GENERAL PATHOLOGY PRELIMS

 DISEASES OF WHITE BLOOD CELLS, LYMPH

NODES, SPLEEN, AND THYMUS
 RBCS AND BLOOD DISORDERS
 DISEASES OF RESPIRATORY SYSTEM
 DISEASES OF WHITE BLOOD
CELLS, LYMPH NODES, SPLEEN,
AND THYMUS
MILA AMOR V. REYES, MD, FPSP
Anatomic and Clinical Pathologist
 INTRODUCTION
☼components of the hematopoietic system:
myeloid tissues—bone marrow and the cells derived from
it (e.g., red cells, platelets, granulocytes, and monocytes)
lymphoid tissues—thymus, lymph nodes, and spleen
☼development and maintenance of hematopoietic tissues
blood cell progenitors first appear during the third week
of embryonic development in the yolk sac
on the third month of embryogenesis, hematopoietic stem
cells migrate to the liver, until shortly before birth
by the fourth month of development, HSCs begin to shift
to the bone marrow
by birth, marrow throughout the skeleton is
hematopoietically active until puberty, soon it becomes
restricted to the axial skeleton
HSCs give rise to two kinds of multipotent cells:
common lymphoid progenitors—T-cell, B-cell, and NK
cell precursors
common myeloid progenitors—myeloblasts,
proerythroblasts, and megakaryoblasts precursors
under conditions of marked stress, e.g., severe anemia—
HSCs are mobilized from the bone marrow and appear in
the peripheral blood
extramedullary hematopoiesis (e.g., spleen and liver)
mature blood elements have finite life spans, their
numbers must be constantly replenished
feedback loops mediated through GFs, allow the
numbers of formed blood elements to be maintained
within appropriate ranges
Differentiation of blood cells. CFU, colony forming unit; SCF, stem cell factor; Flt3L,
Flt3 ligand; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-
macrophage colony-stimulating factor; LIN–, negative for lineage-specific markers; M-
CSF, macrophage colony-stimulating factor.
☼Morphology
bone marrow—supports the orderly proliferation, differentiation,
and release of blood cells
network of thin-walled sinusoids lined by a single layer of
endothelial cells, within the interstitium lie clusters of
hematopoietic cells and fat cells
differentiated blood cells enter the circulation by transcellular
migration through the endothelial cells
normal megakaryocytes lie next to sinusoids—extend cytoplasmic
processes that bud off into the bloodstream to produce platelets
red cell precursors often surround macrophages (nurse cells)—
provide some of the iron needed for the synthesis of hemoglobin
marrow biopsies—estimating marrow activity
in normal adults—ratio of fat cells to hematopoietic elements is
1:1
in hypoplastic states (e.g., aplastic anemia)—proportion of fat
cells is increased
in hyperplastic states (e.g., hemolytic anemias) and neoplastic
proliferations (e.g., leukemias)—propertion of is fat cells is
decreased
 DISORDERS OF WHITE CELLS
☼classified into two broad categories:
leukocytosis—proliferation/increase in the number of
leukocytes
leukopenias—deficiency/decrease in the number of
leukocytes
☼proliferations of white cells can be reactive or neoplastic
reactive proliferation—response to a primary, often
infectious disease, since the major function of leukocytes
is host defense
neoplastic disorders—tumors of hematopoietic origin
net effect—unregulated clonal expansion of
hematopoietic elements, which replace normal marrow
progenitors and often spread to other hematopoietic
tissues
 Leukopenia
Neutropenia/Granulocytopenia (Agranulocytosis)
☼Agranulocytosis—clinically significant reduction in
neutrophils, making individuals susceptible to bacterial
and fungal infections
☼Clinical Features
symptoms and signs of neutropenia—related to
infection (malaise, chills, and fever, marked
weakness and fatigability)
with agranulocytosis—infections are often
overwhelming and may cause death within hours to
days
neutrophil count falls below 500/cu.mm.
☼Pathogenesis
1. inadequate or ineffective granulopoiesis
suppression of HSCs—e.g., aplastic anemia and infiltrative
marrow disorders
suppression of committed granulocytic precursors by
exposure to drugs
disease states associated with ineffective hematopoiesis—
e.g., MDS—defective precursors die in the marrow
2. accelerated removal or destruction of neutrophils from blood
immune-mediated injury to neutrophils—idiopathic,
autoimmune disorders(e.g., SLE), or caused by exposure to
drugs
splenomegaly—splenic sequestration of neutrophils leads to
excessive destruction, usually with increased destruction of red
cells and platelets
increased peripheral utilization—in overwhelming bacterial,
fungal, or rickettsial infections
 Reactive (Inflammatory) Proliferations of White Cells and
Lymph Nodes

Leukocytosis

☼Pathogenesis
in acute infection—rapid increase in mature
granulocytes from the bone marrow pool
in sepsis or severe infections
many immature granulocytes appear in the blood,
simulating a myeloid leukemia (leukemoid reaction)
morphologic changes in the neutrophils, e.g., toxic
granules, Döhle bodies, and cytoplasmic vacuoles are
seen
Reactive changes in neutrophils. Neutrophils containing coarse purple
cytoplasmic granules (toxic granulations) and blue cytoplasmic patches of
dilated endoplasmic reticulum (Döhle bodies, arrow) are observed in this
peripheral blood smear prepared from a patient with bacterial sepsis.
 MECHANISMS OF LEUKOCYTOSIS
INCREASED PRODUCTION IN THE MARROW
Chronic infection or inflammation (growth factor-dependent)
Paraneoplastic (e.g., Hodgkin lymphoma; growth factor-dependent)
Myeloproliferative disorders (e.g., chronic myeloid leukemia; growth factor-
independent)
INCREASED RELEASE FROM MARROW STORES
Endotoxemia
Infection
Hypoxia
DECREASED MARGINATION
Exercise
Catecholamines
DECREASED EXTRAVASATION INTO TISSUES
Glucocorticoids
 CAUSES OF LEUKOCYTOSIS
Type of Leukocytosis Causes
Neutrophilic leukocytosis Acute bacterial infections, especially those caused by pyogenic
(neutrophilia) organisms; sterile inflammation caused by, for example, tissue
necrosis (myocardial infarction, burns)
Eosinophilic leukocytosis Allergic disorders such as asthma, hay fever; certain skin diseases
(eosinophilia) (e.g., pemphigus, dermatitis herpetiformis); parasitic infestations;
drug reactions; certain malignancies (e.g., Hodgkin and some non-
Hodgkin lymphomas); collagen vascular disorders and some
vasculitides; atheroembolic disease (transient)
Basophilic leukocytosis Rare, often indicative of a myeloproliferative disease (e.g., chronic
(basophilia) myeloid leukemia)
Monocytosis Chronic infections (e.g., tuberculosis), bacterial endocarditis,
rickettsiosis, and malaria; collagen vascular diseases (e.g., systemic
lupus erythematosus); inflammatory bowel diseases (e.g., ulcerative
colitis)
Lymphocytosis Accompanies monocytosis in many disorders associated with chronic
immunological stimulation (e.g., tuberculosis, brucellosis); viral
infections (e.g., hepatitis A, cytomegalovirus, Epstein-Barr virus);
Bordetella pertussis infection
 LYMPHADENITIS
Acute Nonspecific Lymphadenitis

☼Morphology
prominence of large reactive germinal centers
containing numerous mitotic figures
macrophages contain particulate debris derived from
dead bacteria or necrotic cells
scattered neutrophils infiltrate the follicles and
accumulate within the lymphoid sinuses
☼nodes are enlarged and painful, overlying skin is red
Chronic Nonspecific Lymphadenitis
☼produce several different patterns of lymph node reaction
1. follicular hyperplasia—stimuli that activate humoral
immune responses
large oblong germinal centers—surrounded by a collar
of small resting B cells (mantle zone)
morphologically similar to follicular lymphoma—
features favoring reactive (non-neoplastic) hyperplasia:
preservation of the lymph node architecture
marked variation in the shape and size of the follicles
presence of frequent mitotic figures, tingible-body
macrophages, and recognizable light and dark
zones—absent from neoplastic follicles
2. paracortical hyperplasia—stimuli that trigger T cell–
mediated immune responses, such as acute viral infections
T-cell regions contain immunoblasts—activated T cells 3
to 4X the size of resting lymphocytes
expanded T-cell zones encroach on and efface the B-
cell follicles
3. sinus histiocytosis (reticular hyperplasia)—increase in
the number and size of the endothelial cells
macrophages are greatly increased in numbers—
expansion and distension of the sinuses
nonspecific, and prominent in lymph nodes draining
cancers such as carcinoma of the breast
☼nodes are nontender
Follicular hyperplasia. A,
Low-power view showing
a reactive follicle and
surrounding mantle zone.
The dark-staining mantle
zone is more prominent
adjacent to the germinal-
center light zone in the
left half of the follicle.
The right half of the
follicle consists of the
dark zone. B, High-power
view of the dark zone
shows several mitotic
figures and numerous
macrophages containing
phagocytosed apoptotic
cells (tingible bodies).
 Neoplastic Proliferations of White Cells
☼3 categories:
1. lymphoid neoplasms—tumors of B-cell, T-cell, and NK-
cell
2. myeloid neoplasms
acute myeloid leukemias—immature progenitor cells
accumulate in the bone marrow
myelodysplastic syndromes—ineffective
hematopoiesis and resultant peripheral blood
cytopenias
chronic myeloproliferative disorders—increased
production of one or more terminally differentiated
myeloid elements (e.g., granulocytes) leads to
elevated peripheral blood counts
3. histiocytoses—proliferative lesions of macrophages and
dendritic cells
 ETIOLOGIC AND PATHOGENETIC FACTORS IN WHITE CELL
NEOPLASIA
☼chromosomal translocations and other acquired mutations
☼inherited genetic factors
☼viruses
HTLV-1—adult T-cell leukemia/lymphoma
EBV—Burkitt lymphoma, 30% to 40% of Hodgkin lymphoma,
B-cell lymphoma, rare NK-cell lymphoma
KSHV/HHV-8—Kaposi sarcoma, unusual B-cell lymphoma
☼chronic immune stimulation
H. pylori infection—gastric B-cell lymphoma
gluten-sensitive enteropathy—intestinal T-cell lymphoma
HIV infection—B-cell lymphoma
☼iatrogenic factors
☼radiation therapy and chemotherapy
☼smoking—acute myeloid leukemia
 LYMPHOID NEOPLASMS
☼leukemia—involvement of the bone marrow and usually the
peripheral blood
☼lymphoma—proliferations that arise as discrete tissue masses
many entities called “lymphoma” have leukemic presentations
tumors identical to “leukemias” sometimes arise as soft-tissue
masses
leukemia and lymphoma merely reflect the usual tissue
distribution of each disease at presentation
☼plasma cell neoplasms—arise in the bone marrow and infrequently
involve lymph nodes or the peripheral blood
☼histologic examination of lymph nodes or involved tissues—required
for diagnosis of lymphoid neoplasia
85% to 90%—B-cell origin; others, T-cell tumors; rarely, NK cell
origin
 The WHO Classification of the Lymphoid Neoplasms
I. PRECURSOR B-CELL NEOPLASMS
B-cell acute lymphoblastic leukemia/lymphoma (B-ALL)
II. PERIPHERAL B-CELL NEOPLASMS
Chronic lymphocytic leukemia/small lymphocytic lymphoma Follicular lymphoma
B-cell prolymphocytic leukemia Marginal zone lymphoma
Lymphoplasmacytic lymphoma Hairy cell leukemia
Splenic and nodal marginal zone lymphomas Plasmacytoma/plasma
cell myeloma
Extranodal marginal zone lymphoma Diffuse large B-cell
lymphoma
Mantle cell lymphoma Burkitt lymphoma
III. PRECURSOR T-CELL NEOPLASMS
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL)
…The WHO Classification… continuation

IV. PERIPHERAL T-CELL AND NK-CELL NEOPLASMS

T-cell prolymphocytic leukemia Enteropathy-associated T-cell
lymphoma
Large granular lymphocytic leukemia Panniculitis-like T-cell
lymphoma
Mycosis fungoides/Sézary syndrome Hepatosplenic γδ T-cell
lymphoma
Peripheral T-cell lymphoma, unspecified Adult T-cell
leukemia/lymphoma
Anaplastic large-cell lymphoma Extranodal NK/T-cell
lymphoma
Angioimmunoblastic T-cell lymphoma NK-cell leukemia
V. HODGKIN LYMPHOMA
Classical subtypes Lymphocyte-rich
Nodular sclerosis Lymphocyte depletion
Mixed cellularity Lymphocyte predominance
 Precursor B- and T-Cell Neoplasms
Acute Lymphoblastic Leukemia/Lymphoma
☼composed of immature B (pre-B) or T (pre-T) cells—lymphoblasts
most common cancer of children
85% B-ALLs—typically manifest as childhood acute “leukemias”
peak incidence about age 3
☼Morphology
marrow—hypercellular and packed with lymphoblasts
tumor cells—scant basophilic cytoplasm, lacks granules and
nuclei larger than small lymphocytes
nuclear chromatin—finely stippled and more condensed
interspersed macrophages ingesting apoptotic tumor cells—
“starry sky”
mitotic rate—high
•
Acute lymphoblastic leukemia/lymphoma. Lymphoblasts
with condensed nuclear chromatin, small nucleoli, and scant
agranular cytoplasm.
☼Clinical Features
abrupt onset
symptoms related to depression of marrow function—
fatigue due to anemia; fever, reflecting infections
secondary to neutropenia; bleeding due to
thrombocytopenia
bone pain due to marrow expansion and infiltration of
the subperiosteum; lymphadenopathy, splenomegaly,
hepatomegaly
CNS manifestations—headache, vomiting, and nerve
palsies resulting from meningeal spread
☼Immunophenotype
TdT, DNA polymerase—expressed only in pre-B and pre-
T lymphoblasts—positive in more than 95% of cases
☼Prognosis
with aggressive chemotherapy
95%—complete remission
75% to 85%—cured
leading cause of cancer deaths in children
factors associated with worse prognosis:
age under 2
presentation in adolescence or adulthood
peripheral blood blast counts greater than 100,000
presence of cytogenetic aberrations
favorable prognostic markers:
age 2 to 10 years
low white cell count
hyperploidy
trisomy of chromosomes 4, 7, and 10 and presence
of t(12;21)
 Peripheral B-Cell Neoplasms
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic
Lymphoma (SLL)
☼diagnostic requirement for CLL absolute lymphocyte count
>4000/mm3
most common leukemia of adults
median age at diagnosis 60 years with 2 : 1 male
predominance
☼Morphology
lymph nodes—diffusely effaced by an infiltrate of small
lymphocytes with round to slightly irregular nuclei, condensed
chromatin, and scant cytoplasm
blood—contains large numbers of small round lymphocytes
bone marrow—almost always involved by interstitial infiltrates
of tumor cells
also, infiltrates in the splenic white and red pulp and the hepatic
portal tracts
Small lymphocytic lymphoma/chronic lymphocytic leukemia (lymph
node). A, Low-power view shows diffuse effacement of nodal
architecture. B, At high power the majority of the tumor cells are small
round lymphocytes. A “prolymphocyte,” larger cell with a centrally
placed nucleolus, is also present in this field (arrow).
Chronic lymphocytic leukemia.
This peripheral blood smear is
flooded with small lymphocytes
with condensed chromatin and
scant cytoplasm. A
characteristic finding is the
presence of disrupted tumor
cells (smudge cells). A
coexistent autoimmune
hemolytic anemia explains the
presence of spherocytes
(hyperchromatic, round
erythrocytes). A nucleated
erythroid cell is present in the
lower left-hand corner of the
field. In this setting, circulating
nucleated red cells could stem
from premature release of
progenitors in the face of
severe anemia, marrow
infiltration by tumor
(leukoerythroblastosis), or both.
☼Immunophenotype
tumor cells express CD19 and CD20, also CD23 and CD5
☼Molecular Pathogenesis
most common—deletions of 13q14.3, 11q, and 17p, and
trisomy 12q
☼Clinical Features
often asymptomatic at diagnosis
when symptoms appear—easy fatigability, weight loss, and
anorexia
lymphadenopathy and hepatosplenomegaly in 50% to 60%
hypogammaglobulinemia—increased susceptibility to
infections, particularly those caused by bacteria
treatment: chemotherapy, immunotherapy, bone marrow
transplantation
Follicular Lymphoma
☼most common form of indolent NHL
☼usually presents in middle age and afflicts males and
females equally
☼likely arises from germinal center B cells
☼Morphology
2 principal cell types :
1. small cells with irregular or cleaved nuclear contours
and scant cytoplasm—centrocytes (small cleaved cells)
2. larger cells with open nuclear chromatin, several
nucleoli, and modest amounts of cytoplasm—
centroblasts
Follicular lymphoma
(lymph node). A,
Nodular aggregates
of lymphoma cells are
present throughout
lymph node. B, At high
magnification, small
lymphoid cells with
condensed chromatin
and irregular or
cleaved nuclear
outlines (centrocytes)
are mixed with a
population of larger
cells with nucleoli
(centroblasts).
☼Immunophenotype
neoplastic cells closely resemble normal germinal center B
cells
BCL2 is expressed in more than 90%—normal follicular
center B cells is BCL2-negative
☼Clinical Features
present with painless, generalized lymphadenopathy
median survival (7–9 years)—not improved by aggressive
therapy
transformation occurs in 30% to 50%—most commonly
DLBCL
median survival is less than 1 year after transformation
Diffuse Large B-Cell Lymphoma
☼most common form of NHL
☼median patient age 60 years, with slight male predominance, but also
occurs in young adults and children
☼Morphology
large cell size (4 to 5X small lymphocyte) and diffuse growth pattern
tumor cells—round or oval vesicular nucleus
nucleoli—2 or 3 in number, located adjacent to the nuclear membrane,
or single and centrally placed
cytoplasm—moderately abundant and pale or basophilic
☼Immunophenotype
mature B-cell tumors— express CD19 and CD20, most have surface Ig
Diffuse large B-cell lymphoma. Tumor cells have large
nuclei, open chromatin, and prominent nucleoli.
☼Molecular Pathogenesis
t(14;18)—leads to the overexpression of anti-apoptotic
BCL2
☼Clinical Features
rapidly enlarging mass at a nodal or extranodal site
Waldeyer ring—oropharyngeal lymphoid tissue commonly
involved
extranodal sites—GIT, skin, bone, brain, and other tissues
primary or secondary involvement of the liver and spleen
aggressive tumors that are rapidly fatal without treatment
with chemotherapy—60% to 80% have complete
remission, and 40% to 50% are cured
Burkitt Lymphoma
☼occur in different settings
African (endemic) Burkitt lymphoma
sporadic (nonendemic) Burkitt lymphoma
HIV-associated lymphomas
☼Morphology
diffuse infiltrate of intermediate-sized lymphoid cells with round or
oval nuclei, coarse chromatin, several nucleoli, and moderate amount
of cytoplasm
exhibits high mitotic index and contains numerous apoptotic cells
nuclear remnants are phagocytosed by benign macrophages—“starry
sky” pattern
☼Immunophenotype
tumors of mature B cells—express surface IgM, CD19, CD20, CD10,
and BCL6, and fail to express the anti-apoptotic protein BCL2
☼Molecular Pathogenesis
all endemic tumors are latently infected with EBV, 15% to
20% of sporadic cases, and in 25% of HIV-associated tumors
☼Clinical Features
endemic and sporadic forms—found mainly in children or
young adults—accounts for 30% of childhood NHLs
most tumors manifest at extranodal sites
endemic form—involves the mandible
sporadic form—involves the ileocecum and peritoneum
very aggressive but responds well to intensive
chemotherapy—most children and young adults can be cured
Burkitt lymphoma. A, At low power, numerous pale tingible body
macrophages are evident, producing a “starry sky” appearance.
B, At high power, tumor cells have multiple small nucleoli and high
mitotic index. The lack of significant variation in nuclear shape
and size lends a monotonous appearance.
Plasma Cell Neoplasms and Related Disorders
☼neoplastic plasma cells
secrete monoclonal Ig in the blood—M component
synthesize excess light or heavy chains
free light chains—excreted in the urine—Bence-Jones proteins
☼different monoclonal gammopathies:
1. Multiple myeloma (plasma cell myeloma)—most common and
most important, tumorous masses scattered throughout the
skeletal system
Solitary myeloma (plasmacytoma)—infrequent variant,
single mass in bone or soft tissue—lungs, oronasopharynx, or
nasal sinuses
Smoldering myeloma—uncommon variant, lack of
symptoms and high M component
2. Waldenström macroglobulinemia—high levels of IgM
lead to hyperviscosity of the blood
3. Heavy-chain disease—rare, seen in
lymphoplasmacytic lymphoma and small bowel
marginal zone lymphoma
4. Primary or immunocyte-associated amyloidosis—
monoclonal proliferation of plasma cells secreting light
chains deposited as amyloid
5. Monoclonal gammopathy of undetermined significance
(MGUS)—serum M protein level is <3 gm/dL—
patients are asymptomatic
Multiple Myeloma
☼plasma cell neoplasm characterized by multifocal
involvement of the skeleton
can spread to lymph nodes and extranodal sites e.g., skin
☼disease of the elderly, peak age of incidence of 65 to 70
years
☼Molecular Pathogenesis
IL-6—important growth factor for plasma cells produced
by the tumor cells and resident marrow stromal cells
factors produced by neoplastic plasma cells activates
osteoclasts, inhibits osteoblasts
net effect—marked increase in bone resorption,
hypercalcemia and pathologic fractures
☼Morphology
destructive plasma cell tumors (plasmacytomas) involving the axial
skeleton
bones most commonly affected—vertebral column, ribs, skull,
pelvis, femur, clavicle, and scapula
bone lesions appear radiographically as punched-out defects
grossly consist of soft, gelatinous, red tumor masses
increased number of plasma cells— >30% of the marrow cellularity
malignant plasma cells—perinuclear clearing due to a prominent
Golgi apparatus and an eccentrically placed nucleus
in advanced disease—plasma cell infiltrates in the spleen, liver,
kidneys, lungs, lymph nodes, and other soft tissues
high level of M proteins—hyperviscosity and rouleaux formation
tumor cells flood the peripheral blood—plasma cell leukemia
Bence Jones proteins are excreted in the kidney—myeloma kidney
Multiple myeloma (bone marrow aspirate). Normal marrow cells are
largely replaced by plasma cells, including forms with multiple nuclei,
prominent nucleoli, and cytoplasmic droplets containing Ig.
☼Clinical Features
bone resorption— pathologic fractures and chronic pain
hypercalcemia can give rise to neurologic
manifestations—confusion, weakness, lethargy,
constipation, and polyuria
decreased production of normal Igs—recurrent bacterial
infections
cellular immunity is relatively unaffected
in 99%—increased levels of Igs in the blood and/or light
chains (Bence Jones proteins) in the urine
monoclonal Igs (“M protein”)—detected as abnormal
protein “spikes” in serum or urine electrophoresis
prognosis is variable but generally poor
median survival is 4 to 6 years
Lymphoplasmacytic Lymphoma
☼B-cell neoplasm of older adults in the sixth or seventh decade
☼unlike multiple myeloma—heavy- and light-chain synthesis is
balanced
bone destruction is not observed
☼Morphology
marrow contains lymphocytes, plasma cells, and
plasmacytoid lymphocytes, with mast cell hyperplasia
PAS-positive Ig inclusions—seen in the cytoplasm (Russell
bodies) or nucleus (Dutcher bodies) of plasma cells
☼Immunophenotype and Molecular Pathogenesis
lymphoid component expresses B-cell markers—CD20 and
surface Ig
plasma cell component secretes IgM
Lymphoplasmacytic lymphoma. Bone marrow biopsy shows a characteristic
mixture of small lymphoid cells exhibiting various degrees of plasma cell
differentiation. In addition, a mast cell with purplish red cytoplasmic granules
is present at the left-hand side of the field.
☼Clinical Features
nonspecific—weakness, fatigue, and weight loss
lymphadenopathy, hepatomegaly, and splenomegaly
monoclonal IgM—increases the viscosity of the blood—
hyperviscosity syndrome—Waldenström
macroglobulinemia:
visual impairment—congestion, tortuosity and distention
of retinal veins, retinal hemorrhages and exudates
neurologic problems—headaches, dizziness, deafness,
and stupor—sluggish blood flow
bleeding—formation of complexes between
macroglobulins and clotting factors and interference with
platelet functions
cryoglobulinemia—produces Raynaud phenomenon and
cold urticaria
incurable progressive disease—symptoms caused by high
IgM levels can be alleviated by plasmapheresis
Mantle Cell Lymphoma
☼uncommon lymphoid neoplasm
☼closely resemble the normal mantle zone B cells that
surround germinal centers
☼Morphology
nodal tumor cells may surround reactive germinal centers
☼Clinical Features
most common presentation—painless lymphadenopathy
prognosis is poor—median survival is only 3 to 4 years
not curable with conventional chemotherapy
Marginal Zone Lymphomas
☼B-cell tumors that arise within lymph nodes, spleen, or
extranodal tissues
☼initially recognized at mucosal sites—MALT (or
“maltomas”)
☼3 exceptional characteristics:
1. arise within tissues involved by chronic inflammatory disorders of
autoimmune or infectious etiology—e.g., Sjögren disease
Hashimoto thyroiditis, and Helicobacter gastritis
2. remain localized for prolonged periods, spreading late
systemically
3. may regress if the inciting agent (e.g., Helicobacter pylori) is
eradicated
Hairy Cell Leukemia
☼rare but distinctive B-cell neoplasm—2% of all leukemias
☼Morphology
leukemic cells—fine hairlike projections
‘hairy cells’—round, oblong, or reniform nuclei,
moderate amounts of pale blue cytoplasm with
threadlike or bleblike extensions
marrow—diffuse interstitial infiltrate of hairy cells
☼Clinical Features
pancytopenia resulting from marrow involvement and
splenic sequestration
splenomegaly is massive—most common finding
respond well with chemotherapy
overall prognosis is excellent
Hairy cell leukemia. A, Phase-contrast microscopy shows tumor cells
with fine hairlike cytoplasmic projections. B, In stained smears, these
cells have round or folded nuclei and modest amounts of pale blue,
agranular cytoplasm.
 Peripheral T-Cell and NK-Cell Neoplasms
Peripheral T-Cell Lymphoma, Unspecified
☼diffuse effacement of lymph nodes
☼prominent infiltrate of reactive cells, e.g., eosinophils and
macrophages
☼express CD2, CD3, CD5
☼present with generalized lymphadenopathy
☼worse prognosis than mature B-cell neoplasms
Anaplastic Large-Cell Lymphoma (ALK Positive)
☼ALK gene—not expressed in normal lymphocytes or other
lymphomas (detection means presence of ALK gene
rearrangements)
☼large anaplastic cells—horseshoe-shaped nuclei and
voluminous cytoplasm—’hallmark cells’
☼tumor cells cluster about venules and infiltrate lymphoid
sinuses—mimicking the appearance of metastatic carcinoma
☼frequently involve soft tissues
☼very good prognosis (unlike other peripheral T-cell
neoplasms)
cure rate with chemotherapy—75% to 80%
Adult T-Cell Leukemia/Lymphoma
☼neoplasm of CD4+ T cells—observed in adults infected by
HTLV-1
☼tumor cells—multilobated nuclei (“cloverleaf” or “flower”
cells)
☼common findings—skin lesions, generalized
lymphadenopathy, hepatosplenomegaly, peripheral blood
lymphocytosis, and hypercalcemia
☼present with rapidly progressive disease—fatal within
months to 1 year despite aggressive chemotherapy
Mycosis Fungoides/Sézary Syndrome
☼tumor of CD4+ helper T cells of the skin
☼Mycosis fungoides
progress through 3 distinct stages:
1. inflammatory premycotic phase
2. plaque phase
3. tumor phase
epidermis and upper dermis—infiltrated by neoplastic T cells with
cerebriform appearance—marked infolding of the nuclear
membrane
late disease progression—extracutaneous spread to lymph nodes
and bone marrow
☼Sézary syndrome—skin involvement is manifested as a generalized
exfoliative erythroderma
with associated leukemia of “Sézary” cells with cerebriform nuclei
Large Granular Lymphocytic Leukemia
☼CD3+T-cell variant—presents with lymphocytosis and
splenomegaly
☼neutropenia and anemia—dominate the clinical picture

Extranodal NK/T-Cell Lymphoma

☼presents most commonly as destructive nasopharygeal
mass
☼highly associated with EBV
☼highly aggressive neoplasms—prognosis is poor
☼respond well to radiation therapy but are resistant to
chemotherapy
 Hodgkin Lymphoma
☼neoplastic Reed-Sternberg cells—derived from germinal
center or post-germinal center B cells
☼WHO classification
1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte-rich
4. Lymphocyte depletion
5. Lymphocyte predominance
☼WHO classification 1 to 4—RS cells have similar B-cell
immunophenotype—positive for PAX5, CD15, and CD30
☼in lymphocyte predominance—RS cells have distinctive B-cell
immunophenotype—positive for CD20 and BCL6
☼Morphology
diagnostic RS cells—large cells with multiple nuclei or a
single nucleus, each with a large inclusion-like nucleolus about
the size of a small lymphocyte, with abundant cytoplasm
RS cell variants:
mononuclear variants—single nucleus with a large
inclusion-like nucleolus
lacunar cells (seen in nodular sclerosis)—more delicate,
folded, or multilobate nuclei and abundant pale
cytoplasm, leaving the nucleus sitting in an empty hole
(lacuna)
lymphohistocytic variants/L&H cells (seen in lymphocyte
predominance)—polypoid nuclei, inconspicuous nucleoli,
and moderately abundant cytoplasm
RS cells undergo cell death in which the cells shrink and
become pyknotic— “mummification”
 DIFFERENCES BETWEEN HODGKIN AND
NON-HODGKIN LYMPHOMAS
Hodgkin Lymphoma
More often localized to a single
axial group of nodes (cervical,
mediastinal, para-aortic)
Orderly spread by contiguity
Mesenteric nodes and Waldeyer
ring rarely involved
Extra-nodal presentation rare
Non-Hodgkin Lymphoma
More frequent involvement of multiple
peripheral nodes
Noncontiguous spread
Waldeyer ring and mesenteric nodes
commonly involved
Extra-nodal presentation common
☼Nodular Sclerosis Type
most common form—65% to 70%
presence of lacunar variant RS cells and deposition
of collagen in bands that divide involved lymph
nodes into circumscribed nodules
RS cells are found in a polymorphous
background—T cells, eosinophils, plasma cells and
macrophages
uncommonly associated with EBV
occurs with equal frequency in males and females—
with propensity to involve the lower cervical,
supraclavicular, and mediastinal lymph nodes of
adolescents or young adults
prognosis is excellent
☼Mixed-Cellularity Type
20% to 25%
involved lymph nodes are diffusely effaced by
heterogeneous cellular infiltrate—T cells, eosinophils,
plasma cells, and benign macrophages admixed with
RS cells
mononuclear variants and diagnostic RS cells—
usually plentiful
associated with EBV in 70%
more common in males
associated with older age, systemic symptoms (e.g.,
night sweats and weight loss) and advanced tumor
stage
overall prognosis is very good
☼Lymphocyte-Rich Type
uncommon form of classical HL
involved lymph nodes are diffusely effaced by reactive
lymphocytes
mononuclear variants and diagnostic RS cells
associated with EBV in 40%
with very good to excellent prognosis
☼Lymphocyte Depletion Type
least common form of classical HL—less than 5%
paucity of lymphocytes and abundance of RS cells or
pleomorphic variants
associated with EBV in over 90%
occurs predominantly in the elderly, in HIV+ individuals of any
age—advanced stage and systemic symptoms are frequent
overall outcome is less favorable
☼Lymphocyte Predominance Type
uncommon “nonclassical” variant of HL—5%
involved nodes are effaced by a nodular infiltrate
of B-cell follicles, with L&H variants, numerous
reactive B cells, and follicular dendritic cells
RS cells with L&H variants—multilobed nucleus
resembling popcorn kernel (“popcorn cell”)
majority are males, younger than 35 years of
age—present with cervical or axillary
lymphadenopathy
prognosis is excellent
Reed-Sternberg cells and variants. A, Diagnostic Reed-Sternberg cell, with two nuclear
lobes, large inclusion-like nucleoli, and abundant cytoplasm, surrounded by lymphocytes,
macrophages, and an eosinophil. B, Reed-Sternberg cell, mononuclear variant. C, Reed-
Sternberg cell, lacunar variant. This variant has a folded or multilobated nucleus and lies
within a open space, which is an artifact created by disruption of the cytoplasm during tissue
sectioning. D, Reed-Sternberg cell, lymphohistiocytic variant. Several such variants with
multiply infolded nuclear membranes, small nucleoli, fine chromatin, and abundant pale
cytoplasm are present.
 Subtypes of Hodgkin Lymphoma
Subtype Morphology and Immunophenotype
Nodular sclerosis Frequent lacunar cells and occasional
diagnostic RS cells; background infiltrate
composed of T lymphocytes, eosinophils,
macrophages, and plasma cells; fibrous
bands dividing cellular areas into nodules.
RS cells CD15+, CD30+; usually EBV-
Mixed cellularity Frequent mononuclear and diagnostic RS
cells; background infiltrate rich in T
lymphocytes, eosinophils, macrophages,
plasma cells; RS cells CD15+, CD30+;
70% EBV+
Lymphocyte rich Frequent mononuclear and diagnostic RS
cells; background infiltrate rich in T
lymphocytes; RS cells CD15+, CD30+;
40% EBV+
Lymphocyte depletion Reticular variant: Frequent diagnostic RS
cells and variants and a paucity of
background reactive cells; RS cells
CD15+, CD30+; most EBV+
Lymphocyte predominance Frequent L&H (popcorn cell) variants in a
background of follicular dendritic cells
and reactive B cells; RS cells CD20+,
CD15-, C30-; EBV-
Typical Clinical Features
Most common subtype; usually stage
I or II disease; frequent mediastinal
involvement; equal occurrence in
males and females (F = M), most
patients young adults
More than 50% present as stage III
or IV disease; M greater than F;
biphasic incidence, peaking in young
adults and again in adults older than
55
Uncommon; M greater than F; tends
to be seen in older adults
Uncommon; more common in older
males, HIV-infected individuals, and
in developing countries; often
presents with advanced disease
Uncommon; young males with
cervical or axillary
lymphadenopathy; mediastinal
Hodgkin lymphoma, nodular sclerosis type. A low-
power view shows well-defined bands of pink, acellular
collagen that subdivide the tumor into nodules.
Hodgkin lymphoma, mixed-cellularity type. A diagnostic,
binucleate Reed-Sternberg cell is surrounded by reactive
cells, including eosinophils (bright red cytoplasm),
lymphocytes, and histiocytes.
Hodgkin lymphoma, lymphocyte predominance type.
Numerous mature-looking lymphocytes surround scattered,
large, pale-staining lymphohistiocytic variants (“popcorn”
cells).
☼Molecular Pathogenesis
EBV-encoded proteins play a part in the metamorphosis of B cells
into RS cells
☼Clinical Features
present as painless lymphadenopathy
nodular sclerosis or lymphocyte predominance types—present
with stages I–II disease and usually free of systemic
manifestations
mixed-cellularity or lymphocyte depletion types—present with
stages III–IV with constitutional symptoms (e.g., fever, night sweats,
and weight loss)
spread of HL— nodal disease, splenic disease, hepatic disease,
and finally involvement of the marrow and other tissues
staging of HL—determines the prognosis and guides therapy
tumor stage rather than histologic type—most important
prognostic variable
 MYELOID NEOPLASMS
☼common feature—origin from hematopoietic progenitor cells
☼primarily involve the marrow and also, the secondary
hematopoietic organs (spleen, liver, and lymph nodes)
☼3 broad categories of myeloid neoplasia:
1. AML—accumulation of immature myeloid forms (blasts) in the
bone marrow suppresses normal hematopoiesis
2. MDS—ineffective hematopoiesis leads to cytopenias
3. MPD—increased production of one or more types of blood
cells
☼normal hematopoiesis—regulated by homeostatic feedback
mechanisms involving cytokines and growth factors
these mechanisms are deranged in marrows involved by
myeloid neoplasms
☼MDS and MPD—“transform” to AML
 Acute Myeloid Leukemia
☼accumulation of immature myeloid blasts in the marrow

☼occurs at all ages, incidence rises throughout life,

peaking after 60 years of age
MAJOR CATEGORIES OF AML FAB classification
AML, minimally differentiated M0
AML without maturation M1
AML with maturation M2
Acute promyelocytic leukemia M3
Acute myelomonocytic leukemia M4
Acute monocytic leukemia M5
Erythroleukemia M6
Acute megakaryoblastic leukemia M7
☼Morphology
presence of at least 20% myeloid blasts in the bone marrow
delicate nuclear chromatin, two to four nucleoli, more
voluminous cytoplasm than lymphoblasts
cytoplasm often contains fine, MPO-positive needle-like
azurophilic granules—Auer rods—numerous in AML-M3 (acute
promyelocytic leukemia)
occasionally, blasts absent from the blood—aleukemic leukemia
BME essential to exclude acute leukemia in pancytopenic
patients
☼Clinical Features
anemia, neutropenia, and thrombocytopenia—fatigue, fever,
spontaneous mucosal and cutaneous bleeding and infections in the
oral cavity, skin, lungs, kidneys, urinary bladder, and colon
☼Prognosis
60% achieve complete remission with chemotherapy
AMLs that follow MDS or genotoxic therapy, or in the elderly—
poor prognosis
A, Acute myeloid leukemia
without maturation (FAB M1
subtype). Myeloblasts have
delicate nuclear chromatin,
prominent nucleoli, and fine
azurophilic granules in the
cytoplasm. B, In the flow
cytometric analysis shown, the
myeloid blasts, represented
by the red dots, express
CD34, a marker of
multipotent stem cells, but do
not express CD64, a marker
of mature myeloid cells. C,
The same myeloid blasts
express CD33, a marker of
immature myeloid cells, and
a subset express CD15, a
marker of more mature
myeloid cells. Thus, these
blasts are myeloid cells
showing limited maturation.
Acute myeloid leukemia
subtypes. A, Acute
promyelocytic leukemia with
the t(15;17) (FAB M3 subtype).
Bone marrow aspirate shows
neoplastic promyelocytes with
abnormally coarse and
numerous azurophilic granules.
Other characteristic findings
include the presence of several
cells with bilobed nuclei and a
cell in the center of the field
that contains multiple needle-
like Auer rods. B, Acute myeloid
leukemia with monocytic
differentiation (FAB M5b
subtype). Peripheral smear
shows one monoblast and five
promonocytes with folded
nuclear membranes.
 Myelodysplastic Syndromes
☼group of clonal stem cell disorders characterized by
maturation defects that are associated with ineffective
hematopoiesis
☼bone marrow—replaced by clonal progeny of
neoplastic multipotent stem cell that retains the
capacity to differentiate but in an ineffective and
disordered fashion
☼may be primary (idiopathic) or secondary to previous
genotoxic drug or radiation therapy (t-MDS)
☼all forms of MDS can transform to AML—with highest
frequency and most rapidly in t-MDS
☼Morphology
bone marrow—usually hypercellular
most characteristic finding—disordered (dysplastic)
differentiation affecting the erythroid, granulocytic,
monocytic, and megakaryocytic lineages
within the erythroid series—ringed sideroblasts,
erythroblasts with iron-laden mitochondria,
megaloblastoid maturation, and nuclear budding
abnormalities
neutrophils—decreased numbers of secondary granules,
toxic granulations, and/or Döhle bodies, pseudo-Pelger-
Hüet cells, with only two nuclear lobes or completely lack
nuclear segmentation
megakaryocytes—with single nuclear lobes or multiple
separate nuclei (pawn ball megakaryocytes)
☼Clinical Course
primary MDS—predominantly a disease of the
elderly
half of the cases—asymptomatic
when symptomatic—weakness, infections, and
hemorrhages (due to pancytopenia)
higher proportion of blasts, more severe
cytopenias, increased risk of progression to AML,
and presence of multiple clonal chromosomal
abnormalities—worse prognosis
median survival in primary MDS—9 to 29 months
(t-MDS—4 to 8 months)
progression to AML—10% to 40%
Myelodysplasia. Characteristic forms of dysplasia are shown. A, Nucleated red
cell progenitors with multilobated or multiple nuclei. B, Ringed sideroblasts,
erythroid progenitors with iron-laden mitochondria seen as blue perinuclear
granules (Prussian blue stain). C, Pseudo-Pelger-Hüet cells, neutrophils with only
two nuclear lobes instead of the normal three to four, are observed at the top
and bottom of this field. D, Megakaryocytes with multiple nuclei instead of the
normal single multilobated nucleus. (A, B, D, marrow aspirates; C, peripheral
blood smear.)
 CLASSIFICATION OF MDS
Blasts in Blasts in Others
blood marrow
Refractory anemia (RA) <1% <5%
RA with ringed sideroblasts (RARS) <1% <5% >15% ringed sideroblasts
RA with excess blasts (RAEB) <5% 5-20%
RAEB in transformation (RAEB-T) >5% 20-30% (+) Auer rods
CMML <5% 5-20% Increased promonocytes
1. Persistent monocytosis >1x109/L
2. Neutrophilia with morphologic abnormalities
CMML-T 5-29% 20-29% (+) Auer rods
MDS, unclassified
 Myeloproliferative Disorders
☼common pathogenic feature: presence of mutated,
constitutively activated tyrosine kinases that promote
growth and survival of marrow progenitors
increase in the production of one or more mature
blood elements
☼common features include:
increased proliferative drive in the bone marrow
extramedullary hematopoiesis
marrow fibrosis and peripheral blood cytopenias
transformation to acute leukemia
 Chronic Myeloid Leukemia
☼presence of BCR-ABL hybrid gene—derived from BCR gene on
chromosome 22 and ABL gene on chromosome 9
☼Molecular Pathogenesis
>90%—BCR-ABL is formed by a reciprocal (9;22)(q34;q11)
translocation—Philadelphia chromosome [Ph]
☼Morphology
marrow is markedly hypercellular—increased numbers of maturing
granulocytic precursors, eosinophils, basophils and megakaryocytes
characteristic finding—scattered macrophages with abundant
wrinkled, green-blue cytoplasm—sea-blue histiocytes
leukocytosis exceeding 100,000 cells/mm3—neutrophils, band
forms, metamyelocytes, myelocytes, eosinophils, basophils and
platelets
splenomegaly, hepatomegaly and lymphadenopathy—due to
extramedullary hematopoiesis
Chronic myeloid leukemia. Peripheral blood smear shows many
mature neutrophils, some metamyelocytes, and a myelocyte.
☼Clinical Features
primarily a disease of adults—peak incidence is in the
fifth to sixth decades of life
detection of the BCR-ABL fusion gene through FISH or
PCR
even without treatment—median survival is about 3
years
50% enter an “accelerated phase”—increasing
anemia and thrombocytopenia—terminates in a
picture resembling acute leukemia (blast crisis)
50%—blast crises occur abruptly without an
accelerated phase
allogeneic bone marrow transplantation performed in
the stable phase—curative in about 75% of cases—
treatment of choice
 Polycythemia Vera
☼increased marrow production of red cells, granulocytes, and
platelets—panmyelosis
☼Molecular Pathogenesis
associated with point mutations in the tyrosine kinase
JAK2—activates multiple hematopoietic growth factor
receptors, including the erythropoietin
☼Morphology
marrow is hypercellular—increase in red cell progenitors,
granulocytic precursors and megakaryocytes
progresses to a “spent phase” (15% to 20%)—extensive
marrow fibrosis that displaces hematopoietic cells, with
increased extramedullary hematopoiesis in the spleen and
liver (organomegaly)
☼Clinical Features
polycythemia—responsible for most of the clinical
symptoms
elevated hematocrit—increased blood viscosity and
abnormal blood flow, thrombocytosis and abnormal
platelet function
thrombosis and bleeding—e.g., deep venous
thrombosis, myocardial infarction, or stroke
minor hemorrhages (epistaxis, bleeding gums)—
common
patients are plethoric and cyanotic—stagnation and
deoxygenation of blood in peripheral vessels
hemoglobin concentration—14 to 28 gm/dL
hematocrit—60% or more
white cell count—12,000 to 50,000/mm3
platelet count—greater than 500,000/mm3, with
giant forms and defective aggregation studies
without treatment—death from bleeding or
thrombosis
maintaining the red cell mass at nearly normal levels
by phlebotomy—extends the median survival to
about 10 years
 Essential Thrombocytosis
☼associated with point mutations in tyrosine kinase JAK2 (50%) or MPL (5–
10%)—activates thrombopoietin
elevated platelet counts, absence of polycythemia and marrow fibrosis
☼bone marrow—increased megakaryocytes with abnormally large forms

☼peripheral blood— increased platelets with abnormally large forms and

demonstrate qualitative abnormalities in functional tests

☼dysfunctional platelets—thrombosis and hemorrhage—deep venous

thrombosis, portal and hepatic vein thrombosis, and myocardial infarction

☼one characteristic symptom: erythromelalgia—throbbing and burning of

hands and feet caused by occlusion of small arterioles by platelet aggregates

☼treatment: chemotherapeutic agents that suppress thrombopoiesis

Essential thrombocytosis. Peripheral blood smear shows
marked thrombocytosis, including giant platelets
approximating the size of surrounding red cells.
 Primary Myelofibrosis
☼replacement of the marrow by fibrosis suppresses bone
marrow hematopoiesis—obliterative marrow fibrosis,
cytopenias and extensive extramedullary hematopoiesis
☼Molecular Pathogenesis
activating point mutations in JAK2 (50%-60% ) and MPL
(1%-5%)
release of fibrogenic factors from neoplastic
megakaryocytes—PDGF and TGF-β
extensive deposition of collagen in the marrow by non-
neoplastic fibroblasts
fibrosis displaces hematopoietic elements, including stem
cells—leads to marrow failure
extramedullary hematopoiesis—spleen, liver, and lymph
nodes
☼Morphology
early course—marrow is hypercellular due to increases in maturing
cells of all lineages, fibrosis is minimal
with progression—marrow becomes hypocellular and diffusely
fibrotic
late course—fibrotic marrow space converted into bone—
“osteosclerosis”
fibrotic obliteration of the marrow space—extensive
extramedullary hematopoiesis (e.g., spleen, liver, lymph nodes)
☼Clinical Features
occurs in individuals older than 60
bone marrow biopsy—essential for diagnosis
complications—anemia, intercurrent infections, thrombotic episodes,
bleeding related to platelet abnormalities, and transformation to
AML (5% to 20%)
treatment—bone marrow transplantation and kinase inhibitors
 LANGERHANS CELL HISTIOCYTOSIS
☼monoclonal proliferations of a special type of immature
dendritic cell—Langerhans cell
presence of Birbeck granules in the cytoplasm—
pentalaminar tubules with dilated terminal end producing
a ‘tennis racket–like’ appearance
☼clinicopathologic entities:
1. Letterer-Siwe disease—multifocal multisystem LCH
 occurs most frequently before 2 years of age
 dominant clinical feature: cutaneous lesions
resembling a seborrheic eruption—infiltrates of
Langerhans cells over the front and back of the trunk
and on the scalp
 hepatosplenomegaly, lymphadenopathy, pulmonary
lesions, and destructive osteolytic bone lesions
2. Eosinophilic granuloma—unifocal and multifocal
unisystem LCH
arises within the medullary cavities of bones—
calvarium, ribs, and femur
unifocal lesion—affects older children or adults
multifocal unisystem disease—affects young children,
with multiple erosive bony masses
combination of calvarial bone defects, diabetes
insipidus, and exophthalmos—Hand-Schuller-
Christian disease
3. Pulmonary LCH
comprises a polyclonal population of Langerhans
cells—reactive hyperplasia rather than a true
neoplasm
seen in adult smokers
Langerhans cell
histiocytosis. A,
Langerhans cells with
folded or grooved
nuclei and
moderately abundant
pale cytoplasm are
mixed with a few
eosinophils. B, An
electron micrograph
shows rodlike Birbeck
granules with
characteristic
periodicity and
dilated terminal end.
 SPLEEN
☼filter for the blood and site of immune responses to blood-
borne antigens
☼cut surface reveals extensive red pulp dotted with gray
specks—white pulp
☼white pulp—artery with an eccentric collar of T lymphocytes—
periarteriolar lymphatic sheath
expands to form lymphoid nodules composed mainly of B
lymphocytes—germinal centers in response to antigenic
stimulation
☼red pulp—traversed by numerous thin-walled vascular sinusoids,
separated by the splenic cords or “cords of Billroth”—contain
macrophages loosely connected through long dendritic processes
to create both a physical and a functional filter
endothelial lining of the sinusoid is discontinuous—passage
for blood cells between the sinusoids and cords
☼blood takes two routes to reach the splenic veins:
1. open circulation or slow compartment—blood flows
through capillaries into the cords
 blood cells squeeze through gaps in the
discontinuous basement of the endothelial lining
to reach the sinusoids
2. closed circuit—blood passes rapidly and directly
from the capillaries to the splenic veins
☼4 functions that impact disease states:
1. phagocytosis of blood cells and particulate matters,
e.g., bacteria
 red cells undergo extreme deformation during
passage from the cords into the sinusoids—when red
cell elasticity is decreased, trapped in the cords and
readily phagocytosed by splenic macrophages
2. antibody production—dendritic cells in the periarterial
lymphatic sheath trap antigens and present them to T
lymphocytes—T- and B-cell interaction leads to the
generation of antibody-secreting plasma cells
3. splenic hematopoiesis—normally ceases before birth,
but can be reactivated in severe anemia, MPD
4. sequestration of formed blood elements—normal
spleen contains 30 to 40 mL of red cells, and 30% to
40% of the total platelet mass
 volume increases greatly with splenomegaly—
pancytopenia
 Disorders Associated with Splenomegaly
I. INFECTIONS
Nonspecific splenitis of various blood-borne infections (particularly infectious endocarditis)
Infectious mononucleosis Syphilis Schistosomiasis
Tuberculosis Malaria Toxoplasmosis
Typhoid fever Echinococcosis Kala-azar
Brucellosis Leishmaniasis Trypanosomiasis
Cytomegalovirus Histoplasmosis
II. CONGESTIVE STATES RELATED TO PORTAL HYPERTENSION
Cirrhosis of the liver Cardiac failure
Portal or splenic vein thrombosis
III. LYMPHOHEMATOGENOUS DISORDERS
Non-Hodgkin lymphomas and lymphocytic leukemias
Hodgkin lymphoma Myeloproliferative disorders
Multiple myeloma Hemolytic anemias
IV. IMMUNOLOGICAL-INFLAMMATORY CONDITIONS
Rheumatoid arthritis Systemic lupus erythematosus
V. STORAGE DISEASES
Gaucher disease Mucopolysaccharidoses
Niemann-Pick disease
VI. MISCELLANEOUS DISORDERS
Primary neoplasms and cysts Amyloidosis
Secondary neoplasms
 Nonspecific Acute Splenitis

☼caused by microbiologic agents and cytokines that are

released as part of the immune response

☼Morphology
spleen is enlarged (200–400 gm) and soft
acute congestion of the red pulp
neutrophils and plasma cells are usually present
throughout the white and red pulp
 Congestive Splenomegaly
☼chronic venous outflow obstruction causing splenic
enlargement

☼venous obstruction may be caused by:

intrahepatic disorders that retard portal venous drainage
extrahepatic disorders that impinge upon the portal or
splenic veins, e.g., portal vein thrombosis, pylephlebitis,
splenic vein thrombosis
systemic, or central, venous congestion—right-sided heart
failure, e.g., tricuspid or pulmonic valvular disease, chronic
cor pulmonale, or following left-sided heart failure
cirrhosis of the liver—main cause of massive congestive
splenomegaly, e.g., “pipe-stem” hepatic fibrosis of
schistosomiasis, alcoholic cirrhosis and pigment cirrhosis
☼Morphology
long-standing splenic congestion produces
marked enlargement (1000–5000 gm)
red pulp is congested early in the course but
becomes fibrotic and cellular
slowing of blood flow from the cords to the
sinusoids prolongs the exposure of the blood cells
to macrophages—excessive destruction
(hypersplenism)
 Splenic Infarcts
☼common lesions caused by the occlusion of the major
splenic artery or any of its branches
☼most often caused by emboli that arise from the heart
☼Morphology
bland infarcts—pale, wedge-shaped, and
subcapsular, overlying capsule is covered with fibrin
septic infarcts—with suppurative necrosis
healing of infarcts—large depressed scars often
develop
•
Neoplasms

☼rare, except in myeloid and lymphoid tumors, which

often cause splenomegaly
☼lymphangiomas and hemangiomas—most common
and often cavernous in type
 Congenital Anomalies
☼complete absence of the spleen—rare and usually
associated with other congenital abnormalities, e.g.,
situs inversus and cardiac malformations

☼hypoplasia of the spleen—common

☼accessory spleens (spleniculi)—common, present singly

or multiply in 20% to 35% of postmortem examinations
histologically and functionally identical to the normal spleen
found at any place within the abdominal cavity
 Splenic Rupture

☼usually precipitated by blunt trauma, also, may occur

in the apparent absence of a physical blow—
“spontaneous ruptures”
predisposing conditions—infectious mononucleosis,
malaria, typhoid fever, and lymphoid neoplasms—
cause the spleen to enlarge rapidly, producing a
thin, tense capsule that is susceptible to rupture
☼often precipitates intraperitoneal hemorrhage—must
be treated by splenectomy to prevent death from
blood loss
 THYMUS
☼grows until puberty, achieves a maximum weight of 20 to 50
gm—progressive involution to 5 to 15 gm in the elderly
☼2 fused, well-encapsulated lobes
fibrous extensions of the capsule divide each lobe into
numerous lobules—each with an outer cortical layer enclosing
the central medulla
☼thymic epithelial cells and immature T lymphocytes
cortical, peripheral epithelial cells—polygonal, abundant
cytoplasm with dendritic extensions
medullary-type epithelial cells—spindle-shaped, scant
cytoplasm devoid of interconnecting processes
whorls of medullary epithelial cells with keratinized
cores—Hassall corpuscles
☼progenitor cells of marrow origin migrate to the thymus and
mature into T cells—exported to the periphery
 Developmental Disorders
☼thymic hypoplasia or aplasia—seen in DiGeorge
syndrome—severe defects in cell-mediated immunity
associated with hypoparathyroidism, and other
developmental defects

☼thymic cysts—uncommon lesions, discovered

incidentally
 Thymic Follicular Hyperplasia

☼appearance of B-cell germinal centers within the

thymus

☼occur in a number of chronic inflammatory and

immunological states
most frequently encountered in myasthenia gravis—
65% to 75%
also, in Graves' disease, SLE, scleroderma,
rheumatoid arthritis, and other autoimmune disorders
Thymomas
☼tumors of thymic epithelial cells—also contain benign immature
T cells (thymocytes)
☼3 histologic subtypes
1. tumors that are cytologically benign and noninvasive
(noninvasive thymomas)—medullary-type epithelial cells or mixture of
medullary- and cortical-type epithelial cells
2. tumors that are cytologically benign but invasive or
metastatic (invasive thymomas)—cortical epithelial cells mixed
with numerous thymocytes
3. tumors that are cytologically malignant (thymic carcinoma)
most are squamous cell carcinomas
lymphoepithelioma-like carcinoma—50% contain
monoclonal EBV
☼most arise in the anterosuperior mediastinum—20% to 30%
 RED CELLS AND
BLEEDING DISORDERS
MILA AMOR V. REYES, MD, FPSP
Anatomic & Clinical Pathologist
 ANEMIAS

• Reduction in the oxygen transport capacity of blood, usually as

a result of a reduction below normal limits of the total
circulating red cell mass

• Lower than normal hematocrit and hemoglobin concentrations

 CLASSIFICATION OF ANEMIA ACCORDING TO UNDERLYING
MECHANISM
1. Blood Loss
Acute: trauma
Chronic: lesions of gastrointestinal tract, gynecologic disturbances

2. Increased Rate of Destruction (Hemolytic Anemias)

A. Intrinsic (intracorpuscular) abnormalities of red cells
a. Hereditary
Red cell membrane disorders
Disorders of membrane cytoskeleton: spherocytosis, elliptocytosis
Disorders of lipid synthesis: selective increase in membrane lecithin
Red cell enzyme deficiencies
Glycolytic enzymes: pyruvate kinase deficiency, hexokinase deficiency
Enzymes of hexose monophosphate shunt: G6PD, glutathione synthetase
Disorders of hemoglobin synthesis
Deficient globin synthesis: thalassemia syndromes
Structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia,
unstable hemoglobins
b. Acquired
Membrane defect: paroxysmal nocturnal hemoglobinuria

Continued on next slide…

 …continuation
B. Extrinsic (extracorpuscular) abnormalities of red cells
Antibody mediated
Isohemagglutinins: transfusion reactions, erythroblastosis fetalis
Autoantibodies: idiopathic (primary), drug-associated, systemic lupus
erythematosus, malignant neoplasms, mycoplasmal infection
Mechanical trauma to red cells
Microangiopathic hemolytic anemias: thrombotic thrombocytopenic
purpura, disseminated intravascular coagulation
Cardiac: traumatic hemolytic anemia
Infections: malaria
Chemical injury: lead poisoning
Sequestration in mononuclear phagocyte system: hypersplenism

3. Impaired Red Cell Production

Disturbance of proliferation and differentiation of stem cells: aplastic
anemia, pure red cell aplasia, anemia of renal failure, anemia of endocrine disorders
Disturbance of proliferation and maturation of erythroblasts
Defective DNA synthesis: deficiency or impaired use of vitamin B12 and folic acid
(megaloblastic anemias)
Defective hemoglobin synthesis
Deficient heme synthesis: iron deficiency
Deficient globin synthesis: thalassemias
Unknown or multiple mechanisms: sideroblastic anemia, anemia of chronic infections,
myelophthisic anemias due to marrow infiltrations
 ANEMIAS OF BLOOD LOSS

ACUTE BLOOD LOSS

• Alterations reflect principally the loss of blood volume—shock
• if the acute episode is survived, marrow compensation is evidenced
by an increase in reticulocytes

CHRONIC BLOOD LOSS

• Anemia usually results when iron reserves are depleted—iron
deficiency anemia
• Marrow is active (erythropoiesis) as iron becomes available
 HEMOLYTIC ANEMIAS

• Characterized by:
• Premature destruction of red cells
• Accumulation of the products of hemoglobin catabolism (e.g.,
bilirubin)
• Marked increase in erythropoiesis within the marrow and
associated reticulocytosis

• Hemolysis may occur intravascularly or extravascularly

• Intravascular hemolysis—red cells are damaged by mechanical
injury (e.g., microangiopathic hemolytic anemia) or by complement-
mediated lysis (e.g., transfusion reactions)

• Extravascular hemolysis—occurs within the mononuclear phagocytic

cells of the spleen and other organs
• Predisposing factors are: injury to the red cell membrane, reduced
deformability, or opsonization of the red cells
HEREDITARY SPHEROCYTOSIS

• 75%—autosomal dominant disorder

• Defects in the red cell membrane that render erythrocytes
spheroidal, less deformable, and vulnerable to splenic
sequestration and destruction

Pathophysiology
• Skeletal proteins that form the red cell membrane are either
reduced in amount or defective in structure
• Deficiency of spectrin—most common abnormality
• Spherocytic red cells have reduced membrane flexibility—
trapped and destroyed in the splenic cords
Morphology
• Many red cells appear small and lack central pallor—spherocytes
• Splenic cords—markedly congested
• Marrow shows normoblastic hyperplasia

Clinical Features
• Anemia, moderate splenomegaly, and jaundice
• Intercurrent infections may trigger 2 types of crises:
1. Hemolytic crisis—massive hemolysis
2. Aplastic crisis—temporary suppression of erythropoiesis,
usually triggered by parvovirus infections
• 40% to 50%—develop gallstones due to chronic
hyperbilirubinemia
• Diagnosis depends on family history, hematologic findings, PBS,
and increased red cell osmotic fragility
• Increased MCHC—due to cellular dehydration
• Hereditary spherocytosis (peripheral smear). Note the anisocytosis and
several dark-appearing spherocytes with no central pallor. Howell-
Jolly bodies (small dark nuclear remnants) are also present in red cells
of this asplenic patient.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

• G6PD—enzyme in the HMP shunt that produces reduced

glutathione, necessary to protect red cells from oxidative injuries
• When G6PD-deficient cells are subjected to oxidant stresses
(infections, drugs)—hemoglobin is oxidized and denatured—
precipitates as Heinz bodies, attach to the cell membrane
• Inclusion-bearing cells—reduce flexibility, damage cell
membranes, susceptible to destruction by the splenic macrophages
• Hemolysis is both extravascular and intravascular
• Inheritance of mutant G6PD gene is X-linked
• G6PD deficiency: effects of oxidant drug exposure (peripheral
blood smear). Inset, Red cells with precipitates of denatured globin
(Heinz bodies) revealed by supravital staining. As the splenic
macrophages pluck out these inclusions, “bite cells” like the one in this
smear are produced.
SICKLE CELL DISEASE

• Hereditary hemoglobinopathy resulting from a point mutation of the globin

gene—substitution of valine for glutamic acid at the 6th position of the β-
globin chain

Sickling Phenomenon
• On deoxygenation, HbS undergo aggregation and polymerization, leading
to sickling of the red cells
• Homozygous state—irreversibly sickled cells can be identified in the
peripheral blood
Consequences of Sickling
• Chronic hemolytic state—sickle cells have rigid and nondeformable cell
membranes and are prone to sequestration and destruction
• Microvascular occlusions—sickle cells tend to occlude small blood vessels;
hypoxic injury (infarction)—clinically important and most debilitating
• Factors that influence sickling of the red cells:
• Amount of HbS
• Heterozygote—40% is HbS, the rest HbA, little tendency to sickle; sickle
cell trait
• Homozygote—all HbS and full-blown sickle cell anemia
• MCHC per cell—the higher the HbS concentration within the cell,
the greater the chances of contact and interaction between HbS
molecules
• Dehydration increases the MCHC, greatly facilitates sickling and may
trigger occlusion of small blood vessels

Morphology
• Spleen—enlarged early in the disease due to trapping of sickled
cells in the splenic cords; repeated episodes of vaso-occlusion and
infarction lead to progressive scarring and shrinkage in size
(autosplenectomy)
• Bone marrow—normoblastic hyperplasia
• Microvascular occlusions—produce tissue damage in several organs
CLINICAL FEATURES
• Chronic hemolytic anemia with chronic hyperbilirubinemia and
propensity to develop gallstones
• Vaso-occlusive crises with painful episodes of ischemic necroses of
the bones, lungs, liver, brain, penis, and spleen
• Increased susceptibility to infections e.g., Salmonella osteomyelitis,
encapsulated organisms (Streptococcus pneumoniae and Haemophilus
influenzae)—progressive splenic fibrosis and impairment of the
alternate complement pathway are believed to predispose to
infections

Diagnosis
• Based on clinical findings, PBS, and detection of HbS by Hb
electrophoresis
• Prenatal detection of heterozygotes and homozygotes is possible
through analysis of fetal DNA
• Sickle cell
disease. A, Low
magnification
shows sickle cells,
anisocytosis, and
poikilocytosis. B,
Higher
magnification
shows an
irreversibly
sickled cell in the
center.
THALASSEMIA SYNDROMES

• Lack of or decreased synthesis of either the normal α-globin or the

normal β-globin chain of HbA (α2β2)

Genetic Defects
• β-Thalassemia—deficient synthesis of the β-globin chains
• β°-Thalassemia—total absence of β -globin chains in the
homozygous state
• β+-Thalassemia—reduced β-globin synthesis in the homozygous
state
• α-Thalassemia—reduced synthesis of α-globin chains because of
deletion of one to all 4 of the normally present α-globin genes
Pathophysiology

• β-Thalassemia—decrease synthesis of β-globin, α-globin produced

cannot find complementary β chains to bind
• Free α-chains form highly unstable aggregates that cause cell
membrane damage—destruction of red cell precursors within
the marrow (ineffective erythropoiesis) and hemolysis of
abnormal red cells in the spleen (hemolytic state)
• Severe anemia causes marked compensatory expansion of the
erythropoietic marrow—encroach on the cortical bone and
cause skeletal abnormalities in growing children

• α-Thalassemia—imbalance in the synthesis of α chains and non-α

chains (β, γ, δ); unpaired non-α chains form unstable aggregates
that damage red cells and their precursors
 CLINICAL AND GENETIC CLASSIFICATION OF THALASSEMIAS
Clinical Genotype Disease Molecular Genetics
Nomenclature
β-Thalassemias

Thalassemia major Homozygous β-thalassemia Severe, requires blood

(β0/β0 β+/β+ β0/β+) transfusions regularly Mainly point
Thalassemia mutations that lead
intermedia Variable Severe, but does not require to defects in the
(β0/β+ β+/β+ β0/β β+/β) regular blood transfusion transcription,
Thalassemia minor splicing, or
Heterozygous β- thalassemia Asyptomatic with mild or absent translation of β-
(β0/β β+/β) anemia; red cell abnormalities globin mRNA
seen
α-Thalassemias

Silent carrier - α/ α α Asymptomatic; no red cell

abnormality

α-Thalassemia - -/ α α (Asian) Asymptomatic, like β- Mainly gene

- α/ - α (black African) thalassemia minor deletions

HbH disease - -/ - α Severe, resembles β-

thalassemia intermedia

Hydrops fetalis - -/- - Lethal in utero

Clinical Classifications

β -Thalassemia—based on the severity of anemia, type of genetic

defect (β+ or β°), and gene dosage (homozygous or heterozygous)

• Thalassemia major
• Severe, transfusion-dependent anemia, Hb= 3-6g/dL
• PBS—marked anisocytosis with microcytic, hypochromic red cells,
target cells, stippled red cells, and fragmented red cells
• Clinical course is brief (unless the patient is supported by blood
transfusions, death occurs at an early age from the profound
effects of anemia)
• In multiply transfused patients, cardiac failure from progressive
iron overload and secondary hemochromatosis—important cause
of morbidity and mortality
• Thalassemia minor—more common
• Presence of one normal gene allows enough β-globin chain
synthesis; affected individuals are usually asymptomatic
• PBS—minor abnormalities with hypochromia, microcytosis,
basophilic stippling, and target cells
• Characteristic finding on Hb electrophoresis: increase in HbA2 (4
to 8% of the total hemoglobin)
• Recognition of β-Thalassemia trait—important for genetic
counselling, and because it may mimic the hypochromic microcytic
anemia of iron deficiency

• Thalassemia intermedia—characterized by clinical features and

severity that are intermediate between the major and minor forms
α-Thalassemia—based on the number of α-globin genes deleted,
which, in turn, determines the severity of anemia

• Silent carrier state (-α/αα)—results from the deletion of a single

α-globin gene
• reduction in α-globin chain synthesis is barely detectable
• completely asymptomatic

• α-Thalassemia trait (--/αα; -α/-α)—deletion of two α-globin

genes occurs either from the same chromosome or from each of the
two chromosomes
• both genetic patterns are identical clinically
• resembles β-thalassemia minor
• Hemoglobin H (HbH) disease (--/-α)—deletion of three of the four
α-globin genes
• unstable tetramers of excess β-globin (HbH) are formed
• clinically resembles α-thalessemia intermedla

• Hydrops fetalis (--/--)—deletion of all four α-globin genes

• In the fetus, excess γ-globin chains form tetramers (Hb Barts)—
extremely high oxygen affinity but are unable to deliver the
oxygen to tissues
• Not compatible with life
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

• Only acquired hemolytic anemia resulting from membrane defect

• Red cells have increased sensitivity to complement-mediated lysis

due to deficiency of GPI-linked membrane proteins that anchored
into the cell membrane through GPI

• 3 GPI-linked proteins that regulate complement activity—deficient

in PNH
1. CD55 or decay-accelerating factor
2. CD59 or membrane inhibitor of reactive lysis
3. C8-binding protein
• Deficiency causes spontaneous in vivo activation of the
alternative complement pathway
IMMUNOHEMOLYTIC ANEMIAS

• Hemolysis is due to the presence of anti-red cell antibodies

• Major diagnostic criterion: Coomb's test (AHG)—which detects antibodies

on the surface of red cells

Warm Antibody Hemolytic Anemia

• Idiopathic in 60%

• IgG anti-red cell antibodies coat the red cells

• Opsonized red cells—spheroidal shape due to partial loss of red cell

membrane in the process of phagocytosis by splenic macrophages

• Spherocytes—sequestered and destroyed in the spleen—splenomegaly

Cold Agglutinin Immune Hemolytic Anemia

• Caused by IgM antibodies that agglutinate red cells at low

temperatures

• Acute—occurs during the recovery phase of certain infectious

disorders e.g., Mycoplasma pneumonia and infectious mononucleosis
• Self-limited and rarely induces manifestations of hemolysis

• Chronic—idiopathic and occurs with lymphoproliferative disorders

• AggIutination of red cells and complement fixation in distal body
parts—temperature may drop below 30°C
• Vascular obstruction by agglutinated red cells results in pallor,
cyanosis of the body parts exposed to cold temperatures, and
Raynaud phenomenon
Cold Hemolysin Hemolytic Anemia

• Characteristic of PCH—acute intermittent massive intravascular

hemolysis after exposure to cold

• Autoantibodies are IgG (Donath-Landsteiner Antibody)— directed

against P blood group antigen

• Antibodies attach to red cells and bind complement at low

temperatures; when the temperature is elevated, hemolysis occurs
• Most cases follow infections e.g., Mycoplasma pneumonia, measles,
mumps, and influenza syndromes
 CLASSIFICATION OF IMMUNE HEMOLYTIC ANEMIAS
Warm Antibody Type
The antibody is of the IgG type, does not usually fix complement, and is active at 37oC.
Primary or idiopathic
Secondary
Lymphomas and leukemias
Other neoplastic diseases
Autoimmune disorder (particularly systemic lupus erythematosus)
Drugs

Cold Agglutinin Type

The antibodies are IgM and are most active in vitro at 0 to 4oC. Antibodies dissociate at 30oC or
above. The antibody fixes complement at warmer temperatures, but agglutination of cells by IgM
and complement occurs only in the peripheral cool parts of the body.
Acute (mycoplasmal infection, infectious mononucleosis)
Chronic
Idiopathic
Associated with lymphoma

Cold Hemolysins (Paroxysmal Cold Hemoglobinuria)

IgG antibodies bind to red cells at low temperature, fix complement, and cause hemolysis when
temperature is raised to 30oC.
HEMOLYTIC ANEMIA RESULTING FROM TRAUMA TO RED CELLS
(MICROANGIOPATHIC HEMOLYTIC ANEMIA)

• Significant trauma to red cells resulting in their fragmentation in the

circulation—intravascular hemolysis

• Causes
• Prosthetic heart valves that create turbulent flow and shearing
forces
• Diffuse narrowing of the microvasculature due to deposition of
fibrin as in DIC

• PBS—schistocytes
• Microangiopathic hemolytic anemia. A peripheral blood
smear from a person with hemolytic-uremic syndrome shows
several fragmented red cells.
 ANEMIAS OF DIMINISHED ERYTHROPOIESIS

• Impaired red cell production may be caused by:

• Deficiency of some vital substrate e.g., iron, vit B12, and folate
• Stem cell failure

MEGALOBLASTIC ANEMIAS
• Caused most commonly by deficiency of vit B12 or folate
• Megaloblasts—cytoplasmic maturation occur without concomitant nuclear
maturation; pyknosis that are normal with maturation of erythroblasts are
delayed or fail to occur
• Prominent anisocytosis—abnormal erythropoiesis with macro-ovalocytes
MCV=>100µ3
• Abnormal granulopoiesis—giant metamyelocytes and hypersegmented
neutrophils
Pathophysiology
• Vitamin B12 and folic acid—essential coE in DNA synthesis
• Deficiency—inadequate DNA synthesis
• Anemia results from:
• Ineffective erythropoiesis
• Production of abnormal erythrocytes
• Ineffective granulopoiesis and thrombopoiesis—pancytopenia
• Absorption of vitamin B12 occurs as follows:
• Peptic digestion releases dietary vitamin B12—bound to salivary
vitamin B12-binding proteins "R binders"
• R-B12 complexes transported to duodenum—split by pancreatic
proteases—released vitamin B12 attaches to IF secreted by
parietal cells of gastric fundic mucosa
• IF-B12 complexes pass to distal ileum—attaches to epithelial IF
receptors—absorption of vitamin B12—transported to the tissues
by transcobalamin II
• Deficiency of vitamin B12 may result from impaired absorption
because of:
• Achlorhydria—impairs release of vitamin B12 from the protein-
bound form
• Gastrectomy—loss of IF
• Pernicious anemia—autoimmune disorder that damages gastric
parietal cells and the production of IF
• Resection of the ileum—preventing absorption of IF-B12 complex
• Malabsorption syndromes
• Increased requirements—e.g. pregnancy
• Inadequate diet—uncommon, body has large reserves of vitamin
B12
PERNICIOUS ANEMIA

• Lack of IF production due to chronic atrophic gastritis

• Gastric mucosal atrophy is marked by loss of parietal cells

• Autoimmune reaction against gastric parietal cells

• Autoantibodies are present in the serum and gastric juice
• Type I Abs—block binding of vitamin B12 to IF (blocking antibodies)
• Type II Abs—prevent binding of IF or IF-B12 complex to its ileal receptor
(binding antibodies)
• Antibodies directed against the gastric proton pump—bind to parietal cells
(parietal canalicular antibodies)
Morphology
• Bone marrow—megalobastic erythroid hyperplasia, giant
myelocytes and metamyelocytes with hypersegmented neutrophils,
large multilobed nuclei in megakaryocytes
• GIT—atrophic glossitis (tongue is shiny, glazed, and red); gastric
fundal atrophy with virtual absence of parietal cells
• CNS—75%, demyelination of the dorsal and lateral tracts of the
spinal cord

Clinical Features
• Insidious onset, patients are in 40's and 50's
• Anemia, involvement of the posterolateral spinal tracts
• Increased risk of gastric cancer
• Diagnosis—measurement of serum vitamin B12 levels
 CAUSES OF MEGALOBLASTIC ANEMIA
Vitamin B12 Deficiency
Decreased intake
Inadequate diet, vegetarianism
Impaired absorption
Intrinsic factor deficiency
Pernicious anemia
Gastrectomy
Malabsorption states
Diffuse intestinal disease, e.g., lymphoma, systemic sclerosis
Ileal resection, ileitis
Competitive parasitic uptake
Fish tapeworm infection
Bacterial overgrowth in blind loops and diverticula of bowel
Increased requirement
Pregnancy, hyperthyroidism, disseminated cancer
Folic Acid Deficiency
Decreased intake
Inadequate diet—alcoholism, infancy
Impaired absorption
Malabsorption states
Intrinsic intestinal disease
Anticonvulsants, oral contraceptives
Increased loss
Hemolysis
Increased requirement
Pregnancy, infancy, disseminated cancer, markedly increased hematopoiesis
Impaired use
Folic acid antagonists
Unresponsive to Vitamin B12 or Folic Acid Therapy
Metabolic inhibitors, e.g., mercaptopurines, flourouracil, cytosine
Unexplained disorders
Pyridoxine- and thiamine-responsive megaloblastic anemia
Acute erythroleukemia (M6) (Di Guglielmo syndrome)
Modified from Beck WS: Megaloblastic anemias. In wyngaarden JB, Smith LH (eds): Cecil Textbook of Medicine, 18th ed. Philadelphia, WB
ANEMIA OF FOLATE DEFICIENCY

• Megaloblastic anemia clinically and hematologically

indistinguishable from vitamin B12 deficiency, but neurologic
changes and gastric atrophy are absent

• Deficiency of folic acid may result from:

• Inadequate intake e.g., chronic alcoholics, elderly, indigent
• Malabsorption syndromes e.g., tropical and nontropical sprue
• Increased demand e.g., pregnancy, infancy, disseminated cancer
• Administration of folate antagonists e.g., methotrexate

• Diagnosis—demonstration of decreased folate levels in serum and

red cells
IRON DEFICIENCY ANEMIA

• Extremely common cause of anemia worldwide

Iron Metabolism
• About 20% of heme iron, and 1 to 2% of nonheme iron is
absorbable
• Duodenum—primary site of absorption
• Dietary heme iron enters the mucosal cells directly; nonheme iron is
transported into the cell by luminal mucins, and cytosolic mobilferrin
• Fraction of absorbed iron is rapidly delivered to plasma transferrin;
the remainder is bound to mucosal ferritin, some to be transferred
more slowly to plasma transferrin and some to be lost with
exfoliation of mucosal cells
• Total body iron content: 2 gm for women, 6 gm for men
• 80% functional body iron is found in hemoglobin, myoglobin, and
iron-containing enzymes (e.g., catalase and cytochromes)
• 15 to 20% total body iron—iron storage pool (hemosiderin and
ferritin-bound iron)
• Found in all tissues—but particularly in liver, spleen, bone marrow,
and skeletal muscle

Etiology
• Negative iron balance and consequent anemia may result from:
• Low dietary intake—rarely the cause of iron deficiency
• Malabsorption e.g., sprue and celiac disease
• Increased demands e.g., pregnancy, infancy
• Chronic blood loss—most important cause of iron deficiency; e.g.,
peptic ulcers, hemorrhoids, hookworm disease, menorrhagia,
metrorrhagia, cancers
Clinical Features
• PBS—microcytic, hypochromic red cells
• Bone marrow—mild normoblastic hyperplasia with loss of
sideroblasts and absence of stainable iron in the reticuloendothelial
cells
• Alopecia, koilonychia, and atrophy of the tongue and gastric
mucosa—depletion of essential iron-containing enzymes
• Plummer-Vinson syndrome—hypochromic microcytic anemia,
atrophic glossitis, and esophageal webs

Diagnosis
• Low serum iron and ferritin
• Increased TIBC
• Reduced plasma transferrin saturation
• Hypochromic microcytic anemia of iron deficiency. Note the
small red cells containing a narrow rim of peripheral
hemoglobin. Scattered fully hemoglobinized cells, present due
to recent blood transfusion, stand in contrast.
ANEMIA OF CHRONIC DISEASE

• May occur in association with:

• Chronic microbial infections e.g., tuberculosis, osteomyelitis
• Chronic immunologic disorders e.g., regional enteritis, RA
• Neoplasms e.g., cancers of breast or lung

• Serum iron levels and TIBC are reduced, with abundant iron storage

• Defect in reutilization of iron due to some impediment in the transfer

of iron from the RES to the erythroid precursors

• Anemia is normocytic normochromic, or microcytic hypochromic

• Treatment of underlying condition or administration of

erythropoietin corrects the anemia
APLASTIC ANEMIA

• Failure or suppression of multipotent myeloid stem cells and resultant

pancytopenia

Etiology
• ldiopathic in 65% or caused by:
• Myelotoxic drugs or chemicals—most common cause
• Predictable myelotoxins—benzene, alkylating agents, and antimetabolites
(e.g., vincristine, busulfan)
• Idiosyncratic reactions—chloramphenicol, chlorpromazine, and streptomycin
• Whole body irradiation
• Infections e.g., non-A, non-B, non-C, and non-G hepatitis
• Inherited diseases e.g., Fanconi anemia
Pathogenesis
• Idiopathic cases—stem cell failure may be due to:
• Primary defect or intrinsic abnormality of stem cells— genetically
damaged stem cells
• Extrinsic, immune-mediated suppression of altered stem cells (T cell-
mediated)

Morphology
• Hypocellular marrow —hematopoietic cells replaced by fat cells
• Secondary effects of granulocytopenia (infections), thrombocytopenia
(bleeding)

Clinical Features
• Insidious onset with symptoms related to pancytopenia
• Splenomegaly is absent
• In cases of chemical or drug exposure, withdrawal of the offending agent
may lead to recovery
• Treatment—BMT or immunosuppressive therapy
 MAJOR CAUSES OF APLASTIC ANEMIA

Acquired
Idiopathic
Primary stem cell defect
Immune mediated
Chemical agents
Dose related
Alkylating agents
Antimetabolites
Benzene
Chloramphenicol
Inorganic arsenicals
Idiosyncratic
Chloramphenicol
Phenylbutazone
Organic arsenicals
Methylphenylethylhydantoin
Streptomycin
Chlorpromazine
Insecticides (e.g., DDT, parathion)
Physical agents (e.g., whole-body irradiation)
Viral infections
Non-A, non-B hepatitis
Cytomegalovirus infections
Epstein-Barr virus infections
Herpes varicella-zoster
Miscellaneous
Infrequently, many other drugs and chemicals

Inherited
Fanconi anemia
• Aplastic anemia
(bone marrow
biopsy). Markedly
hypocellular
marrow contains
mainly fat cells. A,
Low power; B,
high power.
PURE RED CELL APLASIA

• Rare form of marrow failure that results from absence or near-

absence of red cell precursors

• May also appear insidiously in patients with thymomas—anemia is

cured by resection of the tumor
OTHER FORMS OF MARROW FAILURE

Myelophthisic Anemia
• Caused by space-occupying lesions that destroy or distort marrow
architecture and depress its productive capacity
• Pancytopenia, and presence of WBC and RBC precursors in the
blood
• Most common cause—metastatic cancer

Chronic Renal Failure

• Basis of anemia is multifactorial: ACD, reduced red cell production
because of inadequate production of erythropoietin
• r-EPO—associated with significant improvement
 POLYCYTHEMIA

• Increased concentration of red cells

• Relative—due to decreased plasma volume

• Dehydration e.g., deprivation of water or prolonged vomiting
• Stress polycythemia or Gaisbock syndrome—Idiopathic
• Absolute
• Primary—increase in red cell mass due to intrinsic abnormality
of myeloid stem cells; related to myeloproliferative syndrome
• Secondary—increase in red cell mass in response to increased
levels of erythropoietin, which may be:
• Appropriate e.g., lung disease, high-altitude living, cyanotic heart disease
• Inappropriate e.g., erythropoietin-secreting tumors (renal cell carcinoma,
hepatocellular carcinoma, cerebellar hemangioblastoma)
 PATHOLOGIC CLASSIFICATION OF POLYCYTHEMIA
Relative Reduced plasma volume (hemoconcentration)

Absolute
Primary Abnormal proliferation of myeloid stem cells, normal or low
erythropoietin levels (polycythemia vera)

Secondary Increased erythropoietin levels

Appropriate: lung disease, high-altitude living, cyanotic heart
disease
Inappropriate: erythropoietin-secreting tumors (e.g., renal cell
carcinoma, hepatocellular carcinoma, cerebellar
hemangioblastoma)
 BLEEDING DISORDERS

• Hemorrhagic diatheses may be caused by:

• Increased vascular fragility
• Disorders of platelets
• Defects in coagulation

• Evaluation requires laboratory tests:

• Bleeding time
• Coagulation time
• Platelet counts
• Prothrombin time
• Partial thromboplastin time
• Other tests e.g. clotting factor levels
INCREASED VASCULAR FRAGILITY

• Induce petechial and purpuric hemorrhages

• Platelet count and coagulation time are usually normal; bleeding
time is variable
• Conditions include:
• Infections—meningococcemia and rickettsioses; secondary to vasculitis or
DIC
• Drug reactions—mediated by the deposition of immune complexes in the
vessel walls with production of a hypersensitivity vasculitis
• Poor vascular support
• Impaired formation of collagen e.g., scurvy and Ehlers-Danlos syndrome
• Loss of perivascular supporting tissue e.g., Cushing syndrome
• Henoch-Schonlein purpura—systemic hypersensitivity reaction of unknown
cause characterized by a purpuric rash, colicky abdominal pain,
polyarthralgia, and AGN
THROMBOCYTOPENIA

• Decrease in platelet number

• Petechial bleeding—small vessels of the skin and mucous membranes
• Levels of 10,000 to 20,000/cu. mm., bleeding tendency becomes
clinically evident

Causes
• Decreased production of platelets
• Decreased platelet survival
• Sequestration—splenectomy can cure thrombocytopenia
• Dilutional—massive transfusions, blood stored for longer than 24 hours
contains virtually no viable platelets
• HIV-associated—multifactorial; immune complex injury, antiplatelet
antibodies, and suppression of megakaryocytes
 CAUSES OF THROMBOCYTOPENIA
Decreased Production of Platelets
Generalized diseases of bone marrow
Aplastic anemia: congenital and acquired
Marrow infiltration: leukemia, disseminated cancer
Selective impairment of platelet production
Drug-induced: alcohol, thiazides, cytotoxic drugs
Infections: measles, human immunodeficiency virus (HIV)
Ineffective megakaryopoiesis
Megaloblastic anemia
Paroxysmal nocturnal hemoglobinuria
Decreased Platelet Survival
Immunologic destruction
Autoimmune: idiopathic thrombocytopenic purpura, systemic lupus erythematosus
Isoimmune: post-transfusion and neonatal
Drug-associated: quinidine, heparin, sulfa compounds
Infections: infectious mononucleosis, HIV infection, cytomegalovirus
Nonimmunologic destruction
Disseminated intravascular coagulation
Thrombotic thrombocytopenic purpura
Giant hemangiomas
Microangiopathic hemolytic anemias

Sequestration
Hypersplenism
Dilutional
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• Immunologically mediated destruction of platelets

• Acute ITP—self-limited; often in children after a viral infection e.g.,

rubella, CMV infection, viral hepatitis, IM
• Platelet destruction is related to formation of antiplatelet
autoantibodies

• Chronic ITP—often in adults, women of childbearing age

• Platelet destruction results from platelet autoantibodies directed
toward 2 platelet antigens—platelet membrane gp complexes
Ib/IX and llb/llla
 • Long history of easy bruising or nosebleeds
• Antibodies can be demonstrated in the plasma and platelet
surface in 80%
• Destruction of antibody-coated platelets occurs in the spleen
• Splenectomy—beneficial in 75 to 80%

Diagnosis
• Thrombocytopenia
• Increased marrow megakaryocytes
• Bleeding time is prolonged
• PT and PTT are normal
• Also, test for antiplatelet antibodies
THROMBOTIC THROMBOCYTOPENIC PURPURA AND
HEMOLYTIC-UREMIC SYNDROME

• 2 related disorders within the spectrum of thrombotic

microangiopathies
• Thrombocytopenia, microangiopathic hemolytic anemia, fever,
transient neurologic deficits (TTP) or renal failure (HUS)
• Widespread hyaline microthrombi (composed of aggregates of
platelets and fibrin) found in arterioles and capillaries

Pathophysiology
• Basic defect: endothelial injury
• TTP—preceded by influenza-like illness
• HUS—verotoxin-producing E. coli

Clinical Features
• TTP—typically affects women
• HUS—usually occurs in children
HEMORRHAGIC DISORDERS RELATED TO DEFECTIVE PLATELET
FUNCTIONS
• Prolonged bleeding time with normal platelet count

• Congenital
• Defective platelet adhesion—e.g., Bernard-Soulier syndrome,
deficiency of a platelet membrane gp lb/IX complex, platelet
receptor for vWF necessary for platelet-collagen adhesion
• Defective platelet aggregation—e.g., Glanzmann's
thrombasthenia, deficiency of platelet membrane gp lIb/llla
complex, involved in binding fibrinogen
• Disorders of platelet secretion
• Acquired
• Aspirin ingestion—potent inhibitor of cyclooxygenase and
suppress the synthesis of TXA2, necessary for platelet
aggregation; its antiplatelet effect forms the basis of its use in the
prevention of MI
• Uremia
HEMORRHAGIC DIATHESES RELATED TO ABNORMALITIES IN
CLOTTING FACTORS

• Large ecchymoses or hematomas after an injury, or prolonged

bleeding after a laceration or any form of surgical procedure
• Bleeding into the GIT and GUT, and weight-bearing joints
(hemarthrosis) is common

Acquired Deficiencies
• Multiple clotting abnormalities
• Vitamin K deficiency—depressed synthesis of factors II, VII, IX, X
and protein C
• Because liver makes most of the clotting factors—liver disease may
be associated with hemorrhagic diathesis
• DIC—produces deficiency of multiple coagulation factors
Hereditary Deficiencies
• Affect a single clotting factor
• Most common—hemophilia (A and B) and von Willebrand disease
• vWF—necessary for adhesion of platelets to subendothelial
collagen; acts as a carrier for factor VIII; produced by endothelial
cells and megakaryocytes
• Factor VIll—takes part in the coagulation cascade by activating
factor X; produced by hepatocytes
VON WILLEBRAND DISEASE

• Types
1. Type 1—reduced quantity of vWF; AD disorder; most common form;
mild
2. Type 2—assembly of vWF multimer is defective, intermediate and
large multimers (most active form of vWF) are reduced; AD disorder
3. Type 3—reduced quantity of vWF; AR disorder; uncommon; severe

• Levels of factor VIII may be reduced—vWF stabilizes factor VIII in

circulation

• Compound defect—platelet function and coagulation pathway

• Prolonged bleeding time, normal platelet count, prolonged PTT

• Spontaneous bleeding from mucous membranes, excessive bleeding from

wounds, and menorrhagia
FACTOR VIII DEFICIENCY (HEMOPHILIA A)

• Reduced amount or activity of factor VIII

• Inherited as X-linked recessive trait that primarily affects males
• Clinical features develop only in the presence of severe deficiency
(levels <1% of normal)
• Massive hemorrhage after trauma or operative procedures
• Spontaneous hemorrhages—recurrent hemarthroses leading to
progressive, crippling deformities
• Absence of petechiae
• Prolonged PTT and normal bleeding time
• Diagnosis: assay for factor VIII
• Treatment: replacement therapy with factor VIII concentrates
FACTOR IX DEFICIENCY
(CHRISTMAS DISEASE, HEMOPHILIA B)

• Clinically indistinguishable from hemophilia A

• Inherited as X-linked recessive trait
• May occur asymptomatically or with associated hemorrhage
• Diagnosis: assay for factor IX
DISSEMINATED INTRAVASCULAR COAGULATION (CONSUMPTIVE
COAGULOPATHY)

• Acute, subacute, or chronic thrombohemorrhagic disorder occurring

as a secondary complication in a variety of diseases

• Activation of the coagulation pathway—formation of microthrombi

throughout the microcirculation—signs of infarction

• As a consequence of the thrombotic diathesis, there is consumption of

platelets, fibrin, and coagulation factors; and activation of
fibrinolytic mechanisms—hemorrhagic diathesis
Pathogenesis
• 2 major mechanisms by which DIC may be triggered:
1. Release of tissue factor or thromboplastic substances into the
circulation
2. Widespread injury to the endothelial cells
• Endothelial injury causes release of tissue factor from endothelial cells and
promotes platelet aggregation and activation of the intrinsic coagulation
pathway

Morphology
• Kidneys—microthrombi in renal glomeruli, microinfarcts or bilateral
renal cortical necrosis
• Lungs—microthrombi in alveolar capillaries, resembles ARDS
• Brain—microinfarcts and fresh hemorrhages
• Adrenals—massive hemorrhages give rise to Waterhouse-
Friderichsen syndrome seen in meningococcemia
 MAJOR DISORDERS ASSOCIATED WITH DISSEMINATED INTRAVASCULAR COAGULATION
Obstetric Complications
Abruptio placentae
Retained dead fetus
Septic abortion
Amniotic fluid embolism
Toxemia
Infections
Gram-negative sepsis
Meningococcemia
Rocky Mountain spotted fever
Histoplasmosis
Aspergillosis
Malaria
Neoplasms
Carcinomas of pancreas, prostate, lung, and stomach
Acute promyelocytic leukemia
Massive Tissue Injury
Traumatic
Burns
Extensive surgery
Miscellaneous
Acute intravascular hemolysis, snakebite, giant hemagioma, shock, heat stroke, vasculitis, aortic
aneurysm, liver disease
Clinical Features
• 50% with DIC—obstetric patients with pregnancy complications;
33% have carcinomatosis; others, sepsis and major trauma
• Microangiopathic hemolytic anemia resulting from widespread
microvascular occlusion
• Oliguria and acute renal failure
• Respiratory symptoms (e.g., dyspnea, cyanosis)
• Neurologic symptoms (e.g., convulsions and coma)
• Circulatory failure and shock
• Acute DIC—in obstetric complications or major trauma, dominated
by bleeding diathesis
• Chronic DIC—in cancer patients, present initially with thrombotic
complications
• Prognosis—depends on the underlying disorder
• Depending on the clinical picture—anticoagulants (e.g., heparin and
antithrombin III) or coagulants (e.g., FFP) may be administered
 Pathophysiology of disseminated intravascular
coagulation.

• Pathophysiology of disseminated intravascular coagulation.

 DISEASES OF THE
RESPIRATORY SYSTEM
Mila Amor V. Reyes, MD, FPSP
Anatomic and Clinical Pathologist
 CONGENITAL ANOMALIES

• CONGENITAL CYSTS—most common; consist of cystic

spaces lined by bronchial-type epithelium

• complications: infection with suppuration, abscess

formation, and rupture Into bronchi or pleural cavity,
causing hemorrhage or hemoptysis and pneumothorax
• BRONCHOPULMONARY SEQUESTRATION—presence of
lung tissue without a normal connection to the airway
system

• vascular supply derived from the aorta or its branches

• Extralobar – common in infants; associated with other

congenital anomalies

• Intralobar – common in adults; associated with recurrent

infections
• ATELECTASIS—incomplete expansion or collapse of parts
of or a whole lung

1. RESORPTION—follows complete obstruction of an

airway (e.g., excessive bronchial secretions, foreign
body aspiration, bronchial neoplasms)

2. COMPRESSIVE—pleural space is expanded by fluid

(e.g., pleural effusions, hemothorax), or by air (e.g.,
pneumothorax)

3. 3. PATCHY—loss of pulmonary surfactant (e.g.,

neonatal RDS)
 PULMONARY VASCULAR DISEASE

PULMONARY EDEMA

• lungs are heavy, wet, and subcrepitant; fluid accumulates,

especially in the dependent, basal regions of the lower
lobes

• engorged capillaries, filling of the intra-alveolar spaces

by a granular pink precipitate

• chronic edema impairs normal respiration and

predisposes to infection
ADULT RESPIRATORY DISTRESS SYNDROME

• characterized by diffuse alveolar capillary damage, leading

to severe pulmonary edema, respiratory failure, and arterial
hypoxemia refractory to oxygen therapy

• diffuse bilateral infiltrates on x-ray and frequent

superimposed infections resulting in greater than 50%
mortality

• basic lesion is diffuse damage to the alveolar wall (involving

the capillary endothelium and the epithelium)

• increased capillary permeability and edema, fibrin

exudation, formation of hyaline membranes (necrotic
epithelial cell debris and exuded proteins), and septal
inflammation
• mechanisms of injury
• oxygen-derived free radicals
• aggregation of activated PMNs
• activation of lung macrophages
• loss or damage to surfactant

• acute stage—lungs are diffusely firm, red, boggy, and

heavy with acute diffuse alveolar damage (edema,
hyaline membranes, acute inflammation)

• proliferative/organizing stage—patchy areas of

interstitial fibrosis and type II epithelial proliferation, with
superimposed bacterial infection
PULMONARY EMBOLISM, HEMORRHAGE, AND
INFARCTION

• occlusions of pulmonary arteries are almost always

embolic; >95% arise in deep veins of legs

• frequency of pulmonary embolism correlates with a

predisposition to leg thrombosis

• potential consequences
• large emboli (5%)—may cause instantaneous death,
cardiovascular collapse
• middle-sized emboli (20-35%)—induce infarction
 • small emboli (60-80%)- maybe clinically silent in
patients without CV failure; may cause transient chest
pain and hemoptysis owing to pulmonary hemorrhage;
in patients with CV failure, may give rise to small
infarctions (peripheral, wedge-shaped hemorrhagic
areas)

• diagnosis Is difficult (almost two thirds even when fatal,

are not diagnosed before death)

• even without treatment, there is usuaIIy improvement in

perfusion within the first day (fibrinolysis and contraction
of the thrombotic mass)

• may completely resolve or converted to fibrous scar

PULMONARY HYPERTENSION

• Elevated pulmonary artery pressure caused by increased

pulmonary vascular resistance

• Primary (idiopathic)—uncommon; seen in children or in

women aged 20-40; generally progress to severe
respiratory insufficiency, or pulmonale, and death

• treatment includes vasodilators and heart-lung

transplantation
• cause is unknown (endothelial dysfunction and injury
lead to persistent vasoconstriction, intimal and medial
hypertrophy, and resultant increases in vascular
resistance)
• Secondary—more common; COPD, interstitial lung
disease, left-sided heart disease, recurrent pulmonary
emboli

• vascular lesions incude: atheroma in large elastic arteries,

intimal fibrosis or medial hypertrophy in medium-sized
muscular arteries and smaller arterioles
 CHRONIC OBSTRUCTIVE PULMONARY DISEASE

• characterized by increased resistance to airflow

EMPHYSEMA

• abnormal enlargement of airspaces distal to the terminal

bronchioles, with destruction of their walls

• classified according to the anatomic distribution of the

lesion within the acinus
• CENTRIACINAR- involves the central or proximal acinus;
predominant involvement of the upper lobes and
apices; seen primarily in male smokers, often in
association with chronic bronchitis

• PARASEPTAL- involves the distal acinus; found near the

pleura and adjacent to fibrosis or scars; often found in
spontaneous pneumothorax

• PANACINAR- involves the entire acinus; predominance

in lower basal zones; strong association with α1-
antitrypsin deficiency

• IRREGULAR- irregular involvement of the acinus;

associated with scarring; usually asymptomatic
• protease-antiprotease hypothesis holds that destruction
of alveolar walls stems from an imbalance between
proteases (trypsin) and their inhibitors (α1-antitrypsin)

• individuals with a hereditary deficiency of α1-

antitrypsin invariably develop emphysema and at a
younger age if they smoke

• pulmonary instillation of proteolytic enzymes

(neutrophil elastase), results in emphysema in
experimental animals
CHRONIC BRONCHITIS

• persistent cough with sputum production for at least 3

months in at least 2 consecutive years, characterized by:

• hyperemia and edema of mucous membranes of the

lungs
• mucinous secretions or casts filling airways
• increase in size of the mucous glands
• bronchial or bronchiolar mucous plugging, inflammation,
and fibrosis
• squamous metaplasia or dysplasia of bronchial
epithelium
• dominant factor in its pathogenesis: chronic irritation of
the airways by inhaled substances (tobacco smoke)

• irritants cause bronchitis by eliciting

• hypersecretion of mucus
• hypertrophy of mucous glands
• goblet cell metaplasia in bronchiolar epithelium
• bronchiolitis

• infections are a secondary factor that maintain and

promote the injury initiated by smoking
BRONCHIAL ASTHMA

• Chronic relapsing inflammatory disorder and increased

responsiveness of the tracheobronchial tree to various
stimuli, resulting in paroxysmal contraction of bronchial
airways

• lungs are overinflated, show patchy atelectasis, with

occlusion of airways by mucous plugs

• lungs exhibit edema, inflammatory infiltrates in bronchial

walls (eosinophils), hypertrophy of bronchial wall
musculature and submucosal mucous glands, Curschmann
spirals, and crystalloid debris of eosinophil membranes
(Charcot-Leyden crystals) within airways
• two major types:

1. extrinsic atopic (alIergic, reagin-mediated)—most

common, triggered by environmental antigen (e.g.,
dust, pollen, food) often with a positive family
history of atopy; classic type I lgE-mediated
hypersensitivity reaction

2. intrinsic nonatopic (nonreaginic, idiopathic)— often

triggered by respiratory tract infections, chemical
irritants, and drugs; usually without a family history
and with little or no evidence of IgE-mediated
hypersensitivity
BRONCHIECTASIS

• Chronic necrotizing infection of bronchi and bronchioles

leading to or associated with abnormal permanent
dilation of these airways

• Clinical features: cough, fever, abundant purulent sputum,

obstructive respiratory insufficiency

• complications: cor pulmonale,metastatic abscesses, and

systemic amyloidosis
• seen in association with
• bronchial obstruction (tumor, foreign bodies)
• congenital/heriditary conditions (cystic fibrosis, intralobar
sequestrations)
• immotile ciIia syndromes (Kartagener syndrome)
• necrotizing pneumonia

• Persistent obstruction leads to atelestasis and diminished

elastic forces holding airways, resulting in relaxation and
dilation; may become irreversible if they occur during
development or if added infection contributes further damage
to the airways walls

• Dilation of distal airways of lower lobes; mild to necrotizing

acute and chronic inflammation of airways

• Fibrosis develops in chronic cases; extension of bronchial

infection may lead to abscess formation
 PULMONARY INFECTIONS

• Occur when normal lung or systemic defense mechanisms

are impaired

• Pulmonary defense mechanisms induce nasal

tracheobronchial and alveolar mechanisms to filter,
neutralize, and clear inhaled organisms and particles
• Important factors interfering with normal lung defenses
are:

• Loss of or decreased cough reflex leading to

aspiration (e.g., coma, anesthesia, drug effects)
• Injury to mucocillary apparatus (e.g., cigarette or other
smoke inhalations)
• Decreased phagocytic or bacterial function of the
alveolar macrophage (e.g., alcohol, tobacco, oxygen
toxicity)
• Edema or congestion (e.g., CHF)
• Accumulation of secretions
BACTERIAL PNEUMONIA

• Bronchopneumonia—marked by patchy exudative

consolidation of lung parenchyma

• caused most commonly by staphylococci, streptococci,

pneumococi, H. influenzae, P. aeruginosa, and coliform
bacteria

• lungs show dispersed, elevated, focal areas of

palpable consolidates and suppuration, acute (PMNs)
inflammatory exudates filling airspaces and airways
• Lobar Pneumonia—involves a large portion of or an
entire lobe of lung

• caused most commonly by pneumococci, K.

pneumoniae, staphylococci, streptococci, H.
influenzae

• complications: abscess formation, empyema,

organization of exudates into fibrotic scar tissue,
bacteremia, and sepsis
• classic sequence of stages (infrequently seen because
of antibiotic therapy)

1. congestion- predominates in the first 24 hours

2. red hepatization- acute exudation with PMNs and
RBCs, giving a red, firm, liver-like appearance
3. gray hepatization- RBC’s disintegrate and
fibrinosuppurative exudates persists, giving a
gray-brown appearance
4. resolution- favorable final stage in which
consolidated exudates undergoes enzymatic and
cellular degradation and clearance; normal
structure restored
VIRAL AND MYCOPLASMAL (PRIMARY, ATYPICAL)
PNEUMONIA

• infections by viruses (e.g., influenza A or B, RSV,

adenovirus, rhinovirus, HSV, CMV) or M. pneumoniae
result in varied clinical and pathologic patterns (from mild
upper RT involvement to severe lower RT disease)

• patchy or lobar areas of congestion without consolidation

(atypical pneumonia); predominance of interstitial
pneumonitis (widened, edematous alveolar walls with
mononuclear inflammatory infiltrate)

• formation of hyaline membranes; frequent superimposed

bacterial infection
LUNG ABSCESS

• Marked by localized suppurative necrosis of lung tissue

of infectious origin (staphylococci, streptococci, gram-
negative bacteria, and anaerobes)

• Mixed infections are frequent

• Complications include extension into the pleural cavity,

hemorrhage, septic embolization, and secondary
amyloidosis

• More common on the right, reflecting the more vertical

right bronchus; chronic abscessess are often surrounded
by a reactive fibrous wall
• Infections can be initiated by:

• Aspiration of infective material, as in oropharyngeal

surgical procedures, dental sepsis; or aspiration
secondary to diminished consciousness from coma,
drugs, anesthesia, and seizures
• Antecedent primary bacterial infection
• Septic emboli from infected thrombi or cardiac valve
vegetations
• Obstructive tumors
• Direct traumatic punctures
• Spread of infection from adjacent organs
TUBERCULOSIS

• chronic, communicable disease caused by M. tuberculosis

made distinctive by a necrotizing (caseating)
granulomatous tissue response to organisms

• transmission is usually by inhalation of infected droplets

produced by coughing or sneezing of infected individuals

• predisposing factors are any debilitating or

immunosuppressive condition (e.g., diabetes, alcoholism,
malnutrition, chronic lung disease)
• cell wall Iipids and carbohydrates of M. tb appear to
enhance virulence by interfering with phagolysosomal
fusion which allows intracellular survival and replication

• delayed hypersensitivity to the tubercle bacillus develops

in 2 to 4 weeks after initial infection; positive PPD test
indicates sensitivity; not active disease

• granulomatous inflammatory response consists of

epithelioid histiocytes, lymphocytes, Langhan's type giant
cells, fibroblasts with central, caseous necrosis
Several forms of tb occur, depending on the
individuals hypersensitivity and resistance:

1. Primary Pulmonary TB—occurs in individuals

lacking previous contact with tubercle bacilli
• begins as single granulomatous lesion
subjacent to pleura in the inferior upper lobe
or superior lower lobe (Ghon focus) ; spread
to draining ipsilateral bronchial or hilar
lymph nodes (Ghon complex)
• usually asymptomatic; in most cases, infection
does not progress and results in local scarring
and calcification
2. Secondary Pulmonary TB—denotes active
infection in a previously sensitized individual
• most cases represent reactivation of dormant
bacilli from primary lesion;
• generally found in the apices of the lungs
(reflecting the preference for high p02)
• may progress to cavitary fibrocaseous tb, tb
bronchopneumonia, or miliary tb
• causes fever, night sweats, weight loss,
productive cough with blood-streaked sputum,
or hemoptysis
3. Disseminated TB- hematogenous spread may
produce:

1) Miliary tb with myriad minute foci of infection

in many organs, particularly liver, bone
marrow, spleen, and kidneys;

2) Isolated organ tb when organisms become

established in only one or two organs, most
often adrenals, kidneys, bone, female genital
tract (salpingitis, endometritis)
 INTERSTITIAL LUNG DISEASE

• Comprises a heterogenous group of diseases with similar

clinical, radiologic, and pathologic changes

• Clinical restrictive: disease (dyspnea, decreased

lung volumes/TLC, and decreased compliance)

• Radiologic: diffuse infiltrates, ground-glass shadows

• Pathologic: diffuse, chronic inflammation or fibrosis

of alveolar interstitium
• Pathogenetic sequence of events

• Initial event—injury to epithelium or endothelium via

inhaled blood-borne toxins or agents

• Early acute changes of alveolitis—recruitment of

chemotactic factors (e.g., IL-8) of activated
inflammatory cells that release injurious (e.g., oxidants,
cytokines) and fibrogenic (e.g., PDGF, FGF, IL-1)
mediators

• Late effects—result in interstitial fibrosis

PNEUMOCONIOSES

• disorders caused by inhalation of aerosol, including mineral

dust, organic dust, fumes, and vapors

• the following factors determine the health effects of inhaled

dusts
• amount of dust retained, in turn determined by the
concentration, duration of exposure, and effectiveness of
clearance mechanisms
• size, shape, and buoyancy of particles (>5mm are filtered
in upper airways, <1mm can remain suspended and be
exhaled, 1-5mm settle in the alveoli and are the most
potentially dangerous particles
• physicochemical reactivity and solubility of particles may
rapidly cause toxicity, those that resist dissolution may
persist to invoke a chronic fibrotic reaction
• Carbon Dust (Coal Worker’s Pneumoconiosis)

• Anthracosis—small harmless accumulations seen in the

lungs of urban dwellers and smokers

• Simple CWP—more prominent and numerous

aggregates of coal dust-laden macrophages forming
black coal macules (1-5 mm in dia) are present
diffusely especially in the upper zones of the upper
and larger lobes; cough with blackish sputum, but no
significant dysfunction is seen

• Progressive massive fibrosis or complicated CWP—

severe fibrosis and large black scars are present
especially in the upper zones (black lung disease);
results in disabling respiratory insufficiency
• Silicosis

• prolonged inhalation of silica particles produces a chronic, nodular,

dense pulmonary fibrosis

• sources of silica exposure: mining (Au, Sn, Cu, coal) and quarrying,
sandblasting, metal grinding, manufacture of ceramics

• involves persistent Inflammation and fibrosis by the interaction of silica

particles and lung macrophages

• activated macrophages release oxidants, cytokines, and GFs that

cause fibroblast proliferation and collagen deposition

• distinct collagenous nodules in the upper lung but grow larger and
more diffuse forming large areas of dense scars; calcification or
concomitant blackening by coal dust often present

• hyalinized whorls of collagen with scant inflammation; polarized light

shows birefringent silica particles within nodules
• Asbestosis

• Heavy occupational exposure causes diffuse interstitial

fibrosis and the presence of numerous asbestos bodies
within the scarred lung

• Inhaled fibers that reach the alveoli are ingested by

alveolar macrophages, stimulating the release of C5a
and other chemoattractants

• most asbestos is cleared by the macrophages, others

reaches the interstitium and lymphatics
• Possible mechanisms for lung injury and progressive fibrosis
include:
1. Release of enzymes or toxic free radicals by the
macrophages or PMNs
2. Release of fibrogenic cytokines and growth factors by
activated macrophages
3. Direct stimulation of fibroblast collagen synthesis by
asbestos
• Asbestos also induces pleural reactions manifested by:
benign effusions, fibrous pleural adhesions, and dense
fibrocalcific plaques
• Also associated with increased risk of bronchogenic
carcinoma and malignant mesothelioma
SARCOIDOSIS

• relatively common disease of unknown etiology, characterized

by noncaseating granulomas in virtually any tissue, women are
affected more frequently than men

• maybe asymptomatic, may present as isolated cutaneous or

ocular lesions, peripheral lymphadenopathy, or
hepatosplenomegaly, with an acute or insidious onset
accompanied by fever, erythema nodosum and polyarthritis

• diagnosis can be definitely estabIished only by biopsy(often

liver or lymph node)

• other diseases (e.g., tb, berrylliosis, fungal infections) may also

show the same histologic features, diagnosis of sarcoidosis is
then one of exclusion
• distinctive granulomatous response suggests an immune-
mediated phenomenon; immune abnormalities include:

• lymphocytic alveolitis, with numerous activated CD4+ T cells

(increased IL-2 production, HLA-DR antigen proliferation),
and activated alveolar macrophages (increased IL-1,
oxygen free radical production)

• cutaneous anergy to agents that normally induce delayed

hersensitivity reaction (e.g., tuberculin)

• absolute lymphopenia caused by reduced T cells, B cells

are present in normal numbers and are hyper reactive

• activated helper T cells and their secreted cytokines

account for the influx of monocytes and subsequent
granulomas and cell-mediated injury
• granulomas composed of epithelioid histiocytes, often with
multinucleated giant cells; present in 60% are Schaumann
bodies (laminated, calcified proteinaceous concretions) and
asteroid bodies (stellate inclusions within giant cells)

• lymph nodes are virtually always involved (hilar and

mediastinal), tonsils (25-33%), spleen and liver (75%), skin
(33-50%), eye (20-50%)

• may be slowly progressive, may have a remitting or resolving

course, or spontaneously resolve

• in 65-70%, no or only minimal residual manifestations, 20%

permanent lung or ocular dysfunction, and 10% die, primarily
from progressive pulmonary fibrosis and cor pulmonale
IDIOPATHIC PULMONARY FIBROSIS

• Poorly understood disorder of unknown cause

characterized by progressive pulmonary interstitial
fibrosis that results in hypoxemia

• In some cases, immune complex deposition (antigens are

unknown) can be identified, but their role in causing the
disorder is not established

• Most common between 30 and 50 years of age

• Changes vary according to stage

• Early stage—interstitial and intra-alveolar edema,

interstitial infiltration by leukocytes, and type II
pneumonocyte proliferation

• Intermediate stage- interstitial and intra-alveolar

fibrosis

• End stage- honeycomb lung

• Disease is progressive in most cases, resulting in

pulmonary insufficiency, cor pulmonale, and cardiac
failure
HYPERSENSITIVITY PNEUMONITIS

• Immunologically mediated disorder caused by inhaled dusts or

antigens

• Farmer’s lung— spores of thermophilic actinomycetes in hay

• Pigeon breeder’s lung—proteins from bird feathers or excreta
• Humidifier or air conditioner lung- thermophilic bacteria

• Interstitial pneumonitis and fibrosis, noncaseating, loosely formed

granulomas

• Early cessation of exposure prevents progression to serious chronic

fibrosis

• Cough, dyspnea, fever, diffuse and nodular radiographic densities,

and restrictive pattern of pulmonary dysfunction
PULMONARY EOSINOPHILIA

• Infiltration of eosinophils in the interstitial or alveolar spaces

• Simple pulmonary eosinophilia (Loeffler syndrome)—of

uncertain origin; transient, benign infiltrates with prominent
eosinophilia in blood and lung

• Tropical eosinophilia—caused by microfilariae

• Secondary chronic pulmonary eosinophilia—induced by

infections, hypersensitivity, asthma, and allergic
bronchopulmonary aspergillosis

• Idiopathic chronic eosinophilic pneumonia—of unknown

etiology, focal consolidation of lung with prominent
lymphocytes and eosinophils; steroid responsive
BRONCHIOLITIS OBLITERANS-ORGANIZING PNEUMONIA

• common response to infectious or inflammatory injury of

the lungs

• associated with cough, dyspnea, and often a recent RT

infection; also, inhaled toxins, drugs, collagen vascular
disease, and GVHD in bone marrow transplant recipients

• loose fibrous tissue plugs within bronchioles and

organizing pneumonia

• many patients improved gradually or with steroid

therapy
DIFFUSE PULMONARY HEMORRHAGE

• Serious complication of some interstitial lung diseases, so-

called pulmonary hemorrhage syndrome

• Goodpasture syndrome—necrotizing, hemorrhagic

interstitial pneumonitis and progressive glomerulonephritis
caused by antibodies against analogous basement
membrane antigens in lungs and kidneys

• Idiopathic pulmonary hemosiderosis—chronic, episodic

hemorrhage of lung, of unknown cause, resulting in
prominent hemosiderin deposition and fibrosis

• Vasculitis-associated hemorrhage—seen with Wegener

granulomatosis, SLE, and hypersensitivity angiitis
PULMONARY ALVEOLAR PROTEINOSIS

• a disease of obscure etiology and pathogenesis;

characterized radiologically by accumulation of dense,
amorphous, PAS+, lipid-laden material in intra-alveolar
spaces; and clinically by dyspnea, cough, sputum-containing
gelatinous material

• intra-alveolar exudates consists of surfactant-like material,

necrotic alveolar macrophages, and type II epithelial cells

• may occur after exposure to irritating dusts and chemicals,

and immunosuppressed individuals

• most have progressive course, some have benign course with

eventual resolution of the lesion
 TUMORS

BRONCHOGENlC CARCINOMA

• constitutes 90-95% of lung tumors

• most common cause of cancer death in both sexes

• tobacco smoking is well established as the most important

and common etiologic factor in the development of lung
cancer

• other etiologic factors: radiation exposure, asbestos, air

pollution, miscellaneous occupational inhaled substances
• Histologic types

• Adenocarcinoma—most common; presents as a

peripheral mass; gland formation with mucin
production, often with an adjacent desmoplastic
response

• Squamous Cell Carcinoma—has closest correlation with

smoking; most arise in or near the hilus; vary from well-
differentiated keratinizing neoplasms to anaplastic
tumors with only focal differentiation
• Small Cell Carcinoma—most malignant; usually
presents as central or hilar tumor; strongly associated
with cigarette smoking; small, oatlike cells with little
cytoplasm in nests or clusters, without squamous or
glandular organization

oUltrastructuraly exhibit neurosecretory granules, and

immunohistochemicaly positive for neuroendocrine
markers
oMost often produce paraneoplastic syndromes

• Large Cell Carcinoma—probably represents poorly

differentiated squamous cell carcinomas or
adenocarcinomas
• usually present with cough, weight loss, chest pain, and
dyspnea
• overall 5-year survival is approximately 9%
• small cell carcinoma has almost always metastasized by the
time of diagnosis precluding surgical intervention;
responsive to chemotherapy but ultimately recurs
• associated paraneoplastic syndromes
oADH (SIADH)
oACTH (Cushing syndrome)
oPTH or PGE (hypercalcemia)
oCalcitonin (hypocalcemia)
oGonadotropins (gynecomastia)
oSerotonin (carcinoid syndrome)
oothers: myopathy, peripheral neuropathy, acanthosis
nigricans, hypertrophic pulmonary osteoarthropathy (e.g.,
clubbing of finger)
BRONCHIOLOALVEOLAR CARCINOMA

• Uncommon form of adenocarcinoma arising in the

terminal bronchioloalveolar regions, almost always in the
lung periphery

• Tall, columnar, often mucin-producing tumor cells line up

along preserved alveolar septa, forming papillary
projections within the spaces

• Occur in both sexes equally and not usually associated

with smoking
BRONCHIAL CARCINOID

• represents 1-5% of all lung tumors, characterized by

neuroendocrine differentiation

• surgical resection is curative in 90-95%

• 10% are more aggressive, exhibiting local invasion or distant

metastases

• tumors are usually intrabronchial, highly vascular, polypoid, <3-

4 cm in diameter

• uniform, small, round cell in nests or cords; neurosecretory granules

are present

• positive for NSE, serotonin, calcitonin, bombesin

MISCELLANEOUS TUMORS

• Hamartomas—reIatively common, benign, nodular

neoplasms composed of cartilage and admixtures of
other mesenchymal tissues (e.g., fat, blood vessels, fibrous
tissue)

• Mediastinal Tumors—arise from local structures or may

represent metastasis

• Metastatic Tumors—common, occur via direct extension

from contiguous organs or lymphatics or hematogenous
route
 DISEASES OF THE PLEURA

• most pleural lesions are secondary to underlying lung disease

PLEURAL EFFUSIONS

• accumulations of transudate (Hydrothorax) or serous exudates may

appear with
• increased hydrostatic pressure (e.g., CHF)
• increased vascular permeability (e.g., pneumonia)
• decreased oncotic pressure (e.g., NS)
• increased negative intrapleural pressure (e.g., atelectasis)
• decreased lymphatic drainage (e.g., carcinomatosis)

• Hemothorax—ruptured aortic aneurysm

• Chylothorax—neoplastic lymphatic obstruction

PLEURITIS

• Serofibrinous—reflecting inflammatory processes in the

lung (e.g., tb, pneumonia, infarcts, abscesses or systemic
diseases like RA, uremia)

• Suppurative—a.k.a. empyema, reflecting infection of the

pleural space

• Hemorrhagic—occurs with bleeding disorders, neoplasms,

and rickettsial diseases
PNEUMOTHORAX

• air or gas in the pleural cavity

• Traumatic—resulting from air escape from the lung after

rib fractures

• Spontaneous—occurring in young individuals after

rupture of peripheral apical blebs

• Tension—occurs when lung and mediastinal structures are

compressed by the collected air; represents a serious,
potentially fatal complication
PLEURAL TUMORS

• most common are metastatic from lung, breast, ovaries, or

other organs which often cause a malignant effusion

• Pleural Fibroma—a.k.a. benign mesothelioma

• localized, noninvasive, fibroblastic tumor composed of

submesothelial fibroblasts in the pleural surfaces of the
lungs

• resection is curative
• Malignant Mesothelioma

• uncommon tumor, occurs most often on the pleural

mesothelial cells

• associated with occupational exposure to asbestos in

90%, but only 20% have actual pulmonary asbestosis;
nevertheless, bronchogenic carcinoma remains the most
common lung tumor found in asbestos workers

• present with chest pain, dyspnea, and recurrent pleural

effusions

• spreads diffusely over the surface of the lung and its

fissures
• PATTERNS OF GROWTH

1. Sarcomatoid conformation consisting of malignant,

spindle-shaped cells resembling fibrosarcoma
(20%)

2. Epithelioid growth composed of epithelium-like

cells that form tubules and papillary projections
resembling adenocarcinoma (70%)

3. mixed (biphasic)- 10%

• highly malignant tumors that invade the lung and can

metastasize widely, few patients survive longer than 2
years