BoardReviewPart1A BenignHemePath

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Board Review- Part 1:

Benign HemePath
Peripheral Blood
Smear Examination
Elevated MCV = Macrocytosis
MCV > 100um3
• B12/Folate deficiency, aplastic anemia, MDS
• Autoimmune hemolytic anemia
• Liver disease, hypothyroidism, alcoholism
• Cold agglutinin disease
Decreased MCV = Microcytosis
MCV < 80um3

• Iron deficiency
• Thalassemias
• Anemia of chronic
disease
• Hemoglobinopathies
– C, E, S, D
Iron Panel Interpretation
Cause of Serum TIBC Percent
anemia iron saturation

Iron ↓ ↑ ↓
deficiency
Thalassemias ↑ / N ↓/N ↑/N

Sideroblastic ↑ ↓/N ↑
anemia
Chronic N/↓ ↓ N
disease
Pathologic Red Blood Cells in
Peripheral Blood Smears
Type of Cell Underlying Change Disease States

Acanthocyte (spur cell) Altered cell membrane lipids Abetalipoproteinemia, liver


disease, postsplenectomy,
McLeod phenotype
Bite Cell (degmacyte) Heinz body pitting by spleen G6PD deficiency, drug-induced
oxidant hemolysis

Ovalocyte (elliptocyte) Abnormal cytoskeletal proteins Hereditary elliptocytosis


Rouleaux Circulating paraprotein Paraproteinemia
Schistocyte (helmet cell) Mechanical destruction in DIC, TTP, HUS, prosthetic heart
microvasculature valves
Spherocyte Decreased membrane Hereditary sphereocytosis,
redundancy immunohemolytic anemia (warm
Ab)
Stomatocyte Membrane defect with Hereditary stomatocytosis, liver
abnormal cation permeation disease

Target Cell (codocyte) Increased redundancy of cell Liver disease, beta thalassemia
membrane postsplenectomy, Hgb C/D/E/S

Burr Cell (ecchinocyte) Altered membrane lipids Usually artifactual but maybe
uremia
Tear Drop Cell (dacrocyte) Myelofibrosis
Acanthocytes (Spur cells)

•Irregular, long, sharply pointed and


bent spicules
•Absence of central pallor
•Most commonly seen in liver disease
Abetalipoproteinemia: absence of apolipoprotein B results in inability to transport
triglycerides in the blood-> Altered cell membrane lipids-> Acanthocytes
McLeod phenotype/syndrome

• Absence of erythrocyte surface Kx


antigen (part of Kell antigen group)
• Acanthocytes with chronic but well
compensated hemolytic anemia
• Disease processes include muscular
dystrophy, cardiomyopathy
• May be associated with chronic
granulomatous disease
Tear Drop Cells (Dacrocytes)

Myelofibrosis or bone marrow infiltrate


Bite Cells

• G6PD deficiency

G6PD deficiency
STOMATOCYTES

RBC with slit-like or rectangular area of central pallor, a mouth

Most often seen in liver disease


Burr Cells (Ecchinocytes)

Projections- smaller
more regular than
acanthocytes

Often artifactual but


may be seen in
UREMIA
Spherocytes

-Hereditary sphereocytosis,
-Immunohemolytic anemia (warm Ab)
Hereditary spherocytosis
• Northern
European
ancestry
• Spectrin,
ankyrin, band 3
or band 4.1
deficiency
Hereditary spherocytosis

• Defects in vertical stabilization of the phospholipid bilayer of the RBC membrane


cause separation of the spectrin - phospholipid bilayer
• Normal biconcave red cell loses membrane fragments and adopts a spherical shape
• Inflexible cells are trapped in the splenic cords, phagocytosed by macrophages
Osmotic Fragility Test
• Equal volumes of blood are placed in a
series of hypotonic solutions
• Allowed to reach equilibrium (24 hr,
37 C); centrifuged
• The RBC swells and lysis occurs
• As the % saline decreases
further, the amount of lysis
increases (determined by Normal

optical density )

HS
Elliptocytes
Hereditary elliptocytosis

• Autosomal dominant trait


• Spectrin abnormality or deficiency
of protein band 4.1
• Asymptomatic without anemia and
usually with no splenomegaly and
only mild hemolysis
Hereditary Pyropoikilocytosis
• Same mutations as in HE
• Present in the neonatal
period with severe
hemolytic anemia, RBC
fragments, poikilocytes,
elliptocytes,
microspherocytes,
hyperbilirubinemia

21
Hereditary Pyropoikilocytosis
(HPP)
• Reminiscent of erthrocyte morphology seen
after thermal burns
• Rare cause of severe hemolytic anemia
• 1/3 of family members with HPP have HE
• Many HPP patients have severe hemolytic
anemia in childhood that evolves into typical
HE later in life
Target Cells

Characteristic of:
– Liver disease
– Post-splenectomy
– Hemoglobin disorders
• Beta thalassemia
• Hemoglobinopathies
Hb S, C, D and E
Hgb SC disease with C crystals,
Taco cells and sickle cells

“Washington Monument crystals”


Schistocytes

Microangiopathic
hemolytic anemia

DIC, TTP, HUS


Rouleoux and Clumping

RBC Clumping:
cold agglutinin

Rouleaux:
monoclonal gammopathy
vs. polyclonal gammopathy
Hypochromic anemia
MCH < 27 pg
• Disorders of globin synthesis
– Thalassemic syndromes
• α-Thalassemia
• ß-Thalassemia
• Disorders of heme synthesis
– Sideroblastic anemias
• Hereditary (X-linked, auto. dominant)
• Acquired (lead poisoning, alcoholic, medication, MDS)
• Disorders of Fe metabolism
– Fe deficiency
– Chronic disease
– Neoplasia
Iron Deficiency
Reticulocytes

• Decreased cell survival


– Blood loss
– Autoimmune hemolysis
– Nonimmune hemolysis
• TTP, HUS, DIC
• H. spherocytosis
• G6PD
• PNH
• Hemoglobinopathy
• Thalassemia
Nucleated RBCs
• Not normally present in
adult patients PS
• Present in:
– Severe hemolysis
– Myelophthisic condition
– Leukoerythroblastic
smear
Basophilic Stippling
Precipitated ribosomes (RNA)

Fine – variety of anemias:


Siderblastic, sickle cell,
megaloblastic

Coarse – Lead intoxication,


thalassemia
Heinz Bodies

• Precipitated denatured
Hgb
• Seen in G6PD
deficiency
• Seen with supravital
staining
– Crystal violet
– Brilliant cresyl blue
Howell Jolly Bodies

Dense,usually
single

Nuclear remnant

Seen in:
- Postsplenectomy
- Hemolytic anemia
- Megaloblastic
anemia
Pappenheimer bodies
Small, dense basophilic
granules
(mitochondrial remnant
that contains Fe)

Seen in:
- Sideroblastic anemia
- Post-splenectomy
The Malignant Mimicker:
Leukemoid Reaction

• Precursor
granulocytes in the
PBS
• WBC in the range
up to 100K
• Response to severe
stress or infection
• Other signs of
malignancy not
present (i.e. CML)
Neutrophil Disorders with
Abnormal Morphology
• Pelger-Huet anomaly
– Bilobed or nonsegmented nucleus
– asymptomatic
• May-Hegglin anomaly
– Cytoplasmic inclusions resembling Dohle bodies
– Many asymptomatic
• Chediak-Higashi syndrome
– Giant cytoplasmic granules in all granulocytes
– Immunodeficiency
• Alder Reilley Anomaly: inclusion is mucopolysaccharide (PAS+)
• Hypersegmentation
– B12/Folate deficiency, myelodysplasia, chemotherapy, or renal
failure
Pelger-Huet Anomaly

• Inherited, AD
• Acquired =
“pseudo” Pelger-
Huet as in MDS
Chediak-Higashi Syndrome

• Autosomal
recessive
• Giant granules
• Severe
immunodeficiency
May Hegglin Anomaly
• Thrombocytopenia
• Enlarged platelets
• Variable neutropenia
• Inclusions also seen in
eosinophils, basophils, and
monocytes
• Autosomal dominant
• Many patients are
asymptomatic
• Non-muscle myosin heavy
chain A (MYH9) mutation
• No impairment on PMN
function
Alder Reilley Anomaly

• Resemble the large


primary granules of
promyelocytes
• Large, purple to purplish-
black, coarse azurophilic
granules
• No impaired PMN function
• Inclusion is a
mucopolysaccharide
(PAS+)
Alder Reilley Anomaly
• Autosomal recessive
• Associated with several
different types of genetic
mucopolysaccharide
disorders (Hurler, Hunter,
San Fillipo, Maroteaux-
Lamy)
• Affects connective tissues,
heart, bone, CNS
Hypersegmentation

• More than 5 lobes


• Seen most commonly in
B12/folate def
• Uremia
• Chemotherapy
• Also seen in MDS and
other MPN/MDS
neoplasms
Eosinophilia
• Allergic/hypersensitivity reactions
• Drug allergies
• Parasitic infections
• Connective tissue/collagen
vascular disease
• Neoplasms
– T-cell lymphoma
– Hodgkin lymphoma
• Sarcoidosis
• Hypereosinophilic
syndrome/Chronic eosinophilic
leukemia
• Chronic/acute leukemia a/w
PDGFRRA or PDGFRB mutations
Basophilia

• Much more common in


malignancies like CML
vs. reactive
Reactive Lymphocytosis

• Diseases with nonreactive morphology


– Infectious lymphocytosis (Whooping cough)
– Transient stress lymphocytosis
• Diseases with reactive morphology
– EBV,CMV, Toxo, adenovirus, HHV-6, viral
hepatitis
Plasmacytoid
lymphocyte

Atypical/reactive lymphocytes
Ehrlichiosis

• Found in the SE and S. Central US


• Rickettsial organism
• Transmitted by ticks
Histoplasma

<>
Babesiosis
• Protozoa
• Endemic in the NE US
• Transmitted by the
Ixodidae tick
• Morphology similar to
malaria
• Tetrad form is diagnostic
• Risk Factors:
– Post-splenectomy
– Immunocompromised
Malaria

• Ringed stage
(trophozoite)
• Can see other
stages within
RBCs
Trophozoites
(rings)
Multiple rings/cell
Appliqué forms
1-2 chromatin dots

Plasmodium falciparum

Gametocytes
Plasmodium vivax
Early Trophozoites (rings)
Ameoboid rings Enlarged RBCs
Schuffner’s Dots

Mature trophozoite
->schizont
Giant Platelets

• Size of an RBC
• Usually indicates a
hyperreactive bone
marrow 2o to underlying
condition
– ITP, TTP, DIC
• Can be inherited in the
form of Bernard-Soulier
syndrome, May-Heglin
anomaly
Platelet Clumping and
Satellitelosis

• Causes artificially low platelet Solution is to use


counts sodium citrate instead
of EDTA
• 2o to EDTA used in collection tubes
Aplastic Anemia
Aplastic Anemia

• Reduction of erythroid,
granulocytic/monocytic, and
megakaryocytic cell lines in the
bone marrow and their progeny in
the peripheral blood.
Hypocellular Bone Marrow
Aplastic Anemia- Causes

• Constitutional- including Fanconi’s


• Idiopathic
• Secondary
– Chemical/drug
– Radiation
– Infection
– Immune disorders
Fanconi’s Anemia
• 2/3 of constitutional aplastic
anemia
• Autosomal recessive
– DNA repair defect (diagnosis:
chromosome breakage analysis)
• Phenotypic abnormalities- bone,
skin, mental retardation
• Aplasia develops by mid childhood
• Progression to AML
Chemical/Drug

• Dose-dependant
– Chemotherapy
– Benzene
• Idiosyncratic
– Chloramphenicol, anticonvulsants,
sulfonamides, gold, NSAIDs
Ionizing Radiation

• Aplastic anemia- acute

• Long-term effects are


myelofibrosis and acute leukemia
Infections

• Hepatitis
– Rare, often fatal
– Non-A, non-B, non-C, non-G
– Usually 6 wks after clinical
symptoms
– No relation to severity of illness
Parvovirus B19
• Usually red cell aplasia
– Selective cytotoxic invasion of
erthryoblasts
• Mild reduction in granulocyte and
megakaryocyte production
• Chronic hemolytic anemia pts. at risk
– Sensitive to cessation in RBC production
– Transient aplastic crisis
• Self limited
Parvovirus B19
Treatment

• Treat the underlying conditions:


infection, d/c meds
• For immune disorders: androgens,
immune modulation, cytokine therapy
• Transfusions
• Bone marrow transplant
Deficiencies of Glycolytic Pathway
-Mature RBCs have the capacity for a limited number of enzymatic reactions
-No mitochondria in RBC, so it depends entirely on anaerobic glycolysis to produce
energy.
-The mature RBC is completely dependent on glucose as a source of energy. Glucose
usually (90%) is catabolized to pyruvate and lactate in the major anaerobic
glycolytic pathway (Embden-Myerhof Pathway). In the process, ATP is generated to
play its major role in maintaining a cation gradient in the RBC, thus protecting it
from premature death.
-Hereditary deficiency of some of the glycolytic enzymes have been documented,
and several cause a hereditary nonspherocytic hemolytic anemia (HNSHA), whereas
others cause multisystem disease
-Most are rare
-Pyruvate kinase deficiency is the most common and comprises 90% of affected
patients
-Hexokinase (AR) Mild-severe
-Glucose-6-isomerase (AR) Mod-severe
-Phosphofructokinase (AR) Mild myopathy
-Aldolase (AR) Mild-mod
-Phosphoglucerate Mild-severe
kinase (X-linked) retardation
-***Pyruvate kinase (AR) Mod-severe

Deficiencies of Glycolytic pathway


Pyruvate Kinase Deficiency
-AR, patient must be homozygous for the trait to be
expressed fully
-Detected in infancy or childhood due to anemia, jaundice, splenomegaly , gall
stones. The severity of the condition is widely variable, even among patients with
the same level of deficiency.
Lab studies
-Norchromic normocytic, or macrocytic anemia with reticulocytosis in the absence
of blood loss, is suggestive of hemolysis.
-Enzyme assay and, more recently, DNA analysis by PCR or single-strand
polymorphism are available to confirm the diagnosis and to identify the carrier
state if the need arises.
Fluorescent Screening test for Pyruvate kinase deficiency:
Principle: Reduced pyridine nucleotide (NADH) fluoresces when illuminated with
long-wave UV light.
Phosphoenolpyruvate (PEP) + ADP--------------> Pyruvate + ATP
Pyruvate
kinase (PK)
Pyruvate + NADH + H+ ----------------------------> Lactate + NAD+
Lactate dehydogenase
(LDH)
LDH is present in excess of PK, NAD production is limited by PK levels. Thus,
there should be a time dependent loss of fluorescence as NADH is oxidized to
NAD when PK is normal.
In PK-deficiency, fluoresence by NADH fails to disappear.
RBC enzyme activity assays
-Spectrophotometric techniques that depend on the absorption of light of the
reduced pyridine nucleotide, NADPH, or NADH at 340nm.
-Reduction results in formation of NADPH or NADH, with increase in
absorbance at 340 nm, and oxidation results in formation of NADP or NAD with
a decrease in absorbance.
-The change in absorbance may be used to calculate enzyme activity.
Deficiencies of Hexose Monophosphate
Shunt Pathway
Hexose monophosphate Shunt (HMP)

G6PD deficiency Common


Gamma-Glutamylcysteine synthase Rare
GSH synthetase Rare
Glutathione reductase Rare
G6PD Deficiency:
-G6PD enzyme located on X chromosome
-> 30 different mutations give rise to a variety of clinical diseases
-Normally 2 isotypes of G6PD: A and B. Can be differentiated based on
electrophoretic mobility
-B isoform most common type of enzyme found in all population groups
-A isoform, found in 20% black men in US, migrates more rapidly on
electrophoretic gels than B. It has similar enzyme activity as B, and does not cause
disease
-11% of US black men have G6PD variant (G6PD A-). It has same electrophoretic
mobility as A, but is unstable, resulting in enzyme loss and ultimate enzyme
deficiency. Older RBC have only 5-15% enzyme
-G6PD A- most clinically significant type of abnormal G6PD among US Blacks
-Other G6PD variants predominate in other racial groups: G6PDMED in Sicilians,
Greeks, Sepharic Jews, Arabs. G6PDCANTON or G6PDMAHIDOL in Asian population
-X linked, so sex-linked inheritance pattern.
-Effect fully seen in affected men
-Carrier women are variable affected depending X chromosome inactivation
Clinical findings
-Episode of hemolysis following infection or ingestion of an oxidant drug
-In G6PD A- def, the hemolytic anemia is self-limited as the young RBC produced in
response to hemolysis have nearly normal enzyme.
-Five classes of G-6-PD deficiency exist based on enzyme activity levels, as follows:
1.Enzyme deficiency with chronic hemolytic anemia
2.Severe enzyme deficiency (enzyme level <10%)
3.Moderate-to-mild enzyme deficiency (enzyme level 10-60%)
4.Very mild-to-no enzyme deficiency (enzyme level > 60%)
5.Increased enzyme activity
Laboratory Tests:
-Acute hemolysis is associated with formation of Heinz bodies (denatured Hgb).
-Bite cells (eccentrocytes) may be seen
-Fluorescent Screening test for G6PD Deficiency:
In the presence of NADP+, G6PD is oxidized to form 6-phosphogluconate and
NADPH. Then

6-Phophogluconate + NADP+ ----------------------- > Ribulose-5-P + NADPH + H+


6-phosphogluconate
dehydrogenase

NADPH can be detected by fluorescence


When G6PD is low, less NADPH is formed.
Normal sample shows a bright fluorescence after 5-10 minutes of incubation,
whereas deficient sample shows no fluorescence.
Quantitative G6PD assay:
-Formation of NADPH from NADP+ from G6P is measurable by a change in
absorbance created by NADPH at 340 nm in a spectrophotometer

Heinz body test:


Crystal violet or neutral red is added to blood
Paroxysmal Nocturnal
Hemoglobinuria (PNH)
Introduction
• Recurrent, episodic
– Intravascular hemolysis
– Hemoglobinuria
– Venous thrombosis
• May not always be
– Paroxysmal (acute)
– Nocturnal
– hemoglobinuric
Additional Points
• Clonal disorder
– Not a malignant clone
• Deficiency of complement-control proteins
– On all affected hematopoietic cells
• Increased susceptibility to complement lysis
– Erythrocytes not able to endocytose
membrane attack compex (MAC: end product
of complement cascade) as opposed to
nucleated cells
Complement Control Proteins
•CD55 (decay accelerating
factor: DAF)
–Regulates C3 convertase

•CD59 (membrane inhibitor of


reactive lysis: MIRL)
–Modulates complement-
mediated lysis
Complement Control Proteins

•CD55 (DAF)
–Inhibits association of
Regulation of C3 Convertase

C4b and C2
–Promotes dissociation
of C4bC2a complex
(C3 Convertase)
Complement Control Proteins

• CD59 (MIRL) prevents formation of


Membrane Attack Complex and lytic
action
Clinical
Nocturnal Hemoglobinuria

•Classical
description
–Dark urine in morning
that clears through
the day
–Sleep decreases pH,
increases
complement activity
-Accumulation of
urine
Flow Cytometry
•Preferred
confirmatory test
•Decreased
expression of CD55
and/or CD59

Normal

PNH

PNH
AUTOIMMUNE
HEMOLYTIC
ANEMIAS
WARM TYPE
-Abrupt onset
-May be severe
-Slight female preponderance
-IgG antibodies
-Extravascular hemolysis
-Antibodies commonly against broad Rh
antigens
WARM AIHA
COLD TYPE
-Acute or insidious onset
-Mild to severe anemia
-Female preponderance
-IgM antibodies
-Agglutination of red cells at low temperatures
-Complement activation
-Intravascular and extravascular hemolysis
-Antibodies commonly against I or I antigens
COLD TYPE
• Acute: postinfectious, self limited, younger patients
• Chronic: idiopathic, older patients
• Cold agglutinin disease (CAD): insidious, elderly women,
associated with lymphoproliferative disorders
COLD AIHA


LAB PARAMETERS
WARM COLD

DAT 2+ TO 4+ 2+ TO 4+

ANTI IgG + -

ANTI C3 RARE +
TREATMENT
WARM AIHA
-Corticosteroid therapy
-Intravenous IVIG
-Immunosuppressants
-Splenectomy

COLD AIHA
-Immunosuppressants and splenectomy: no role
-Keeping patient warm
-Treatment of underlying disease
-Plasmapheresis
Hemophagocytic syndrome
Syndrome Definition
• “Hemophagocytosis” – Process by which
macrophages engulf RBCs, WBCs,
platelets and their precursors
• Hemophagocytic syndrome =
Hemophagocytic lymphohistiocytosis
(HLH)
– Two main groups: Genetic and acquired
– Mechanism: highly active yet ineffective
immune response that is life-threatening
Bone marrow aspirate
HLH - Pathophysiology
• Theory: Inappropriate immune reaction caused by
proliferating, active T cells and macrophages with
inadequate apoptosis of immunogenic cells
• Impaired cytotoxic function of NK cells
– Decreased NK activity with persistent T-cell
activation
• Cytokine hypersecretion, inflammatory response
– IFN-gamma, TNF-alpha, IL-6, IL-10, M-CSF
– Responsible for clinical signs, cytopenias,
coagulopathy, high triglycerides
– Infiltrate tissues and lead to necrosis and organ
failure
HLH – Criteria

• sCD25 (alpha chain of


soluble IL-2 receptor)
HLH and Infection
• Viruses (esp. EBV), bacteria, parasites, spirochetes,
mycobacteria, fungi

• Difficulty distinguishing acquired from familial


– Familial cases may be precipitated by infection
– May mimic an infectious illness
HLH and Infection
• Impractical to exclude all possible infectious causes
• If HLH criteria are met, then screen for EBV, CMV,
parvovirus B19, HIV
• History should guide testing
– HIV infection: Pneumococcus, Pneumocystis,
Histoplasma, Penicillium marneffei
– Animal exposure: Brucella, Rickettsia
– Travel exposure: Leishmania, malaria
HLH and other Associations
• Malignancy
– T-cell lymphoma

• Autoimmune diseases
– Juvenile RA, Still’s disease (systemic-onset juvenile
idiopathic arthritis), SLE
HLH - Laboratory
• CBC, AST/ALT, bilirubin, triglycerides, ferritin, fibrinogen
• Bone marrow: Insensitive
– May be negative in 2/3 of initial aspirates
• sCD25 >2400 U/ml
– Highly specific serum parameter
• NK cell perforin expression
• Genetic testing
– PRF1, Munc13-4 (available at Cincinnati Children's Hospital)
HLH - Treatment
• Immediate goal: Immune suppression
– Corticosteroids
– Cyclosporin A: prevents T cell activation
– Etoposide: Critical for EBV-infected pts, inhibits
EBNA synthesis in EBV-infected cells

• Genetic HLH: Bone marrow transplant


CRYOGLOBULINAEMIA
CRYOGLOBULINS
• Cryoglobulins are plasma proteins that
precipitate at low temperature ( 0 to 4 degree
Celsius ) and dissolve at higher temperature
• They were first described in 1933 by Wintrobe
and Buell (at John Hopkins Hosp)
• In 1962, Lospaluto et al. showed that
cryoglobulins contains more than one
immunoglobulin ( Am J Med 1962;32:142-7 )
Peripheral blood smear with clumps of
precipitated cryoglobulin
CLASSIFICATION( Brouet et al.’s )
• TYPE I:- Single Monoclonal Immunoglobulins
– Type I CGB consists of a single monoclonal Ig, usually IgG or IgM,
infrequently IgA, and very rarely monoclonal light chain protein
• TYPE II :- Mixed Monoclonal/ polyclonal IG
– Type II CGB are mixed CGB consist of two or more IG of different
classes. One component of the complex is a monoclonal protein
(with a high proportion being IgM), that has rheumatology factor
activity, in association with polyclonal IG component
• TYPE III :- Mixed polyclonal IG
– Type III CGB are also mixed CGB, consisting of two or more IG of
different classes, however, each component is a polyclonal IG
CRYOGLOBULIN TYPES &
ASSOCIATED DISEASES
Types of CGB Immunochemical Associated diseases Comments
composition

IgG B-cell dyscrasis: Cryoglobulin


Type I : Myeloma
Single IgA W. Macroglobulinemia
concentratio
Monoclonal IG CLL n is usually
Monoclonal
L-Chain
Hairy Cell Leukaemia HIGH (>
5mg/ml )
IgM
CRYOGLOBULIN TYPES &
ASSOCIATED DISEASES

Type of CGB Immunochemical Associated Diseases Comments


composition

IgM-IgG B- Cell dyscasias: Circulating


Type II: immune
Myeloma
Mixed IgG-IgG W. Macroglobulinaemia
complexes
Monoclonal CGB con.
IgA-IgG CLL
/Polyclonal IG usually(5mg/ml)
HCV
CRYOGLOBULIN TYPES & ASSOCIATED DISEASES

Type of CGB Immunochemical Associated Diseases


Comments
composition
Autoimmune disease: Circulating
Type III : IgM-IgG
Rheumatoid arthritis immune complexes
Mixed IgM-IgG-IgA SLE
in response to Ig
Polyclonal IG challenge in
Sjogren’s syndrome
Rheumatoid disease
Hepatitis and chronic
Vasculitis infections
CGB conc. is
usually < 1mg/ml )
CLINICAL ASSOCIATION
• Type I cryoglobulinemia are more likely to be symtomatic
and are usually associated with acrocyanosis, retinal
haemorrhage, Raynaud’s phenomenon, and arterial
thrombosis
• High levels of type I cryoglobulins are associated with
symptoms of hyperviscosity
• Mixed CG, are less commonly symptomatic and are
usually associated with vascular purpura and arthritis/
arthalgia; this is secondary to deposition within tissue
(immune complexes ) which activate complement and
induce localized inflammation
HEPATITIS C VIRUS-ASSOCIATED
CRYOGLOBULINEMIA
• When no underlying disease is present, this is referred
to as essential mixed cryoglobulinaemia ( EMC )
• In EMC, the possible role of hepatotropic viruses has
been suggested by the high frequency of co-existing
liver abnormalities
• The prevalence of anti-hepatitis C virus (HCV )
antibodies and the correlation with clinical and
serological parameters of EMC have been
investigated
ANALYSIS PROCEDURE

• A white precipitate (cryoglobulin) appears in the


serum after 24-72 hours of storage at 37oC
• The cryoglobulins can be quatitated by:
Measuring the cryoglobulin protein
spectrophotometrically by absorbance at 280mm
• Ig component of cryoglobulins can be determine by:
– Immunoelectrophoresis
– Isoelectric focusing in asociation with
immunofaxition
THERAPEUTIC MODALITIES FOR
SYMPTOMATIC PATIENTS
• Corticosteriods
• Subcutaneous interferon alpha ( IFN ), with or without plasma
exchange
• Care must be given to ensure blood components are warmed
before infusion
Bone Marrow Disorders
of Nonhematopoietic
Elements
Lipid Storage Disorders
• Hereditary lysosomal
enzyme deficiency
– Autosomal recessive
• Partially degraded
lipids accumulate in
macrophages
– Liver, spleen, bone
marrow, etc.
• Organomegaly,
cytopenias
Gaucher’s Disease
• Enzyme deficiency: Glucocerebrosidase
• Accumulate Glucocerebroside
• 3 clinical forms, all AR
– Type I- adult
– Type II- acute infantile, neuronopathic
– Type III- subacute juvenile, neuronopathic
Gaucher’s Disease
• Gaucher cell
– “Wrinkled
cigarette paper”
or “crepe paper”
– PAS positive
Pseudo-Gaucher Cell
• Indistinguishable from true Gaucher
cell
• Conditions with high cell membrane
turnover
– CML, hemoglobinopathies, myeloma
– Increased burden of glucocerebroside
Gaucher Cell Look-alike
• MAI infection
• Macrophages packed
with organisms
– Negatively staining
organisms mimics
striations of Gaucher
cells.
Niemann-Pick Disease
• Enzyme deficiency: Sphingomyelinase
• Accumulate Sphingomyelin
• 3 clinical forms, all AR
• Type A- early onset
• Type B- adult, no cerebral involvement
• Type C- late onset
Niemann-Pick Disease

• Foamy macrophages
– “Bubbly” appearance
– Weak PAS+
– Oil Red O and Sudan
black positive
• May also present as
Sea blue histiocytes
Sea Blue Histiocytes
• Macrophages contain ceroid
– Lipofuscin-like pigment
– H&E-> yellow-brown
– Wright/Geimsa-> bright blue green
– PAS positive
• High turnover states: CML, ITP
• Lipidoses and hyperlipidemia
Sea Blue Histiocytes Geimsa

H& E
Sarcoidosis

• Epitheloid granulomas in lung and


other organs
– Bone marrow involvement 17%
– A/w lymphadenopathy, spleenomegaly,
lymphopenia
Sarcoidosis
• Epitheloid histiocytes
– Small, noncaseating
granulomas
Bone Marrow Infarction

• Coagulative necrosis
• Associated with neoplastic
process, vasocculsive disorders
and hemoglobinopathies
Bone Marrow Infarction
• Homogenously
staining
• Ghost cells
Serous Fat Atrophy
• AKA gelatinous
transformation
• Associated with
starvation and
wasting diseases
• Homogenous
extracellular
substance with
“gelantinous”
appearance
Renal Osteodystrophy
• Chronic renal insufficiency

– 2o hyperparathyroidism
• Increased osteoclast activity- irregular
scalloping of bony trabeculae and
peritrabecular fibrosis
Renal Osteodystrophy
• “Scalloping” of
bony trabeculae
• Peritrabecular
fibrosis
Nonmalignant
Lymphadenopathy
Reactive Lymphoid Hyperplasia
Follicular Pattern
• Numerous enlarged, oddly shaped follicles
• Prominent germinal centers
• Tingible body macrophages
• Nonhomogenous lymphoid population
• Frequent mitoses
• Polyclonal surface immunoglobulins
• Germinal centers negative for bcl-2
Reactive Lymphoid Hyperplasia
Sinus Pattern

• Prominent sinuses
• Histiocyte hyperplasia
• Proliferation of plasma cells
• Polyclonal surface immunoglobulins
Progressive Transformation of Germinal Center
Progressive Transformation of Germinal Center: expanded
follicular center infiltrated by mantle cells. A benign process.
Maybe a/w NLPHL
Infectious Mononucleosis
• EBV virus
• Clinical information: febrile, exudative pharyngitis, cervical
lymphadenopathy, splenomegaly, abnormal LFTs, common
in adolescence/young adulthood, rare after 40 y/o
• Peripheral blood lymphocytosis with atypical lymphocytes
• Expanded paracortex (T-cell zone) by many immunoblasts
& R-S like cells
• Mottled pattern, foci of necrosis
• Different from NHL: polymorphous background of
transformed lymphocytes, persistent of reactive follicles,
architecture preservation. Immuno for R-S like cells: (+) for
CD45, CD30 and CD20; (-) for CD15. Also many large
CD8-pos cells
Measles Lymphadenitis
• Measles (rubeola) or history of recent
vaccination
• Axillary, cervical, inguinal lymph nodes
• Mottled histologic pattern
• Follicular hyperplasia
• Proliferation of immunoblasts
• Warthin-Finkeldey giant cells (syncytia of
lymphocytes)
HIV Lymphadenitis (persistent generalized
lymphadenopathy)
• Pattern A (Acute): Enlarged lymph node with
hyperplastic follicles and reactive germinal centers,
naked follicular centers, folliculolysis by mantle-zone
cells, monocytoid B cells in sinus, Warthin-Finkeldey
giant cells
• Pattern B (Chronic): Involution of germinal centers,
depletion of lymphocytes, increased plasma cells,
vascular hyperplasia
• Pattern C (Burnout): Small or absent follicles with
hyalinized germinal centers and collagen-ensheathed
arterioles (“lollipop”), plasma cells, more severe
lymphocyte depletion-> naked stroma
Toxoplasma Lymphadenitis

• Most common parasitic infection in US


• Cat definitive host; Toxoplasma gondii
• Posterior cervical LN most often affected
• Triad: Reactive germinal centers; perifollicular
and intrafollicular clusters of epithelioid
histiocytes; patches of monocytoid cells in
sinus
• Serologic tests for confirmation
Kikuchi-Fujimoto
(Subacute necrotizing lymphadenitis)

• Affects predominantly young Asians


• Females more often than males
• Benign course, spontaneous remission
• Fever, cervical lymphadenapthy
• Patchy necrosis, marked apoptosis, nuclear debris
• Aggregates of histiocytes
• Neutrophils, eosinophils absent
• Kawasaki’s disease: infancy and childhood. Histology similar to
Kikuchi + fibrin thrombi
Systemic Lupus
Lymphadenopathy

• Architecture effaced
• Follicles inconspicuous
• Necrosis focal or confluent
• Nuclear debris and hematoxylin bodies (basophilic masses of
DNA)
• Presence of plasma cells, immunoblasts
• Vasculitis with fibrinoid necrosis
• Granulomas, neutrophils and eosinophils: absent
SHML-Rosai-Dorfmann Disease
Histologic Features

• Effacement of follicles
• Dilatation of sinuses
• Proliferation of sinus histiocytes with
emperipolesis (lymphocytes in histiocytes)
• Lipid-laden macrophages
• Absence of necrosis
• Lack of mitoses
Castleman
Lymphadenopathy
• Hyaline-vascular type
• Plasma cell type
• Mixed type
• Multicentric
Castleman Lymphadenopathy:
Hyaline-Vascular Type

• More common; younger patients


• Isolated lymph node mass; often mediastinal
• Frequently asymptomatic
• Hyaline deposits in atrophic germinal centers
• Collagen-ensheathed (“lollipop”) arterioles
• Concentric layering of lymphocytes (“target”
follicles)
• Interfollicular vascular hyperplasia
Castleman Lymphadenopathy:
Plasma Cell Type
• Older patients
• Systemic symptoms
• Possible associations: polyneuropathies,
organomegaly, endocrinopathy, monoclonal
gammopathy, skin changes (POEMS
syndrome)
• Hyperplastic lymphoid follicles with active
germinal centers
• Interfollicular sheets of plasma cells
Castleman’s Disease, plasma cell type
Castleman Lymphadenopathy
Multicentric Form

• Atypical lymphoproliferative disorder


• Most are plasma cell type or mixed type
(features of both types)
• Older patients
• Severe systemic symptoms
• Multiple lymphoid organs involved
• High levels of IL-6 in lymph nodes & serum
• Kaposi sarcoma/HHV-8 often present
• HIV infection often associated
Dermatopathic Lymphadenopathy

• LNs draining areas of dermatitis, also a/w cutaneous


T cell lymphoma
• Pruritis, eosinophilia
• Axillary, inguinal lymphadenopathy
• Architecture preserved; follicular hyperplasia
• Paracortical, palely stained, confluent areas of
histiocytes/interdigitating dendritic cells/ Langerhan’s
cells. Histiocytes are the major component.
• Melanin pigment-laden macrophages
• Immuno: CD1a+ (LCs); and S100+ (IDCs and LCs)

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