WHITE BLOOD CELLS, LYMPH NODE, SPLEEN

Components of the Hematopoietic System

 Myeloid tissues: bone marrow and cells derived from it (RBCs, platelets, granulocytes, monocytes)
o Bone marrow is the source of all lymphoid progenitor cells
o Neoplastic disorders of myeloid progenitor cells (myeloid leukemias) originate in bone
marrow but secondarily involve the spleen and (lesser degree) lymph nodes
 Lymphoid tissues: thymus, lymph nodes, spleen

Development and Maintenance of the Hematopoietic Tissues

 Hematopoietic Stem Cells (HSCs)

o Formation
 Initial site of blood cell progenitor production is yolk sac (3 rd week) (not HSCs)
 Mesoderm: source of HSCs
 3rd month: HSCs migrate to liver – chief site of blood cell formation until shortly
before birth
 4th month: HSCs shift to bone marrow
 At birth bone marrow throughout the skeleton is active and liver shuts down
blood cell production
 At puberty, activity is restricted to the axial skeleton
o Properties
 Pluripotency: ability of one HSC to generate all mature hematopoietic cells
 Capacity for self-renewal: when an HSC divides, at least one daughter cell must be
capable of self-renewal (may occur in in niches in stromal cells under influence of
secreted factors)
 NOT sessile: can be mobilized to blood in stress (severe anemia), or extramedullary
hematopoiesis
o Marrow response to short-term physiologic needs is regulated by hematopoietic growth
factorss through effects on committed progenitors
 As progenitors differentiate they express receptros for lineage-specific growth factors
that stimulate their short-term growth and survival (stem cell factor (c-KIT), FLT3-
ligand, EPO, GM-CSF, thrombopoietin); operate on feedback loops
 Tumors of hematopoietic origin are often associated with mutations that block
progenitor cell maturation or abrogate their growth factor dependence (unregulated
clonal expansion of hematopoietic elements)
 Can originate from transformed HSCs that can differentiate or more
differentiated progenitors that have capacity for self-renewal
 Leukoerythroblastosis: abnormal release of immature precursors into the
peripheral blood
 Nurse cells: red cell precursors that surround macrophages and provide
some of the iron needed for synthesis of hemoglobin
 Formed elements of blood: RBCs, granulocytes, monocytes, platelets, lymphocytes have common
origin in HSCs (pluripotent cells that sit at the apex of hierarchy of bone marrow progenitors)
o HSCs give rise to 2 multipotent types of cells:
 Common lymphoid progenitors: source of T-cell, B-cell and NK cell precursors
 Common myeloid progenitors : give rise to Colony Forming Units, CFUs- committed
progenitors restricted to differentiation along particular lineages
 Precursors (myeloblasts, proerythroblasts, megakaryocytes) give rise to
mature granulocytes, RBCs and platelets
Table 13.1 Adult reference ranges for Blood Cells
Cell Type
White cells 4.8-10.8 (x10^3/uL)
Granulocytes 40-70%
Neutrophils 1.4-6.5 (x10^3/uL)
Lymphocytes 1.2-3.4 (x10^3/uL)
Monocytes 0.1-0.6 (x10^3/uL)
Eosinophils 0-0.5 (x10^3/uL)
Basophils 0-0.2 (x10^3/uL)
Red Cells 4.3-5 (men); 3.5-5.0 (women (x10^3/uL)
Platelets 150-450 (x10^3/uL)
Disorders of White Cells

Leukopenia – deficiency of leukocytes, usually results from reduced numbers of neutrophils (neutropenia,
granulocytopenia),

 Lymphopenia – decreased number of lymphocytes; less common

o Causes: congenital immunodeficiency, AIDS, steroids, cytotoxic drugs, autoimmune
disorders, malnutrition, acute viral disorders
 In acute viral disorder stems from activation not decreased number
 Neutropenia – reduction in the number of neutrophils
 Agranulocytosis – clinically significant reduction,
o Causes:
 Inadequate or ineffective granulopoiesis (hypoplastic marrow): suppression of HSCs,
suppression of committed granulocytic precursors by drugs (most common
cause), disease states with ineffective hematopoiesis, rare congenital conditions
(Kostmann syndrome,impairment of granulocytic differentiation)
 Drugs responsible: aminopyrine, chloramphenicol, sulfonamides,
chlorpromazine, thiouracil, phenylbutazone
o Antibody mediated destruction of mature neutrophils
 Accelerated removal of the neutrophils from the blood (hyperplastic marrow):
immunologically mediated injury to neutrophils (lupus, drug exposure (antibiotics)),
splenomegaly (sequesteration and hypersplenism), increased peripheral utilization
(overwhelming bacterial, fungal and rickettsial infections)
o Clinical features: infection (severe bacterial and fungal infections when neutrophil count
<500/mm^3), malaise, chills, fever, weakness, fatigue, ulcerating necrotizing lesion of oral
cavity
o Treatment: if caused by myelosuppressive chemotherapy, can be treated with G-CSF

Reactive (Inflammatory) Proliferations of White Cells and Lymph nodes – expansion of

leukocytes in response to underlying primary, often microbial, disease

 Leukocytosis – increased number of white cells in the blood, common reaction to variety of
inflammatory states, usually a shift from the splenic pool to blood
o Pathogenesis: blood count is influenced by size of storage pools, rate of release from pools,
proportion of cells adherent to blood vessel walls (marginal pool), and rate of extravasation
of cells from blood to tissues
o Leukocyte homeostasis is maintained by cytokines, growth factors, and adhesion molecules
o Most important cause of neutrophilic leukocytosis is infection – release of IL-1, TNF
and other cytokines stimulates production of hematopoietic growth factors
 G-CSF induces neutrophilia
 IL-5 stimulates eosinophilia
o In sepsis or severe inflammatory disorders leukocytosis is accompanied by morphologic
changes in neutrophils (toxic granulation, Döhle bodies, and cytoplasmic vaculoes)
o Leukemoid reaction: severe infection (like viral infection in children) causes many
immature granulocytes to appear in the blood, simulating myeloid leukemia; left shift (more
immature cells, bands)
Table 13.3 Causes of Leukocytosis
Type of Leukocytosis Causes
Neutrophil Acute bacterial infections (esp pyogenic), tissue
necrosis (MI, burns)
Eosinophil Allergic, parasitic, drugs, certain malignancies
(lymphomas), vascular disorders
Basophil Myeloproliferative disease (CML)
Monocye Chronic infections (TB), IBD (Crohns)
Lymphocyte Chronic infections (TB), viral infections, pertussis,
CLL

 Lymphadenitis – activation of resident immune cells leads to morphological changes in lymph

nodes (primary follicles changed to germinal centers); degree and pattern of the changes are
dependent on the inciting stimulus and intensity of the response; infections and inflammatory
stimuli elicit regional or systemic immune reactions in lymph nodes
o Acute nonspecific lymphadenitis: enlarged, painful, red, abscesses, draining sinuses; focal
or systemic; large reactive germinal centers, when caused by pyogenic bacteria can cause
node to undergo necrosis
o Chronic nonspecific lymphadenitis: nontender; follicular hyperplasia (B-cell responses; RA,
toxoplasmosis, HIV), paracortical hyperplasia (T-cell responses; viral infections), reticular
hyperplasia/sinus histiocytosis (increased number and size of cells lining lymphatic
sinusoids; cancer-draining nodes), organized collections in non-immune tissues (H. pylori
stimulate Peyer’s patches; lymphotoxin)

Neoplastic Proliferations of White Cells – expansion of leukocytes due to primary neoplasm

 Etiologic and Pathogenic Factors in White Cell Neoplasia

o Chromosome translocations and other acquired mutations
 Nonrandom chromosomal abnormalities, most commonly translocations, occur in the
majority of white cell neoplasms
 Mutated or altered genes often play critical roles in the development, growth,
or survival of the normal counterparts of the malignant cells ( e.g.
MALTomas)
 Oncoproteins created by genomic aberrations often block normal maturation
often at stages when they are proliferating rapidly (activating mutations in
tyrosine kinases that increase cell survival and proliferation)
 Proto-oncogenes are often activated in lymphoid cells by errors that occur
during antigen receptor gene rearrangement and diversification (e.g. in
germinal center B cells during antibody diversification)
 Upregulation of activation-induced cytosine deaminase (AID) (for class
switching and somatic hypermutation): causes c-MYC and BCL6
activation
 Sometimes V(D)J recombinase mechanism goes awry causing tumors
of T-cell precursors
o Inherited genetic factors – promote genetic instability; increased risk for leukemia
 Bloom syndrome, Fanconi anemia, Down syndrome, NF1, ataxia telangiectasia
o Viruses – “lymphotropic viruses”
 HTLV-1 (adult T cell leukemia/lymphoma), EBV (Burkitt, Hodgkin, B-cell and NK-cell
lymphomas), HHV-8 (B-cell lymphoma that presents as malignant effusion in pleural
cavity)
o Chronic Immune stimulation – environmental agents, H. pylori (B-cell lymphoma), Celiac
disease (intestinal T-cell lymphomas), HIV (B-cell lymphomas)
o Iatrogenic factors – radiation and chemotherapy (increase risk of myeloid and lymphoid
neoplasms
o Smoking – increased incidence of acute myeloid leukemia
 Lymphoid neoplasms
o Definitions and classification
  Leukemia: widespread involvement of the bone marrow and peripheral blood;
present with signs and symptoms of suppression of normal hematopoiesis by tumor
cells in bone marro
 Lymphoma: discrete tissue masses; most present as enlarged, nontender lymph
nodes; if not then present as extranodal symptoms (skin, stomach, brain)
 Hodgkin lymphoma
 Non-Hodgkin lymphoma
 Plasma cell neoplasms: arise in bone marrow and only infrequently involve lymph
nodes or peripheral blood; some cause symptoms through secretion of circulating
factors
 Multiple myeloma: causes bony destruction of skeleton and presents with pain
due to pathologic fractures
o Important principles: Diagnosis can be suspected from clinical features, but histological
examination of lymph nodes or other involved tissues is required for diagnosis; antigen-
receptor gene rearrangement preceeds transformation (all daughter cells have same gene
configuration); 85-90% are B-cell origin (remainder T-cell; NK cell rare); often associated
with immune abnormalities (loss of protective immunity (susceptibility to infection) and
breakdown of tolerance (autoimmunity), inherited or acquired immunodeficiency);
neoplastic B and T cells tend to behave like their normal counterparts (home to certain
tissue sites by using same adhesion molecules and receptors); most tumors are widely
disseminated at time of diagnosis (except Hodgkin); Hodgkin lymphoma spreads in orderly
fashion (staging is important in guiding therapy)
o Types:
 Precursor B-cell or T-cell neoplasms (immature cells = lymphoblasts)
 Acute Lymphoblastic Leukemia/Lymphoma (ALL):
 Pathogenesis: 85% are B-ALLs, typically manifest as childhood acute
leukemias, less common T-ALLs present in adolescent males as thymic
lymphomas; most common cancer in children, hispanics > whites
> blacks, B-ALL peaks at age 3 (greatest # of pre-B cells), T-ALL
peaks in adolescence (largest thymus); marrow is hypercellular and
packed with lymphoblasts; lymphadenopathy, hepatosplenomegaly,
“starry sky” appearance; must be distinguised from AML (for chemo
reasons; definitive dx by antibodies for T- and B-cell antigens);
Immunostaining for terminal deoxynucleotidyl-transferase (TdT)
positive in >95%; 90% have numerical or structural chromosomal
changes; Many of the chromosomal aberrations seen in ALL
dysregulate the expression and function of transcription factors that
are required for normal b and t cells development; Single mutations
are not sufficient to produce ALL
 Clinical features: Abrupt stormy onset, Symptoms related to bone
marrow suppression (fever, fatigue, bleeding, petichieae), Mass effect
caused by neoplastic infiltration (bone pain, generalized
lymphadenopathy, splenomegaly, hepatomegaly, testicular
enlargement, compression of large vessels in mediastinum), CNS
manifestations (headache, nerve palsies from meningeal spread,
vomiting)
 Prognostic factors: 95% obtain complete remission, 75-85% are
cured with chemotherapy; ALL remains leading cause of cancer
deaths in children
 Worse prognosis: <2YOA (MLL gene translocations),
presentation in adolescence or adulthood, peripheral blast
counts >100,000, presence of particular cytogenic aberrations
(Ph chromosome)
 Favorable prognosis: 2-10 YOA, low WBC count, hyperploidy,
Trisomy of 4,7,10, presence of t(12;22)
 Peripheral B-cell neoplasms (mature B cells)
 Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma
(SLL)
  Pathogenesis: Two disorders differ only in degree of peripheral
lymphocytosis; CLL= absolute lymphocyte count >4000/m^3; Most
common leukemia of adults in the western world, median age 60,
males>females; proliferation centers are pathognomic, smudge
cells, distinctive immunophenotype (CD19, CD20, CD23, CD5, surface
Ig), chromosomal translocations are rare, cell of origin may be a
postgerminal center memory B cell or a naïve B cell; growth of
CLL/SLL cells is confined to proliferation centers, stimulate NF-kB
(promotes cell growth and survival)
 Clinical Features: Often asymptomatic at diagnosis; Nonspecific –
fatigue, weight loss, anorexia; Generalized lymphadenopathy;
Hepatosplenomegaly, Disrupts normal immune function through
uncertain mechanisms (hypogammaglobulinemia common, hemolytic
anemia or thrombocytopenia due to autoantibodies against non-
neoplastic B-cells)
 Prognosis: Variable course and prognosis depending on stage;
Tendency to transform to more aggressive tumors
 Prolymphocytic and large-cell transformations (Richter
syndrome) – poor prognosis, worsening cytopenias, increasing
splenomegaly, increased number of prolymphocytes, rapidly
enlarging mass in lymph node or spleen
 Treatment: Patients treated with “gentle chemotherapy” to control
symptoms
 Follicular Lymphoma
 Pathogenesis: Most common form of indolent NHL in the US, middle
age, males=females; arises from germinal center B cells; strongly
associated with chromosomal translocations involving BCL2; Principle
cell types: centrocytes and centroblasts; Hallmark t(14;18)
translocation which leads to overexpression of BCL2
 Clinical Features: painless, generalized lymphadenopathy, histologic
transformation to diffuse large B-cell lymphoma (30-50%) from
chromosomal translocations involving c-MYC; undergo somatic
hypermutation (like normal germinal B-cells) leading to point
mutations
 Prognosis: indolent waxing and waning course, usually treated with
low-dose chemotherapy or immunotherapy; median survival <1yr
after transformation
 Diffuse Large B-cell Lymphoma
 Pathogenesis: most common form of NHL, slightly male>female,
median age 60yrs; large cell size and diffusion pattern of growth; cells
resemble Reed-Sternberg cells; CD19, CD20, surface Ig; dysregulation
of BCL6 leading to overexpression which silences p53; 10-20%
t(14;18);
 Subtypes: 1) immunodeficiency-associated large B-cell
lymphoma in the setting of T-cell immunodeficiency = EBV; 2)
Primary effusion lymphoma = KSV/HHV-8
 Clinical Features: typically presents as rapidly enlarging mass at
nodal or extranodal site, anywhere in the body, Waldeyer ring in oral
cavity common involved; primary and secondary involvement of liver
and spleen; aggressive and rapidly fatal without treatment (anti-CD20
antibody); 5% of CLBCLs have c-MYC translocations, must be
distinguished from Burkitt lymphoma (chemo)
 Burkitt Lymphoma
 Pathogenesis: Types: African (endemic, EBV), Sporadic
(nonendemic), subset in HIV pts (aggressive) –they are histologically
identical; “starry sky pattern” = high mitotic index and numerous
apoptotic cells; translocations of c-MYC gene on chromosome 8,
 increases c-MYC expression and inactivation p53 (increases frequency
of c-MYC translocations)
 Clinical Features: children or young adults, 30% of childhood NHL;
most present as tumor in extranodal site, endemic Burkitt presents as
mass involving the mandible, also seen in abdominal viscera
(kidneys, adrenals, ovaries), sporadic involves ileocecum and
peritoneum
 Prognosis: very aggressive but responds well to intensive chemo;
most children and young adults can be cured
 Plasma Cell Neoplasms and related disorders (monoclonal
gammaopathies)– secrete a monoclonal Ig or Ig fragment, often synthesize
excess light or heavy chains along with complete Igs; Bence-Jones proteins
excreted in urine
 Multiple myeloma: most common and deadly, men>women, elderly;
multifocal tumorous masses scattered throughout the skeletal system;
Ig genes in myeloma cells always show evidence of hypermutation;
proliferation and survival of myeloma cells are dependent on several
cytokines (esp IL-6); factors produced by the neoplastic plasma cells
mediate bone destruction; rearrangements involving the Ig heavy
chain gene of Chromosome 14q32; axial skeleton; punched out
defects 1-4cm in diameter; plasmablasts, flame cells, mott cells,
russell bodies, dutcher bodies, Rouleaux formation (RBCs look like
stacks of coins); myeloma kidney
 Clinical Features: bone resorption leading to pathologic
fractures, chronic pain and hypercalcemia, recurrent bacterial
infections (decreased normal Igs), renal insufficiency (trails
only infection as cause of death), SPE M protein; 99% Bence-
Jones proteinuria and Igs in blood and/or light chains,
amyloidosis, hyperviscosity; definitive diagnosis required bone
marrow examination
 Prognosis: variable, but generally poor
 Treatment: thalidomide, bisphosphonates, bone marrow
transplant
 Waldenstrom macroglobulinemia: high levels of IgM leads to
hyperviscosity syndrome, occurs in older adults in association with
lymphoplasmacytic lymphoma
 Heavy chain disease: synthesis and secretion of free heavy-chain
fragments; seen in lymphoplasmacytic lymphoma and Mediterranean
lymphoma
 Primary or immunocyte-associated amyloidosis: secrete light
chains and are deposited as amyloid, some patients have multiple
myeloma
 Monoclonal gammopathy of uncertain significance (MGUS):
moderately large M components in their blood, common in the elderly
 Lymphoplasmacytic lymphoma: plasma cell component secretes
monoclonal IgM leading to hyperviscosity syndrome (Waldenstrom
macroglobulinemia); B-cell neoplasm of older adults (60-70s),
resembles CLL/SLL (except cells are terminally differentiated); Russell
bodies and Dutcher bodies
 Clinical features: weakness, fatigue, weight loss,
lymphadenopathy, hepatosplenomegaly, anemia, autoimmune
hemolysis, hyperviscosity syndrome (visual impairment,
neurological problems, bleeding, cryoglobulinemia)
 Prognosis: incurable, plasmapheresis alleviates hyperviscosity,
anti-CD20 chemotherapy; median survival is 4 years
 Mantle Cell Lymphoma: tumor cells closely resemble the normal mantle
zone B cells that surround the germinal centers; express high levels of cyclin
D1, t(11;14)
  Clinical features: Male 50-60yoa, painless generalized
lymphadenopathy, extranodal involvement (bone marrow, spleen,
liver, gut), occasionally lymphomatoid polyposis; poor prognosis (3-4
years), most die of organ infiltration of tumor, bone marrow transplant
and proteasome inhibitors may be helpful
 Marginal Zone Lymphomas: “Maltomas”, often arise in areas of chronic
inflammation (Sjögren syndrome, Hashimoto thyroiditis, H. pylori gastritis),
remain localized for prolonged periods, may regress if inciting agent is
eradicated; begins as polyclonal immune reaction; continuum between
reactive lymphoid hyperplasia and full-blown lymphoma; tumors may acquire
mutations and translocations that upregulate BCL10 or MALT1 which activate
NF-kB (promotes growth and survival of cells); tumors can spread to distant
sites and become diffuse large B-cell lymphomas
 Hairy Cell Leukemia: CD19, CD20 markers, high incidence of somatic
hypermutation (possible post-germinal center memory B-cell origin);
leukemic cells have fine hair-like projections seen under phase contrast
microscopy
 Clinical features: white males, median 55YOA; dry tap on bone
marrow because infiltrated cells are enmeshed in ECM of bone
marrow; lymphadenopathy is rare; spleen and liver usually involved
(hepatomegaly, splenomegaly), pancytopenia, infections (atypical
mycobacterial infections); indolent course, excellent prognosis with
response to gentle chemotherapy, many relapse but respond to
retreatment
 Peripheral T-cell and NK-cell neoplasms (mature cells)
 Peripheral T-cell Lymphoma, unspecified: pleimorphic mixture of variably
sized malignant T-cells often with prominent infiltrate of reactive cells
(eosinophils and macrophages); diagnosis requires immunophenotyping with
DNA confirmation
 Clinical features: generalized lymphadenopathy, sometimes
eosinophilia, pruritis, fever, weight loss; poor prognosis
 Anaplastic Large-cell Lymphoma (ALK positive): ALK gene on
chromosome 2p23 (activates tyrosine kinases and JAK/STAT pathway); large
anaplastic cells containing horseshoe-shaped nuclei and voluminous
cytoplasm (hallmark cells)
 Clinical features: children or young adults, involve soft tissues, good
prognosis, cure rate 70-80%
 Adult T-cell Leukemia/Lymphoma: CD4+ cells, HTLV-1 endemic areas;
tumor cells have multilobed nuclei (“cloverleaf” or “flower” cells); tumor cells
contain clonal HTLV-1 provirus; HTLV-1 encodes Tax protein that activates
NF-kB
 Clinical features: skin lesions, generalized lymphadenopathy,
hepatosplenomegaly, peripheral blood lymphocytosis and
hypercalcemia; fatal within months to one year; in addition HTLV-1
infection sometimes causes demyelinating disease of CNS and spinal
cord
 Mycosis Fungiodes/Sézary Syndrome: CD4+ helper T-cell tumor, homes
to skin (epidermis and dermis); progresses in three distinct phases
(premycotic, plaque, and tumor); late disease charachterized by
extracutaneous spread (lymph nodes and bone marrow); tumor cells express
adhesion molecule CLA and chemokine receptors CCR4 and CCR10 (contribute
to homing of normal CD4+ T-cells to the skin; median survival 8-9yrs, can
transform to aggressive T-cell lymphoma
 Sézary syndrome variant has generalized exfoliative erythroderma,
associated leukemia with cerebriform nuclei
 Large Granular Lymphocytic Leukemia: mainly adults; mild to moderate
lymphocytosis and splenomegaly; large lymphocytes with abundent blue
cytoplasm seen on peripheral smears; T-cell variants are CD3+, NK-cell LGLL
 are CD3-, CD56+; neutropenia and anemia, increased rheumatologic
disorders; autoimmunity may be cause; course is variable
 Felty Syndrome: Triad of RA, splenomegaly, neutropenia; have this
disorder as underlying cause
 Extranodal NK/T-cell Lymphoma: destructive nasopharyngeal mass,
surrounds and invades blood vessels leading to ischemic necrosis; associated
with EBV (rare in US); highly aggressive but respond well to radiation
(resistant to chemo), prognosis is poor in pts with advanced disease
 Hodgkin Lymphoma: arises in a single node or chain of nodes and spreads first to
anatomically contiguous lymphoid tissue; staging important in treatment (involves
PE, imaging and bone marrow biopsy); neoplastic giant cells (Reed-Sternberg cells
derived from germinal center or post-germinal B-cells) release factors that induce
accumulation of reactive lymphocytes, macrophages and granulocytes (make up
90% of tumor cellularity); activation of NF-kB
 Clinical Features: average age at diagnosis is 32 years, one of the most
common cancers of young adults and adolescents; painless
lymphadenopathy, fever, night sweats, weight loss, cutaneous anergy,
spread is stereotyped: node, spleen, liver, marrow, other tissue
 Prognosis: curable in most cases, may develop secondary cancers from
chemo and radiation (myelodysplastic syndromes, AML, lung cancer, NHL,
breast cancer, gastric cancer, sarcoma, melanoma)
 Classification (five subtypes): first 4 are classic types and Reed-Sternberg
cells have similar immunophenotype; lymphocyte predominance type Reed-
Sternberg cells have B-cell immunophenotype
 Nodular sclerosis – most common, males=females, young adults;
lacunar variant RS cells; collagen bands divide lymph nodes into
circumscribed nodules
 Mixed cellularity – males>females, biphasic incidence (young adults
and >55YOA); T-cells, eosinophils, plasma cells, macrophages, RS
cells, EBV
 Lymphocyte-rich – uncommon, males>females, >55YOA; reactive
lymphocytes most of cellular infiltrate, EBV
 Lymphocyte depletion – uncommon, older males, HIV-infected pts,
developing countries; paucity of lymphocytes, EBV
 Lymphocyte predominance – uncommon, young males with cervical or
axillary lymphadenopathy, mediastinal; non-classical RS cells, L&H
(popcorn cell) variants

Table 13.9 Clinical Staging of NHL and HL

Stage Distribution of Disease
I Single node region (I) or single extra-lymphatic site
(E)
II 2+ node regions on same side of diaphragm (II)
with localized involvement of extranodal site (IIE)
III Node regions on both sides of diaphragm (II) with
localized involvement of extranodal site (IIIE)
IV Diffuse involvement of one or more extra-lymphatic
organs or sites with/without lymphatic involvement
All stages are further subdivided with (A) absence or (B) presence of: unexplained fever, drenching night
sweats, and/or unexplained weight loss >10% of normal body weight

 Myeloid Neoplasms – common feature of this group is origin from hematopoietic progenitor cells;
primarily involve the bone marrow; usually present with altered hematopoiesis; normal
hematopoiesis has homeostatic feedback mechanisms involving cytokines and growth factors that
modulate production of RBCs, WBCs, and platelets; myeloid neoplasm manifestations influenced by
the position of the transformed cell within the hierarchy of progenitors, effect of transporting
events on differentiation; both myelodysplastic syndrome and myeloproliferative disorders can
“transform” into AML, also CML can transform into ALL
o Acute Myeloid Leukemia (AML)– caused by acquired oncogenic mutations that impede
differentiation leading to accumulation of immature myeloid blasts (progenitor cells) in the
marrow leading to marrow failure (neutropenia, anema, thrombocytopenia); many recurrent
genetic aberrations seen in AML disrupt genes encoding transcription factors required for
normal differentiation; evidence that mutated tyrosine kinases collaborate with transcription
factors to produce AML; t(15;17) important pathologically and guides treatment
 Clinical Features: incidence after 60YOA, >20% myeloid blasts in bone marrow,
Auer rods, immunophenotype helps distinguish myeloblasts from lymphoblasts (stain
for myeloid-specific antigens); cytogenetics have central role in classification; most
patients present with anemia, neutropenia, thrombocytopenia, fever, fatigue,
mucosal and cutaneous bleeding (petichiae, eccymoses), infections are frequent;
occasionally presents as a localized soft-tissue mass (myeloblastoma, granulocytic
sarcoma, or chloroma)
 Prognosis: difficult to treat; high risk forms treated with bone marrow transplants
 Classification: 4 Major Subtypes (AML with genetic aberrations, AML with MDS-like
features, AML therapy-related, AML not otherwise specified)
o Myelodysplastic Syndromes – associated with ineffective hematopoeisis and resultant
peripheral blood cytopenias; group of clonal stem cell disorders characterized by:
maturation defects, ineffective hematopoiesis (hallmark is bone marrow progenitors
that undergo apoptotic death at an increased rate), high risk of transformation to
AML; neoplastic multipotent stem cell retains the capacity to differentiate but does so
ineffectively and in disordered fashion; can be primary (idiopathic) or secondary (genotoxic
drug or radiation), all forms of MDS can transform to AML; cytogenetic analysis is helpful;
most characteristic finding is disordered (dysplastic) differentiation affecting erythroid,
granulocytic, monocytic, and megakaryocyte lineages to varying degrees (ringed
sideroblasts, megaloblastic maturation, nuclear budding abnormalities, Pseudo-Pelger-Huet
cells, pawn ball megakaryocytes, myeloid blasts usually <10%)
 Clinical Features: elderly, usually found incidentally on blood test; when
symptomatic presents as weakness, infection and hemorrhages (pancytopenia);
median survival 9-29 months; progression to AML in 10-40% (associated with
additional cytogenetic abnormalities); pts often die of complications of
thrombocytopenia (bleeding) and neutropenia (infection); treatment is limited (bone
marrow transplant in younger patients, older pts treated with antibiotics and blood
product transfusions, thalidomide and DNA methylase inhibitors improve
effectiveness of hematopoiesis in some
o Myeloproliferative Disorders – increased production of one or more terminally
differentiated myeloid elements leads to elevated peripheral blood counts; common
features: mutated, constitutively activated tyrosine kinases (circumvent normal controls and
lead to growth factor-independent proliferation and survival of marrow progenitors); most
originate in multipotent myeloid progenitors; extramedullary hematopoiesis is seen, variable
transformation to spent phase, variable transformation to acute leukemia
 Chronic Myeloid Leukemia (CML): chimeric BCR-ABL gene created by
Philadelphia chromosome t(9;22) (q34;q11); adults 4500 new cases/yr;
hypercellular marrow, WBC>100,000; “blast crisis”; cell of origin is pluripotent
hematopoietic stem cell; BCR-ABL drives proliferation of progenitors and causes
abnormal release of immature cells from the marrow to the blood; characteristic
feature is sea-blue histiocytes; originates from pluirpotent stem cell with both
myeloid and lymphoid potential
 Clinical Features: adults >50YOA; insidious onset (mild-moderate anemia
and hypermetabolism due to increased cell turnover leading to fatigue,
weakness, weight loss, and anorexia), slow progression, splenomegaly
(causes dragging sensation in abdomen or acute LUQ pain from splenic
infarct); Dx: chromosomal analysis or PCR; median survival 3 yrs, after 3
years 50% develop accelerated phase with increasing anemia and
thrombocytopenia, sometimes with increased basophils in blood within 6-12
months this phase terminates in blast crisis resembling acute leukemia
  Treatment: drugs that target BCR-ABL (imatinib), bone marrow transplant
(curative in 75% in stable phase)
 Polycythemia Vera: increased marrow production of red cells, granulocytes, and
platelets (panmyelosis), but increas in red cells (polycythemia) is responsible for
symptoms; strongly associated with activating point mutations in tyrosine kinase
JAK2; progenitor cells have decreased requirement for EPO and other growth factors;
serum EPO levels in PVC are very low; elevated hematocrit leads to increased
blood viscosity and sludging; patients are prone to thrombosis and bleeding; marrow
is hypercellular, peripheral blood contains increased basophils and abnormally large
platelets; there is extensive marrow fibrosis, increased extramedullary hematopoiesis
(spleen and liver) later in disease causing organomegaly (early organomegaly caused
by congestion); transformation in 1-2% of patients to AML
 Clinical Features: uncommon, insidious, middle-aged adults; pts are
plethoric and cyanotic (stagnation and deoxygenation of blood); headache,
dizziness, hypertension, GI symptoms, intense pruritis, peptic ulceration;
Complications: DVT, Budd-Chiari syndrome, MI, stroke, bowel infarction;
minor hemorrhages (epistaxis, bleeding gums); Hgb (14-28gm/dL), Hct
>60%, chronic bleeding leads to iron deficiency which can suppress EPO and
lower Hct into normal range; WBCs 12,000-50,000 /mm^3; platelets are
usually large and ineffective
 4 H’s of PCV: Hyperviscosity (-> thrombosis), Hypervolemia (increased
plasma volume), Histaminemia (from mast cells -> generalized
pruritis), Hyperuricemia (increased cell breakdown -> pruritis and
GOUT)
 Treatment/Prognosis: phlebotomy (extends like 10 years); without
treatment death occurs from bleeding or thrombosis (within months of dx);
may evolve to spent phase (with prolonged treatment) with myelofibrosis and
extramedullary hematopoiesis
 Essential thrombocytosis: activating point mutations in JAK2 (50%) or MPL (5-
10%) makes progenitors thrombopoietin-independent and leads to
hyperproliferation; bone marrow cellularity mildly increased, megakaryocytes
markedly increased; peripheral smears show abnormally large platelets with mild
leukocytosis; absent polycythemia and marrow fibrosis; some cases may be PVC
disguised by iron deficiency
 Clinical features: elevated platelet counts (but they don’t funtion properly
leading to thrombosis and hemorrhage), mild organomegaly (extramedullary
hematopoiesis); can transform to AML; DVT, portal and hepatic vein
thrombosis, MI; erythromelalgia (throbbing, burning of hands and feet
caused by occlusion of small arterioles by platelet aggregates; indolent
disorder; median survival 12-15 years; therapy is “gentle chemo”
 Primary myelofibrosis: hallmark is development of obliterative marrow
fibrosis; replacement of bone marrow by fibrosis suppresses bone marrow
hematopoiesis, leading to cytopenias and extensive neoplastic dysordered
extramedullary hematopoiesis; 50-60% have activating JAK2 mutations, MPL
mutations in 1-5%; fibrosis probably caused by release of fibrogenic factors from the
neoplastic megakaryocytes (PDGF and TNF-); leukoerythroblastosis (premature
release of nucleated erythroud and early granulocyte progenitors) and immature
cells from EMH; teardrop cells (dacrocytes) (damaged by escape from fibrotic
marrow)
 Clinical features: older than 60YOA, progressive anemia and splenomegaly,
fatigue, weight loss, night sweats, increase in metabolism, hyperuricemia and
secondary gout due to high cell turnover; lab studies show moderate to
severe normochromic normocytic anemia with leukoerythroblastosis; bone
marrow biopsy essential for diagnosis
 Treatment/prognosis: 3-5 year survival, death by incurrent infections,
thrombotic episodes, bleeding related to platelet abnormalities,
transformation to AML (5-20%); Tx: bone marrow transplant and kinase
inhibitors
  Others: Systemic mastocytosis, Chronic eosinophilic leukemia, Stem cell
leukemia
 Histiocytosis: proliferative disorders of dendritic cells or macrophages; homing of neoplastic
Langerhans cells is caused by aberrant expression of chemokine receptors that allow the cells to
migrate to tissues that express relevant chemokines (CCL20 ligand for CCR6 in skin and bone;
CCK19 and 21 ligands for CCR7 in lymphoid organs)
o Langerhans cell histiocytosis: immature dendritic cell, monoclonal proliferation; have
abundant vaculolated cytoplasm and vesicular nuclei containing linear grooves or folds;
presence of Birbeck granules in cytoplasm is characteristic (“tennis racket cells”)
contain protein langerin; tumor cells express HLA-DR, S-100, CD1a
 Clinicopathologic entities:
 Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe
disease): <2YOA; development of cutaneous lesions resembling seborrheic
eruption (caused by infiltrates of langerhans cells on trunk and scalp), does
not respond to cortisone; most have hepatosplenomegaly, lymphadenopathy,
pulmonary lesions, eventually osteolytic bone lesions; extensive infiltration of
marrow leads to anemia, thrombocytopenia, predisposition to recurrent
infections (otitis media and mastoiditis); untreated is rapidly fatal, 50% 5YSR
with aggressive chemo
 Unifocal and multifocal unisystem langerhans cell histiocytosis
(eosinophili granuloma): proliferations of langerhans cells mixed with
eosinophils, lymphocytes, plasma cells, and neutrophils; typically arises from
medullary cavities of bones (calvarium, ribs, femur); less common unisystem
lesions (skin, lungs, stomach)
 unifocal lesions (skeleton); bone lesions can be asymptomatic or cause
pain, tenderness, pathologic fx; unifocal indolent, cured by local
excision or radiation;
 multifocal unisystem disease affects young children, multiple erosive
bony masses, posterior pituitary stalk leads to diabetes insipidus;
spontaneous remission or chemo treatment
 Hand-Schuller-Christian Triad: calvarial bone defects,
diabetes insipidus and exophthalmos
 Pulmonary Langerhans cell histiocytosis: adult smokers, may regress
when smoking is stopped, may be reactive hyperplasia (not neoplasia)

Spleen: filter for the blood, site of immune responses to blood-borne pathogens; two routes for blood
through red pulp to splenic veins

Functions:
 Phagocytosis of blood cells and particulate matter – also responsible for “pitting”of red cells (excision
of inclusions like Heinz bodies and Howell-Jolly bodies)
 Antibody production – dendritic cells trap antigens and present to T-cells; important source of
antibodies against platelets and RBCs in immune thrombocytopenia purpura and immunohemolytic
anemias
 Hematopoiesis – can be reactivated in severe anemia and extramedullary hematopoiesis in
myeloproliferative disorders
 Sequestration of formed blood elements – red cell volume can increase with splenomegaly, platelets
can be sequestered causing thrombocytopenia, or white cells and produce leukopenia

Splenic insufficiency - spleen is rarely site of primary disease, hyposplenism caused by autoinfarction or
splenectomy have increased susceptibility to sepsis caused by encapsulated bacteria (pneumococcus,
meningococcus, H. influenza); asplenic pts should be vaccinated

Splenomegaly – dragging sensation in LUQ, discomfort after eating; can cause hypersplenism
characterized by anemia, leukopenia, and thrombocytopenia (alone or in combination), probably cause is
increased sequestration and increased phagocytosis by splenic macrophages
o Nonspecific acute splenitis – blood-borne infection, caused by pathogens and cytokines; spleen is
enlarged and soft, acute red pulp congestion, white pulp may undergo necrosis (esp in hemolytic
strep)
 Congestive splenomegaly – chronic venous outflow obstruction causing splenic enlargement; disorders
that directly impinge on portal or splenic veins leading to portal or splenic hypertension (liver cirrhosis
is main cause, also spontaneous portal vein thrombosis, pylephlebitis, infiltrating tumors, carcinomas
of stomach or pancreas); systemic or central venous congestion is caused by cardiac decompensation;
spleen is firm and there is collagen deposition in basement membrane of sinusoids resulting in slowing
of blood and increased destruction by macrophages (hypersplenism)
 Splenic infarcts – caused by occlusion of major splenic artery or branches; frequent site of lodged
emboli (usually from heart); infarcts can be small or large, single or multiple, or involve entire organ,
usually bland (b/c of end organ, usually pale and wedge-shaped) or can be septic in pts with infectious
endocarditis

Neoplasms – rare; benign fibromas, osteomas, chrondromas, lymphangiomas (cavernous),

hemangiomas (cavernous)

Congenital anomalies – complete absence (rare, usually associated with other abnormalities, ie situs
inversus), hypoplasia is more common; accessory spleens are common (can be important in hereditary
spherocytosis and immune thrombocytopenia purpura)

Rupture – precipitated by blunt trauma, “spontaneous ruptures” spleens are never normal (usually fragile
due to mono, malaria, typhoid fever, and lymphoid neoplasms); often precipitates intraperitoneal
hemorrhage, treated with splenectomy; chronically enlarged spleens are less likely to rupture because of
extensive reactive fibrosis

Thymus – 3rd, sometimes 4th pharyngeal pouches; Hassall corpuscles, T-cell maturation; involute in
children and young adults in response to severe illness and HIV infection

Developmental Disorders

o Thymic hypoplasia or aplasia: seen in DiGeorge syndrome (22q11 deletion syndrome) (severe
defects in cell-mediated immunity and variable abnormalities in parathyroid development,
associated with hypoparathyroidism)
o Thymic cysts: isolated (uncommon, incidental); neoplastic-related cysts (caused by
compression of the normal thymus, if seen, look for thymoma or lymphoma)

Thymic hyperplasia – appearance of B-cell germinal centers within the thymus (thymic follicular
hyperplasia), seen in chronic inflammatory and immunological states, most frequently myasthenia gravis,
also scleroderma, Grave’s disease, SLE, RA, other autoimmune disorders; may be mistaken for thymoma

Neoplasms

o Thymomas – tumor of thymic epithelial cells and typically contains benign immature T-cells
(thymocytes); 3 histological types (benign and noninvasive, benign but invasive or metastatic, and
malignant carcinoma); usually adults >40YOA, anterior mediatinum, neck, thyroid, or pulmonary
hilus; 40% present because of impingement on other mediastinal structures, 30-45% from
evaluation of MG, rest are incidentally discovered; also associated with hypogammaglobulinemia,
pure red cell aplasia, Grave’s disease, pernicious anemia, dermatomyositis-polymyositis, and
Cushing syndrome; give rise to long-lived CD4+ and CD8+ T-cells; abnormalities in the
selection of maturing T-cells in the neoplasm may contribute to development of
autoimmune disorders
o Other neoplasms (germ cell tumor, lymphoma, carcinoid)