diffusely
efface the node.
→ Typically, the proliferation consists of a homogeneous
population of small lymphocytes with irregular to
occasionally deeply clefted (cleaved) nuclear contours
→ Large cells resembling centroblasts and proliferation centers
are absent, distinguishing mantle cell lymphoma from
follicular lymphoma and CLL/SLL, respectively.
→ nuclear chromatin is condensed, nucleoli are inconspicuous,
and the cytoplasm is scant.
→ Tumors composed of intermediate-sized cells with more
open chromatin
Figure 5. Mantle Cell Lymphoma
Marginal Cell Lymphoma
• Heterogeneous group of B-cell tumors that arise within lymph
nodes, spleen, or extranodal tissues.
• The extranodal tumors were initially recognized at mucosal sites
and are often referred to as mucosa-associated lymphoid
tumors (or “MALTomas”).
• Tumor cells show evidence of somatic hypermutation and are
considered to be of memory B-cell origin.
• Pathogenesis:
→ They often arise within tissues involved by chronic
inflammatory disorders of autoimmune or infectious
etiology
→ They remain localized for prolonged periods, spreading
systemically only late in their course.
→ They may regress if the inciting agent (e.g., Helicobacter
pylori) is eradicated.
→ The disease begins as a polyclonal immune reaction. With
the acquisition of still-unknown initiating mutations, a B-cell
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
clone emerges that still depends on antigen-stimulated T-
helper cells for signals that drive growth and survival.
→ Tumors may acquire additional mutations that render their
growth and survival antigen-independent, such as the
(11;18), (14;18), or (1;14) chromosomal translocations,
which are relatively specific for extranodal marginal zone
lymphomas.
→ All of these translocations up-regulate the expression and
function of BCL10 or MALT1, protein components of a
signaling complex that activates NF-κb and promotes the
growth and survival of B cells.
Hairy Cell Lymphoma
• Distinctive B-cell neoplasm constitutes about 2% of all
leukemias.
• It is predominantly a disease of middle-aged white males, with
a median age of 55 and a male-to-female ratio of 5:1
• Pathogenesis
→ Associated in more than 90% of cases with activating point
mutations in the serine/threonine kinase BRAF, which is
positioned immediately downstream of RAS in the MAPK
signaling cascade
→ The specific mutation, a valine to glutamate substitution at
residue 600, is also found in diverse other neoplasms,
including many melanomas and Langerhans cell histiocytosis
• Immunophenotype
→ Express the pan-B-cell markers CD19 and CD20, surface
Ig (usually IgG), and certain relatively distinctive
markers, such as CD11c, CD25, CD103, and annexin A1
supporting an origin from a naive B cell.
Figure 6 Hairy Cell Lymphoma (Phase-Contrast Microscope)
Figure 7. Hairy Cell Lymphoma (Stained Smear)
• Clinical Features
→ Splenomegaly, hepatomegaly, lymphadenopathy
→ About one third of those affected present with infections.
→ There is an increased incidence of atypical mycobacterial
infections, possibly related to frequent unexplained
monocytopenia.
→ Exceptionally sensitive to “gentle” chemotherapeutic
regimens, which produce long lasting remissions.
→ Tumors often relapse after 5 or more years, yet generally
respond well when retreated with the same agents
10 of 24
 → BRAF inhibitors appear to produce excellent responses in
tumors that have failed conventional chemotherapy.
→ The overall prognosis is excellent
→ Leukemic cells with fine hairlike
→ projections that are best recognized under the phase-
contrast microscope
→ On routine peripheral blood smears, hairy cells have round,
oblong, or reniform nuclei and moderate amounts of pale
blue cytoplasm with threadlike or bleblike extensions
→ The number of circulating cells is highly variable.
→ The marrow is involved by a diffuse interstitial infiltrate of
cells with oblong or reniform nuclei, condensed chromatin,
and pale cytoplasm.
→ Because these cells are enmeshed in an extracellular matrix
composed of reticulin fibrils, they usually cannot be
aspirated (a clinical difficulty referred to as a “dry tap”) and
are only seen in marrow biopsies.
→ The splenic red pulp is usually heavily infiltrated, leading
to obliteration of white pulp and a beefy red gross
appearance.
→ Hepatic portal triads are also involved frequently
D. PERIPHERAL T-CELL AND NK CELL NEOPLASMS
Peripheral T-cell lymphoma, Unspecified
• Not easily categorized and are lumped into a “wastebasket”
diagnosis, peripheral T-cell lymphoma, unspecified.
• No morphologic feature is pathognomonic, but certain findings
are characteristic
• These tumors efface lymph nodes diffusely and are typically
composed of a pleomorphic mixture of variably sized malignant
T cells (Figure 6)
• There is often a prominent infiltrate of reactive cells, such as
eosinophils and macrophages, probably attracted by tumor-
derived cytokines.
• Brisk neoangiogenesis may also be seen
• They usually express CD2, CD3, CD5, and either αβ or γδ T-
cell receptors.
• Some also express CD4 or CD8; such tumors are taken to be of
helper or cytotoxic T-cell origin, respectively.
• DNA analysis is used to confirm the presence of clonal T-cell
receptor rearrangements.
• Most patients present with generalized lymphadenopathy,
sometimes accompanied by eosinophilia, pruritus, fever, and
weight loss.
• These tumors have a significantly worse prognosis than
comparably aggressive mature B-cell neoplasms (e.g., diffuse
large B-cell lymphoma).
Figure 8. Peripheral T-cell lymphoma, unspecified
Anaplastic Large Cell Lymphoma (ALK Positive)
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
• Typically composed of large anaplastic cells, some containing
horseshoe-shape nuclei and voluminous cytoplasm (so-called
hallmark cells)
• The tumor cells often cluster about venules and infiltrate
lymphoid sinuses, mimicking the appearance of metastatic
carcinoma.
• ALK is not expressed in normal lymphocytes; thus, the detection
of ALK protein in tumor cells is a reliable indicator of an ALK
gene rearrangement.
• Defined by the presence of rearrangements in the ALK gene on
chromosome 2p23.
• These rearrangements break the ALK locus and lead to the
formation of chimeric genes encoding ALK fusion proteins,
constitutively active tyrosine kinases that trigger the RAS and
JAK/STAT signaling pathways
• T-cell lymphomas with ALK rearrangements tend to occur in
children or young adults, frequently involve soft tissues, and
carry a very good prognosis (unlike other aggressive peripheral
T-cell neoplasms).
• The cure rate with chemotherapy is 75% to 80%. Inhibitors of
ALK have been developed and are being evaluated as a form of
selective, targeted therapy.
Figure 9. Anaplastic Large cell lymphoma
Adult T-cell leukemia/Lymphoma
• This neoplasm of CD4+ T cells is only observed in
adultsinfected by human T-cell leukemia retrovirus type 1
(HTLV-1)
• Mainly in regions where HTLV-1 is endemic, namely southern
Japan, West Africa, and the Caribbean basin.
• Common findings include skin lesions, generalized
lymphadenopathy, hepatosplenomegaly, peripheral blood
lymphocytosis, and hypercalcemia.
• Appearance of the tumor cells varies, but cells with multilobated
nuclei (“cloverleaf” or “flower” cells) are frequently observed
• Tumor cells contain clonal HTLV-1 provirus, which is believed to
play a critical pathogenic role. Notably, HTLV-1 encodes a
protein called Tax that is a potent activator of NF-κB which
enhances lymphocyte growth and survival.
• Most patients present with rapidly progressive disease that is
fatal within months to 1 year despite aggressive chemotherapy.
• Less commonly, the tumor involves only the skin and follows a
much more indolent course, like that of mycosis fungoides
• In addition to adult T-cell leukemia/lymphoma, HTLV-1 infection
sometimes gives rise to a progressive demyelinating disease of
the central nervous system and spinal cord
Mycosis Fungosis/Sezary syndrome
• Different manifestations of a tumor of CD4+ helper T cells that
home to the skin.
11 of 24
• Histologically, the epidermis and upper dermis are infiltrated by
neoplastic T cells, which often have a cerebriform appearance
due to marked infolding of the nuclear membrane.
• The tumor cells express the adhesion molecule cutaneous
leukocyte antigen (CLA) and the chemokine receptors CCR4
and CCR10, all of which contribute to the homing of normal
CD4+ T cells to the skin.
• Although cutaneous disease dominates the clinical picture,
sensitive molecular analyses have shown that the tumor cells
circulate through the blood, marrow, and lymph nodes even
early in the course.
• Median survival of 8 to 9 years.
• Transformation to aggressive T-cell lymphoma occurs
occasionally as a terminal event.
• Clinically, the cutaneous lesions of mycosis fungoides typically
progress through three somewhat distinct stages, an
inflammatory premycotic phase, a plaque phase, and a tumor
phase
• Late disease progression is characterized by extracutaneous
spread, most commonly to lymph nodes and bone marrow.
• Sézary syndrome is a variant in which skin involvement is
manifested as a generalized exfoliative erythroderma.
• In contrast to mycosis fungoides, the skin lesions rarely proceed
to tumefaction, and there is an associated leukemia of “Sézary”
cells with characteristic cerebriform nuclei.
Large, Granular, lymphocytic leukemia
• T-cell and NK-cell variants of this rare neoplasm are recognized,
both of which occur mainly in adults.
• The tumor cells are large lymphocytes with abundant blue
cytoplasm and a few coarse azurophilic granules, best seen in
peripheral blood smears. The marrow usually contains sparse
interstitial lymphocytic infiltrates, which can be difficult to
appreciate without immunohistochemical stains.
• Infiltrates are also usually present in the spleen and liver. As
might be expected, T-cell variants are CD3+, whereas NK-cell
large granular lymphocytic leukemias are CD3−, CD56+.
• Recent work has shown that 30% to 40% of large granular
lymphocytic leukemias have acquired mutations in the
transcription factor STAT3, which functions downstream of
cytokine receptors.
• Individuals with T-cell disease usually present with mild to
moderate lymphocytosis and splenomegaly.
• Lymphadenopathy and hepatomegaly are usually absent
• Despite the relative paucity of marrow infiltration, neutropenia
and anemia dominate the clinical picture.
• Neutropenia is often accompanied by a striking decrease in late
myeloid forms in the marrow. Rarely, pure red cell aplasia is
seen.
• There is also an increased incidence of rheumatologic
disorders.
• Some patients with Felty syndrome, a triad of rheumatoid arthritis,
splenomegaly, and neutropenia,have this disorder as an underlying
cause
Extranodal NK/T-cell Lymphoma
• Rare in the United States and Europe, but 3% of NHLs in Asia.
• Presents most commonly as a destructive nasopharyngeal
mass
• Less common sites: testis and the skin
• The tumor cell infiltrate surrounds and invades small vessels,
leading to extensive ischemic necrosis.
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
• Large azurophilic granules are seen in the cytoplasm of the
tumor cells that resemble those found in normal NK cells
• Extranodal NK/T-cell lymphoma is highly associated with EBV.
• Tumor originates from a single EBV-infected cell.
• How EBV gains entry is uncertain, since the tumor cells do not
express CD21, the surface protein that serves as the B-cell EBV
receptor.
• Most tumors are CD3− and lack T-cell receptor rearrangements
and express NK-cell markers, supporting an NK-cell origin. No
consistent chromosome aberration has been described.
• Most extranodal NK/T-cell lymphomas are highly aggressive
neoplasms that respond well to radiation therapy but are
resistant to chemotherapy.
• Prognosis is poor in patients with advanced disease.
E. HODGKIN’S LYMPHOMA
• Hodgkin lymphoma (HL) encompasses a group of lymphoid
neoplasms that differ from NHL in several respects
• HL arises in a single node or chain of nodes and spreads first to
anatomically contiguous lymphoid tissues.
• characterized by the presence of neoplastic giant cells called
Reed- Sternberg cells. These cells release factors that induce
the accumulation of reactive lymphocytes, macrophages, and
granulocytes, which typically make up greater than 90% of the
tumor cellularity.
• In the vast majority of HLs, the neoplastic Reed-Sternberg cells
are derived from germinal center or postgerminal center B cells.
• The average age at diagnosis is 32 years. It is one of
• the most common cancers of young adults and adolescents,but
also occurs in the aged.
• It was the first human cancer to be successfully treated with
radiation therapy and chemotherapy, and is curable in most
cases.
Pathogenesis
• Ig genes of Reed-Sternberg cells have undergone both V(D)J
recombination and somatic hypermutation, establishing an
origin from a germinal center or postgerminal center B cell
• Despite having the genetic signature of a B cell, the Reed-
Sternberg cells of classical HL fail to express most B-cell–
specific genes, including the Ig genes
• cause of this wholesale reprogramming of gene expression is
presumably the result of widespread epigenetic changes of
uncertain etiology
• Activation of the transcription factor NF-κB is a common
event in classical HL. This can occur by several mechanisms:
→ NF-κB may be activated either by EBV infection or by
some other mechanism and turns on genes that promote
lymphocyte survival and proliferation.
→ EBV tumor cells express latent membrane protein-1
(LMP-1), a protein encoded by the EBV genome that
transmits signals that up-regulate NF κB.
12 of 24
 → Activation of NF-κB may occur in EBV-tumors as a result
of acquired loss-of-function mutations in IκB or A20 (also
known as TNF alpha-induced protein 3, or TNFAIP3),
which are both negative regulators of NF-κB.
→ It is hypothesized that activation of NF-κB by EBV or
other mechanisms rescues “crippled” germinal center B
cells that cannot express Igs from apoptosis, setting the
stage for the acquisition of other unknown mutations that
collaborate to produce Reed-Sternberg cells. • Lymphohistiocytic variants (L&H cells / popcorn cells)
→ Seen in the lymphocyte predominance subtype
• EBV-infected B cells resembling Reed-Sternberg cells are found → Polypoid nuclei, inconspicuous nucleoli, and moderately
in the lymph nodes of individuals with infectious mononucleosis, abundant cytoplasm
strongly suggesting that EBV-encoded proteins play a part in
the remarkable metamorphosis of B cells into Reed-Sternberg
cells.
• The florid accumulation of reactive cells in tissues involved by
classical HL occurs in response to a wide variety of cytokines
(e.g., IL-5, IL-10, and M-CSF) chemokines (e.g.,eotaxin), and
other factors (e.g., immunomodulatory factor galectin-1) that are
secreted by Reed-Sternberg cells. Once attracted, the reactive
cells produce factors that support the growth and survival of the
tumor cells and further modify the reactive cell response. B. Subtypes of Hodgkin Lymphoma
• eosinophils and T cells express ligands that activate the CD30 1. Nodular sclerosis type
and CD40 receptors found on Reed-Sternberg cells, producing → Most common form (65-70% of cases)
signals that up-regulate NF- B. → Tends to involve the lower cervical, supraclavicular, and
• Someof the factors produced by RS cells give rise to a state of mediastinal lymph nodes
immunodeficiency by impairment of T helper and cytotoxic cells → Collagen is deposited in bands that divide involved lymph
nodes into circumscribed nodules
and enhancing the generation of regulatory T cells
• Reed-Sternberg cells are aneuploid and possess diverse clonal
chromosomal aberrations. Disease stage I or II
• Copy number gains in the REL proto-oncogene on chromosome Cellular infiltrate Heterogenous
2p are particularly common and may also contribute to RS cells Lacunar cells
increases in NF-κB activity. Immunophenotype Classic
Associated with No
EBV?
A. Morphology of Reed-Stenberg Cells
More common in… Young adults; equal
• Classic diagnostic RS cells occurrence in males &
→ Large cells (45 µm in diameter) with multiple nuclei females
→ A single nucleus with multiple nuclear lobes, each with a “Classic” immunophenotype = (+) PAX5, CD15, CD30
large inclusion-like nucleolus about the size of a small
lymphocyte (5 to 7 µm in diameter)

• Mononuclear variant
→ Single nucleus with a large inclusion-like nucleolus

2. Mixed-cellularity type
→ 20-25% of cases
→ Associated with systemic symptoms (i.e. night sweats &
weight loss) and advanced tumor stag
• Lacunar cells Disease stage III or IV
→ Seen in the nodular sclerosis subtype Cellular infiltrate Heterogenous
→ More delicate, folded, or multilobate nuclei RS cells Diagnostic & mononuclear
→ Abundant pale cytoplasm that is often disrupted during Immunophenotype Classic
the cutting of sections, leaving the nucleus sitting in an Associated with EBV? Yes; 70% of cases
empty hole (a lacuna) More common in… Males, biphasic incidence
(peak in young adults &
>55 yrs old)

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 13 of 24
 • Most cases present with cutaneous immune
unresponsiveness (anergy)
→ Results from depressed cell-mediated immunity
(because factors released by RS cells suppress TH1
immune responses)

• Patients with the nodular sclerosis & lymphocyte predominance

types:
→ Tend to have stage I-II disease; free of systemic
symptoms
3. Lymphocyte-rich type • Patients with disseminated disease (stages III-IV) or the mixed
→ Uncommon cellularity or lymphocyte depletion types:
Cellular infiltrate Mostly reactive → More likely to have constitutional symptoms, such as
lymphocytes fever, night sweats, and weight loss
RS cells Diagnostic & mononuclear
Immunophenotype Classic • Spread of HL:
Associated with EBV? Yes; 40% of cases → Nodal disease → splenic disease → hepatic disease →
More common in… Males, older adults involvement of marrow & other tissues
--------------------------------------------------------------
4. Lymphocyte depletion type Clinical Staging of Hodgkin and Non-Hodgkin Lymphomas
→ Least common type (<5% of cases) (Ann Arbor Classification)
→ Often presents with advanced disease
Stage 1: Involvement of a single lymph node region (I) or a single
extralymphatic organ or site (IE)

Stage 2: Involvement of 2 or more lymph node regions on the

same side of diaphragm alone (II) or localized involvement of an
extralymphatic organ or site (IIE)

Stage 3: Involvement of lymph node regions on both sides of the

diaphragm without (III) or with (IIIE) localized involvement of an
extralymphatic organ or site
Cellular infiltrate Scarce Stage 4: Diffuse involvement of 1 or more extralymphatic organs
RS cells Diagnostic & other variants or sites with or without lymphatic involvement
Immunophenotype Classic
Associated with EBV? Yes; 90% of cases • All stages are further divided on the basis of the absence (A) or
More common in… Older males, HIV(+) presence (B) of the following symptoms:
patients, developing
countries → Unexplained fever
→ Drenching night sweats
5. Lymphocyte predominance type → Unexplained weight loss of greater than 10% of normal
→ Uncommon (5% of cases) body weight

Disease stage I or II • Tumor stage is the most important prognostic variable.

Cellular infiltrate Small lymphocytes
admixed with
macrophages, follicular
dendritic cells, reactive B
cells
RS cells L&H / popcorn cells
Immunophenotype (+) for CD20 & BCL6
(iba!!) (-) for CD15 & CD30
Associated with EBV? No
More common in… Young males with cervical
or axillary
lymphadenopathy;
mediastinal
Clinical Features
• HL most commonly presents as painless lymphadenopathy.
• Stage I-II: cure rate = ~90%
• Advanced disease (Stage IVA & IVB) cure rate = 60-70%
• Low-stage localized HL can be cured with involved field
radiotherapy.
→ However, long-term survivors have a higher incidence of
certain malignancies, including lung cancer, melanoma,
and breast cancer.
→ Non-neoplastic complications of radiotherapy
include pulmonary fibrosis and accelerated
atherosclerosis.
→ Chemotherapy with alkylating agents also increases the
incidence of secondary tumors.
MYELOID NEOPLASMS
• Common feature: origin = hematopoietic progenitor cells
• Primarily involve the marrow and, to a lesser degree, the
secondary hematopoietic organs (spleen, liver, lymph nodes)
• 3 categories
→ Acute myeloid leukemias
o Accumulation of immature myeloid forms (blasts) in
the bone marrow suppresses normal hematopoiesis
→ Myelodysplastic syndromes (MDS)
o Defective maturation of myeloid progenitors gives
rise to ineffective hematopoiesis, leading to
cytopenia

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 14 of 24
 → Myeloproliferative disorders
o Increased production of one or more types of blood
cells
• Manifestations of myeloid neoplasms are influenced by:
→ The position of the transformed cell within the hierarchy
of progenitors (i.e., a pluripotent hematopoietic stem cell
versus a more committed progenitor)
→ The effect of the transforming events on differentiation,
which may be inhibited, skewed, or deranged by
particular oncogenic mutations
• The number of leukemic cells in the blood is highly variable.
Occasionally, blasts are entirely absent from the blood
(aleukemic leukemia)
Types of myeloid blasts:
A. Myeloblasts
→ Delicate nuclear chromatin, 2-4 nucleoli, more
voluminous cytoplasm than lymphoblasts
o Fine, Peroxidase-positive azurophilic granules

A. ACUTE MYELOID LEUKEMIA

• Tumor of hematopoietic caused by acquired oncogenic
mutations that impede differentiation, leading to the
accumulation of immature myeloid blasts in the marrow.
• Replacement of the marrow with blasts produces marrow failure
and complications related to anemia, thrombocytopenia, and
neutropenia. AML occurs at all ages, but the incidence rises
throughout life, peaking after 60 years of age B. Auer rods
→ Needle-like azurophilic granules
CLASSIFICATION → Numerous in AML with the t(15;17) (acute
• SEE APPENDIX FOR FULL WHO CLASSIFICATION promyelocytic leukemia)

PATHOGENESIS
• Recurrent genetic aberrations seen in AML disrupt genes
encoding transcription factors that are required for normal
myeloid differentiation. For example:
→ RUNX1 and CBFB genes encode polypeptides that bind
one another to form a RUNX1/CBFB1β transcription
factor that is required for normal hematopoiesis.
→ The two most common chromosomal rearrangements,
t(8;21) and inv(16), disrupt the RUNX1 and CBFB
genes, respectively. C. Monoblasts
→ Folded or lobulated nuclei; lack Auer rods
• Mutations that lead to activation of growth signaling pathways + → Nonspecific esterase-positive
transcription factor aberrations = AML
• Mutations affecting factors that impact the state of the
“epigenome”, suggesting the epigenetic alterations have a
central role in AML
→ DNA methylation
→ Posttranslational modifications of histones (e.g.,
acetylation, methylation, phosphorylation)

• Immunophenotype of AML
→ Because it can be diffiult to distinguish myeloblasts and
lymphoblasts morphologically, the diagnosis of AML is
confimed by performing stains for myeloid-specific
antigens (flow sytometry).
• Cytogenetic analysis
→ AMLS arising de novo in younger adults
o Associated with balanced chromosomal
translocations, particularly t(8;21), inv(16), and
t(15;17)
→ AMLs following MDS or exposure to DNA-damaging
agents (chemo/radiation therapy)
o Deletions or monosomies involving chromosomes 5
and 7
o Lack chromosomal translocations
→ AMLs occurring after treatment with topoisomerase II
inhibitors
→ Translocations involving the MLL gene on chromosome
11q23
MORPHOLOGY
• The diagnosis of AML is based on the presence of at least 20%
myeloid blasts in the bone marrow.
• The number of leukemic cells in the blood is highly variable.
• Blasts may be more than 100,000/mm3, but are under
10,000/mm3 in about 50% of patients
• Occasionally, blasts are entirely absent from the blood
(aleukemic leukemia).
• For this reason, a bone marrow examination is essential to
exclude acute leukemia in pancytopenic patients.
CLINICAL FEATURES
• Most patients present within weeks or a few months of the onset
of symptoms with complaints related to anemia, neutropenia,
and thrombocytopenia, most notably fatigue, fever, and
spontaneous mucosal and cutaneous bleeding
• Very similar to those produced by ALL. Thrombocytopenia
• Results in a bleeding diathesis, which is often prominent.
• Cutaneous petechiae and ecchymoses, serosal hemorrhages
into the linings of the body cavities and viscera, and mucosal
hemorrhages into the gingivae and urinary tract are common

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 15 of 24
• Procoagulants and fibrinolytic factors released by leukemic 2. RNA Splicing Factors
cells, especially in AML with the t(15;17), exacerbate the - involves components of 3’ end of the
bleeding tendency. RNA splicing machinery
• Infections are frequent, particularly in the oral cavity, skin, lungs, 3. Transcription Factors
kidneys, urinary bladder, and colon, and are often caused by - TFs that are required for normal
opportunists such as fungi, Pseudomonas, and commensals. myelopoiesis resulting to deranged
• Signs and symptoms related to involvement of tissues other differentiation (feature of MDS)
than the marrow are usually less striking in AML than in ALL, 4. TP53 (tumor suppressor gene)
but tumors with monocytic differentiation often infiltrate the skin - loss-of-function mutation
(leukemia cutis) and the gingiva; - seen in 10% of MDS cases
• Central nervous system spread is less common than in ALL. - results to presence of a complex
• AML occasionally presents as a localized soft-tissue mass karyotype
known variously as a myeloblastoma, granulocytic sarcoma, or and poor clinical outcomes
chloroma.
• Without systemic treatment, such tumors inevitably progress to Primary and t-MDS
full-blown AML over time. - associated with recurrent chromosomal
• abnormalities including:
Prognosis. a. monosomies 5 and 7
• AML is generally a difficult disease to treat; about 60% of b. deletions of 5q, 7q, and 20q
patients achieve complete remission with chemotherapy, but c. trisomy 8
only 15% to 30% remain free of disease for 5 years.
• Outcome varies markedly among different molecular subtypes. • Marrow may be: hypercellular
• With targeted therapy using all-trans retinoic acid and arsenic (common), normocellular or hypocellular
salts AMLs with the t(15;17) now have the best prognosis of (rare)
any type, being curable in more than 80% of patients.
• AMLs with t(8;21) or inv(16) have a relatively good prognosis Most characteristic finding:
with conventional chemotherapy, particularly in the absence of disordered/dysplastic differentiation
KIT mutations. affecting erythroid, granulocytic, monocytic
• In contrast, the prognosis is dismal for AMLs that follow MDS or and megakaryocytic lineages
genotoxic therapy, or that occur in older adults, possibly
because in these contexts the disease arises out of a Abnormalities in RBCs:
background of hematopoietic stem cell damage or depletion. a. Ring sideroblasts
- Erythroblasts with iron-laden
• “Highrisk” forms of AML (as well as relapsed AML of all types)
mitochondria visible as perinuclear
are treated with hematopoietic stem cell transplantation when
granules in Prussian blue-stained aspirates
possible.
or biopsies
• Sequencing of AML genomes has recently revealed new
b. Megaloblastoid maturation
molecular predictors of outcome.
- Resembles abnormality in vitamin B12
• Insights gained from DNA sequencing will have an increasingly
and folate deficiency
important role in selecting therapy and stratifying patient in
MORPHOLOGY c. Nuclear budding abnormalities
clinical trials of new therapeutics, such as drugs that target the
- Nuclei with misshapen, often polyploid,
tumor epigenome.
outlines
Abnormalities in neutrophils:
B. MYELODYSPLASTIC SYNDROMES
- Decreased numbers of secondary
• Group of clonal stem cell disorders characterized by maturation
granules
defects that are associated with ineffective hematopoiesis and a
- Toxic granulations
high risk of transformation to AML
- Dohle bodies
• Bone marrow is partly or wholly replaced by clonal progeny of
- Pseudo-Pelger-Hut cells (neutrophils with
neoplastic multipotent stem with an ineffective and disordered
only two nuclear lobes)
differentiation
- Lack of nuclear segmentation 

→ Abnormal cells stay within bone marrow progressing to
peripheral blood cytopenia
Abnormalities in megakaryocytes:
• Primary vs Secondary MDS
- Single nuclear lobes or multiple separate
→ Primary – Idiopathic
nuclei (pawn ball megakaryocytes)
→ Secondary – previous genotoxic drug or radiation therapy
• All can transform to AML by t-MDS has the highest risk of Abnormalities in myeloid blasts:
transformation - Increased (>20%) overall marrow
→ Morphological changes and chromosomal aberrations are cellularity
often observed Primary MDS
Mutations in: - Disease of older adults (>70 yrs)
1. Epigenetic Factors CLINICAL
PATHOGENESIS - Weakness and infections due to
- includes factors the regulate DNA FEATURES
cytopenia
methylation and histone modifications - Poor prognosis for higher blast counts

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 16 of 24
 and sever cytopenia
- Median survival: 9-29 months
- Death due to bleeding
(thrombocytopenia) or infections
(neutropenia)
t-MDS
- Poorest prognosis
- Median survival: 4-8 months
- Characterized by severe cytopenia and
rapid progression to AML
Tx:
Younger patients – allogeneic
hematopoietic stem cell transplantation
Older patients – supportive therapy only
C. MYELOPROLIFERATIVE DISORDERS
• Common pathogenic feature: mutated, constitutively activated
tyrosine kinases or acquired aberrations in signaling pathways
that lead to growth factor independence
→ Mutated tyrosine kinases → growth factor-independent
proliferation and survival of marrow progenitors →
↑production of one or more mature blood elements
→ Does not impair differentiation
• Common features:
→ Increased proliferative drive in bone marrow
→ Extramedullary hematopoiesis
→ Marrow fibrosis and peripheral blood cytopenia
→ Transformation to acute leukemia
Chronic Myelogenous Leukemia
• Presence of chimeric BCR-ABL gene derived from portions of
BCR gene on chromosome 22 and the ABL gene on
chromosome 9
→ BCR-ABL – directs synthesis of constitutively active BCR-
ABL tyrosine kinase
→ In 90% of cases, BCR-ABL is created by a reciprocal
(9;22)(q34;q11) translocation = Philadelphia chromosome
(Ph) 

• Cell origin: Pluripotent hematopoietic stem cell
Dimerization domain of BCR-ABL self-
associates
↓
ABL tyrosine kinase activation
↓
ABL tyrosine phosphorylates proteins that
induce signaling through the same pro-growth
and pro-survival pathways, RAS & JAK/STAT
PATHOGENESIS
pathways, (turned on by hematopoietic
growth factors)
- Preferentially drives the proliferation of
granulocytic and megakaryocytic progenitors
- Causes abnormal release of immature
granulocytic forms from marrow into blood
- Marrow is hypercellular due to massive
increased numbers of maturing granulocytic
precursors
MORPHOLOGY - Megakaryocytes: increased; small,
dysplastic forms
- Erythroid progenitors: normal or mildly
decreased
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
- Characteristic finding: presence of
scattered macrophages with abundant
wrinkled, green-blue cytoplasm (sea-blue
histiocytes)
Blood: leukocytosis (>100,000 cells/mm3)
consisting of neutrophils, band forms,
metamyelocytes, myelocytes, eosinophils and
basophils
- Platelets: increased
- Spleen: greatly enlarged due to extensive
extramedullary hematopoiesis and often with
infarcts
- Disease of adults but also occurs in children
and adolescents
- Peak incidence: Fifth to sixth decades of
life
- Onset is insidious
- Mild to moderate anemia and
hypermetabolism due to increased cell
turnover lead to fatigability, weakness, weight
loss and anorexia
- First symptoms: dragging sensation in
abdomen due to splenomegaly or acute onset
of LUQ pain due to splenic infarction
Natural history:
Slow Progression (for 3 years)
Accelerated Phase, increasing anemia and
thrombocytopenia (for 6-12 months)
CLINICAL
Blast Crisis (resembling acute leukemia)
FEATURES - In 50% of cases, blast crisis occur without
an accelerated phase
Tx:
BCR-ABL inhibitors (not clear if truly
curative)
- Markedly decrease BCR-ABL positive cells
in marrow but do not extinguish CML “stem
cell” which persists at low levels
Hematopoietic stem cell transplantation
- Should be performed in stable phase (slow
progression phase) 

- In younger patients
Treatments have less favorable outlook after
slow progression phase due to the extensive
damage and rapid progression of the disease
Polycythemia Vera
• Strongly associated with activating point mutations in tyrosine
kinase JAK2
• Characterized by increased marrow production of red cells,
granulocytes and platelets (panmyelosis)
• Increase in red cells (polycythemia) is responsible for most
clinical symptoms 

Point mutation in JAK2 (valine-to-phenylalanine
substitution)
PATHOGENESIS
↓
Constitutive JAK2 signaling
17 of 24
 ↓
Increased marrow production of RBC
independent of growth factors
↓
Decreased requirements for erythropoietin and
other hematopoietic growth factors
↓
Low serum erythropoietin levels
Secondary forms of polycythemia is
characterized by high erythropoietin levels
- Elevated hematocrit leads to increased blood
viscosity and sludging
- Thrombocytosis with abnormal platelet function
leads to increased risk for thrombosis and
bleeding
- Marrow is hypercellular with some residual fat
- Increase in red cell progenitors is subtle and
usually accompanied by an increase in
granulocytic precursors and megakaryocytes
- In 10% of cases, moderate to marked
increased in reticulin fibers is seen
- Mild organomegaly
- Due to congestion
MORPHOLOGY - Blood contains increased basophils and
abnormally large platelets
- Late PCV: “Spent Phase”
- extensive marrow fibrosis that
displaces hematopoietic cells
- increased extramedullary
hematopoiesis in spleen and liver prominent
organomegaly
- Transformation to AML is rare (1%) 
 - Major clinical manifestations: Thrombosis
- Uncommon (1-3 per 100,000 per year)
- Insidious onset, usually in adults of late middle
age
- Increased red cell mass and hematocrit +
increased total blood volume → abnormal blood
flow (esp. on veins → becomes distended)
- Cyanosis due to stagnation and deoxygenation
of blood in peripheral vessels
- Headache, dizziness, hypertension and GI
symptoms
- Intense pruritus and peptic ulceration due to
histamine release of basophils
- Hyperuricemia due to high cell turnover
- Increased risk of bleeding and thrombosis due
to abnormal blood flow and platelet function.
CLINICAL
Without treatment, death occurs within months of
FEATURES
diagnosis
Lab findings:
- Hemoglobin concentration: 14-28 g/dL
- Hematocrit: >/=60%
- WBC count: 12,000-50,000 cells/mm3
- Platelet count: > 500,000 platelets/mm3
- Platelets exhibit morphologic abnormalities
(giant forms) and defective aggregation
Tx:
- Phlebotomy maintains red cell mass at near
normal levels
- JAK2 inhibitors
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
Essential Thrombocytosis
• Associated with activating point mutations in JAK2 (50% of
cases), MPL (5-10% of cases) or calreticulin (remaining cases)
→ MPL – a receptor tyrosine kinase that is activated by
thrombopoietin
→ Calreticulin – protein with functions in endoplasmic
reticulum and cytoplasm
→ JAK2 and calreticulin mutations are mutually exclusive hence
calreticulin mutations are hypothesized to cause increase
JAK-STAT signaling
Point mutations in JAK2, MPL or calreticulin
↓
Constitutive JAK2 or MPL signaling
↓
PATHOGENESIS
Renders progenitors thrombopoietin-
independent
↓
Hyperproliferation
- Marrow cellularity is mildly increased but
megakaryocytes are markedly increased
and with abnormally large forms
- Delicate reticulin fibers are seen but overt
MORPHOLOGY fibrosis (in primary myelofibrosis) is absent
- Mild leukocytosis
- Mild organomegaly (50% of cases) due to
extramedullary hematopoiesis
- Incidence: 1-3 per 100,000 per year
- Usually occurs in 60 years old or older
- Long asymptomatic periods with occasional
thrombotic or hemorrhagic crises
- Median survival: 12-15 years
CLINICAL and hemorrhage due to platelet dysfunctions
FEATURES
- Separated from PCV and primary
myelofibrosis based on: absence of
polycythemia and marrow fibrosis,
respectively 

Tx: Gentle chemotherapeutic agents that
suppress thrombopoiesis
Primary Myelofibrosis
• Hallmark:
→ Development of obliterative marrow fibrosis
▪ Reduces bone marrow hematopoiesis → cytopenias and
extensive extramedullary
• hematopoiesis
Activating mutations of JAK2 (50-60% of
cases), MPL (1-5% of cases) or calreticulin (remaining cases)
= similar to ET
Chief pathologic feature:
- Extensive deposition of collagen in
marrow by non- neoplastic fibroblasts
caused by inappropriate release of fibrogenic
factors (PDGF & TGF-β) from neoplastic
PATHOGENESIS megakaryocytes
- TGF-β – promotes collagen deposition and
causes angiogenesis
- Fibrosis displaces hematopoietic elements
(stem cells) causing marrow failure
18 of 24
 - Circulating hematopoietic stem cells take up
residence in spleen, liver and lymph nodes
extramedullary hematopoiesis
- Moderate to severe anemia due to
disordered red cell production in
extramedullary sites and suppression of
marrow function
Early myelofibrosis:
- Marrow is hypercellular due to increasing
maturing hematopoietic cells (similar to PCV)
- Erythroid and granulocytic precursors:
normal
- Megakaryocytes: large, dysplastic and
abnormally clustered
- Minimal fibrosis
- Blood: leukocytosis and thrombocytosis
Late myelofibrosis:
- Marrow is more hypercellular and
diffusely fibrotic
- Clusters of atypical megakaryocytes with
unusual nuclear shapes (“cloud-like”)
MORPHOLOGY - Hematopoietic elements found within dilated
sinusoids
Very late myelofibrosis:
- Fibrotic marrow space is converted into
bone (osteosclerosis)
- Features are identical to spent phase of
other myeloproliferative disorders
- Marrow distortion due to fibrosis leads to
premature release of nucleated erythroid and
early granulocyte progenitors
(leukoerythroblastosis)
Teardrop-shaped red cells (dacryocytes)
- Cells that are damaged during irthing
process in fibrotic marrow
- Less common than PCV and ET
- Usually occurs in individuals older than 60
years
- Median survival: 3-5 years
- Progressive anemia and splenomegaly
(sensation of fullness in LUQ)
- Fatigue, weight loss and night sweats due to
CLINICAL
increase in metabolism associated with
FEATURES
expanding mass of hematopoietic cells
- Hyperuricemia and secondary gout due to
high rate of cell turnover
Lab findings:
- Moderate to severe normocytic
normochromic anemia accompanied by
leukoerythroblastosis
- WBC count: normal or mildly reduced but
can be markedly elevated (80,000- 100,000
cells/mm3) early in the course
- Platelet count: normal or elevated
but
continuation of thrombocytopenia as disease progresses
CLINICAL
FEATURES Tx:
JAK2 inhibitors – effective in decreasing
symptoms
Hematopoietic stem cell transplantation
only effective for young patients
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
LANGERHANS CELL HISTIOCYTOSIS
• Histiocytosis” – variety of proliferative disorders of dendritic cells
or macrophages 

• A spectrum of proliferations of a special type of immature
dendritic cell called Langerhans cell
• Majority of mutations are oncogenic
→ Aberrant expression of chemokine receptors
▪ a factor that contributes to homing of neoplastic
Langerhans cells
• Most common mutation: activating valine-to-glutamate
substitution at residue 600 in BRAF
• Less common mutation: TP53, RAS and tyrosine kinase MET
• Proliferating Langerhans cells: abundant, vacuolated cytoplasm
and vesicular nuclei with linear grooves or folds 

→ Presence of Birbeck granules in cytoplasm is characteristic
→ Birbeck granules: pentalaminar tubules with dilated terminal
end producing a tennis racket-like appearance which contain
the protein langerin
A. MULTIFOCAL MULTISYSTEM LANGERHANS CELL
HISTIOCYTOSIS (LETTERER-SIWE)
• Occurs most frequently before 2 years of age but occasionally
affects adults 

• Dominant clinical feature: development of cutaneous
lesions resembling a seborrheic eruption
→ Caused by infiltrates of Langerhans cells over the front and
back of trunk and on scalp
• Most have hepatosplenomegaly, lymphadenopathy, pulmonary
lesions and destructive osteolytic bone lesions 

• Extensive infiltration of marrow → anemia, thrombocytopenia
and predisposition to recurrent infections 

• In some instances, the tumor cells are anaplastic = Langerhans
cell sarcoma 

B. UNIFOCAL AND MULTIFOCAL UNISYSTEM
LANGERHANS CELL HISTIOCYTOSIS
• Characterized by proliferations of Langerhans cells admixed
with variable numbers of eosinophils, lymphocytes, plasma
cells and neutrophils.
→ Eosinophils are usually a prominent component of infiltrate
• Unifocal lesions commonly affects the skeletal system in older
children or adults
→ Asymptomatic or may cause pain, tenderness and pathologic
fractures
→ May heal spontaneously or be cured by local excision or
irradiation
• Multifocal unisystem disease usually affects young children
→ Presents with multiple erosive bony masses that may expand
to adjacent tissues
→ Involvement of the posterior pituitary stalk that may lead to
diabetes insipidus
→ Hand-Schuller-Christian triad
▪ Calvarial bone defects
▪ Diabetes insipidus
▪ Exophthalmos
C. PULMONARY LANGERHANS CELL HISTIOCYTOSIS
• Most often seen in adult smokers
→ May regress spontaneously upon smoking cessation
• Reactive proliferations of Langerhans cells
• 40% are associated with BRAF mutations (neoplastic in origin)
19 of 24
 III. SPLEEN
• 5 to 6 inches in length, 4 inches width, 150 g weight
• Storage and removal of worn-out erythrocytes
• Recycling of iron contained in the hemoglobin
• Blood forming organ in fetus

A. COMPONENTS OF THE SPLEEN

RED PULP
• primarily a filter designed to screen and eliminate defective
or foreign cells
• Traversed by numerous thin walled vascular sinusoids
• Separated by splenic cords or cords of Billroth
• Endothelial lining-discontinuous
• Macrophages creates a physical and functional filter
• Major repository mononuclear phagocytic cell

WHITE PULP
• Site where lymphoid cells can be found
• Is composed of masses of T and B lymphocytes
• Ensheathing a central artery
• Represented by the splenic nodule
• Each nodule has a peripheral or marginal zone of densely
packed lymphocytes

B. FUNCTIONS OF THE SPLEEN

1. Phagocytosis of blood cells and particulate matter
• In conditions in which red cell deformability is decreased,
red cells become trapped in the cords and phagocytosed
by macrophages.
• Splenic macrophages are also responsible for “pitting” of
red cells, the process by which inclusions bodies are
excised, and for the removal of particles, such as
bacteria, from the blood.
2. Antibody production.
• Dendritic cells in the periarterial lymphatic sheath trap
antigens and present them to T lymphocytes.
• T- and B-cell interaction at the edges of white pulp
follicles leads to the generation of antibody-secreting
plasma cells within the sinuses of the red pulp
3. Hematopoiesis.
• During fetal development, the spleen may be a minor site
of hematopoiesis, but this normally disappears by birth. Nonspecific Acute Splenitis
However, the spleen can become a major site of
compensatory extramedullary hematopoiesis in the ETIOLOGY • occurs in any blood-borne infection
setting of severe chronic anemia and in patients with • caused both by the microbiologic agents
myeloproliferative disorders, such as chronic PATHOGENESIS themselves and by cytokines that are
myelogenous leukemia and primary myelofibrosis. released as part of the immune response
4. Sequestration of formed blood elements • Spleen is enlarged (200-400 gm) and
• Normal spleen contains only about 30 to 40 mL of red soft
cells, but this volume increases greatly with • major feature: acute congestion of the
splenomegaly. red pulp
• Normal spleen also harbors approximately 30% to 40% • Neutrophils, plasma cells, and
of the total platelet mass. MORPHOLOGY eosinophils are usually present
→ With splenomegaly up to 80% to 90% of the total platelet throughout the white and red pulp
mass can be sequestered → thrombocytopenia. • At times the white pulp follicles may
• Enlarged spleen can trap white cells → leukopenia undergo necrosis, particularly when the
causative agent is a hemolytic
streptococcus
C. DISEASES OF THE SPLEEN
SPLENOMEGALY/HYPERSPLENISM Congestive Splenomegaly
• When sufficiently enlarged, the spleen causes a dragging ETIOLOGY Chronic venous outflow obstruction
sensation in the left upper quadrant and, through pressure on
Causes of obstruction:
the stomach, discomfort after eating.
• Intrahepatic d/o reducing portal venous
• Hypersplenism - increased sequestration of formed elements
drainage
and the consequent enhanced phagocytosis by the splenic PATHOGENESIS • Extrahepatic d/o that directly impinge
macrophages
upon the portal or splenic veins
→ characterized by anemia, leukopenia, thrombocytopenia,
• Sytemic or central venous congestion- in
alone or in combination right-sided cardiac decompensation

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 20 of 24
 • Liver cirrhosis - main cause of massive
congestive splenomegaly
• Spontaneous portal vein thrombosis
• Pylephlebitis - inflammation of the portal
vein
• Long-standing congestion produces
marked enlargement (1000 to 5000 gm)
• The organ is firm, and the capsule is
usually thickened and fibrous
• Microscopically, the red pulp is
congested early in the course but
MORPHOLOGY becomes increasingly fibrotic and cellular
with time
• The elevated portal venous pressure
stimulates the deposition of collagen in
the basement membrane of the
sinusoids, which appear dilated because
of the rigidity of their walls
Splenic Infarcts
Occlusion of the major splenic artery or any of
its branches
ETIOLOGY
• most often caused by emboli that arise
from the heart
• Bland infarcts - pale, wedge-shaped, and
subcapsular in location. The overlying
capsule is often covered with fibrin.
MORPHOLOGY
• Septic infarcts - appearance is modified
by the development of suppurative
necrosis
Fig. 10 Splenic infarct
Recent infarcts are hemorrhagic, whereas older, more fibrotic infarcts are a
pale yellow-gray color.
NEOPLASMS
• Neoplastic involvement of the spleen is rare except in myeloid
and lymphoid tumors.
• Benign fibromas, osteomas, chondromas, lymphangiomas,
and hemangiomas may arise
→ Most common: lymphangiomas and hemangiomas (often
cavernous in type)
CONGENITAL ANOMALIES
THYMIC HYPOPLASIA OR APLASIA
• Complete absence of the spleen is rare and is usually
associated with other congenital abnormalities, such as
situs inversus and cardiac malformations.
• Hypoplasia is a more common finding.
• Accessory spleens (spleniculi) - small, spherical
structures that are histologically and functionally identical to
the normal spleen.
→ great clinical importance in some hematologic disorders,
such as hereditary spherocytosis and immune
ISOLATED THYMIC CYSTS
thrombocytopenia purpura, where splenectomy is used as a
treatment
RUPTURE
Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus
• Usually precipitated by blunt trauma
• Spontaneous ruptures - occur in the apparent absence of a
physical blow.
→ stem from some minor physical insult to a spleen made
fragile by an underlying condition.
→ The most common predisposing conditions are infectious
mononucleosis, malaria, typhoid fever, and lymphoid
neoplasms, which may cause the spleen to enlarge rapidly,
producing a thin, tense capsule that is susceptible to rupture.
• Chronically enlarged spleens are unlikely to rupture
because of the toughening effect of extensive reactive
fibrosis
IV. THYMUS
• Lobulated organ covered by a capsule; irregularly pyramidal
• From the 3rd and 4th pair of pharyngeal pouches
• Weight:10 to 35g at birth
→ Maximum weight of 20 to 50g at puberty
→ Then undergoes progressive involution with a weight of
5 – 15g, although it never disappears completely
→ May also involute in children and young adults in
response to severe illness and HIV infection
• Two fused, well-encapsulated lobes
• Divisions:
→ Outer cortical layer: cortical, peripheral, epithelial cells are
polygonal in shape, has an abundant cytoplasm, with
dendritic extension that contacts adjacent cells and abundant
thymocytes
→ Central medulla – the epithelial cells are densely packed
spindle-shaped; scant cytoplasm devoid of interconnecting
processes
• 2 major cell types:
→ Thymic epithelial cells at the periphery
→ Bone marrow-derived / immature T lymphocytes
• Whorls of medullary epithelial cells create Hassall
corpuscles
• Progenitor cells of marrow origin→ migrate to the thymus→
mature into T cells → exported to the periphery
• During adulthood the thymic production of T cells slowly
declines as the organ atrophies
• Other components found inside the thymus:
→ Macrophages
→ Dendritic cells
→ Minor population of B lymphocytes o rare neutrophils and
eosinophils
→ Small population of neuroendocrine cells, which may
explain how neuroendocrine tumors arise in this organs
→ Scattered myoid (muscle-like) cells
→ Myoid cells are of particular interest because of the suspicion
that they play some role in the development of myasthenia gravis
A. DEVELOPMENTAL DISORDES
• seen in DiGeorge syndrome
→ marked by severe defects in cell-mediated immunity and
variable abnormalities of parathyroid development
associated with hypoparathyroidism
→ often associated with other developmental defects as part of
the 22q11 deletion syndrome
• usually discovered incidentally postmortem or during
surgery
• rarely exceed 4 cm in diameter, can be spherical or
arborizing, and are lined by stratified to columnar epithelium
21 of 24
 • Fluid contents - serous or mucinous and are often modified
by hemorrhage

B. THYMIC HYPERPLASIA
• The term thymic hyperplasia is a bit misleading, since it
usually applies to the appearance of B-cell germinal centers
within the thymus, a finding that is referred to as thymic
follicular hyperplasia
• Most frequently encountered in myasthenia gravis, found
in 65% to 75% of cases
→ Similar thymic changes are sometimes encountered in
Fig. 11 Benign thymoma (medullary type)
Graves disease, systemic lupus erythematosus,
scleroderma, rheumatoid arthritis, and other autoimmune
disorders

C. THYMOMAS
• The designation “thymoma” is restricted to tumors of thymic
epithelial cells
→ also contain benign immature T cells (thymocytes)
• Classification relies on the most important prognostic
features, surgical stage and presence or absence of overt
cytologic features of malignancy.
• Three histologic subtypes: Fig. 12 Malignant thymoma, type I
→ Tumors that are cytologically benign and noninvasive
→ Tumors that are cytologically benign but invasive or Clinical features:
metastatic • 40% of thymomas - present with symptoms stemming from
impingement on mediastinal structures.
→ Tumors that are cytologically malignant (thymic
• 30% to 45% - detected in the course of evaluating patients
carcinoma) with myasthenia gravis.
• In all categories, the tumors usually occur in adults older • The rest - discovered incidentally during imaging or surgery
than 40 years of age (M=F); are rare in children • Other associated autoimmune disorders
• Most arise in the anterior superior mediastinum, but → hypogammaglobulinemia
sometimes they occur in the neck, thyroid, pulmonary hilus, → pure red cell aplasia
or elsewhere.
→ Graves disease
MORPHOLOGY → pernicious anemia
• most often composed of medullary-type → dermatomyositis-polymyositis
epithelial cells or a mixture of medullary → Cushing syndrome.
and cortical type. • Thymocytes that arise within thymomas give rise to long-lived
NONINVASIVE • The medullary type epithelial cells are CD4+ and CD8+ T cells, and cortical thymomas rich in
elongated or spindle-shaped. There is thymocytes → more likely to be associated with autoimmune
THYMOMA
usually a sparse infiltrate of thymocytes disease
• Mixed thymomas - there is an admixture • Llikely that abnormalities in the selection of T cells maturing
of polygonal cortical type epithelial cells within the environment of the neoplasm contribute to the
and a denser infiltrate of thymocytes. development of diverse autoimmune disorders.
• epithelial cells are most commonly of the
cortical variety, with abundant cytoplasm REFERENCES
and rounded vesicular nuclei, and are Robbins
usually mixed with numerous thymocytes.
2020 Trans (Incomplete; completed in this trans)
INVASIVE • invasive thymomas penetrate through
the capsule into surrounding structures.
THYMOMA
• With minimal invasion, complete excision
yields a 5-year survival rate of greater
than 90%, whereas extensive invasion is
associated with a 5-year survival rate of
less than 50%.
• Macroscopically: usually fleshy, obviously
invasive masses, sometimes
accompanied by metastases to sites
such as the lungs
• Microscopically: most are squamous cell
THYMIC carcinomas
CARCINOMA • The next most common variant is
lymphoepitheliomalike carcinoma, a
tumor composed of sheets of cells with
indistinct borders that bears a close
histologic resemblance to
nasopharyngeal carcinoma.

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 22 of 24
 APPENDIX

Table 1. Subtypes of Hodgkin Lymphoma

Figure 1. Signals mediating cross talk in Hodgkin Lymphoma

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 23 of 24
 Table 2. Subtypes of AML

Patho Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 24 of 24