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Home , Acanthocyte, Basophilic stippling, Codocyte, Dacrocyte

Board Review- Part 1: Benign HemePath Peripheral Blood Smear Examination Elevated MCV = MCV > 100um3 • B12/Folate deficiency, aplastic anemia, MDS • Autoimmune • disease, hypothyroidism, alcoholism • Cold agglutinin disease

Decreased MCV = MCV < 80um3

• Iron deficiency • • 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 (spur cell) Altered cell membrane lipids Abetalipoproteinemia, liver disease, postsplenectomy, McLeod phenotype Bite Cell (degmacyte) pitting by G6PD deficiency, drug-induced oxidant hemolysis

Ovalocyte () Abnormal cytoskeletal proteins Hereditary elliptocytosis Circulating paraprotein Paraproteinemia (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 () Increased redundancy of cell Liver disease, beta membrane postsplenectomy, Hgb C/D/E/S

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

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

• 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

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 and only mild hemolysis

Hereditary Pyropoikilocytosis • Same mutations as in HE • Present in the neonatal period with severe hemolytic anemia, RBC fragments, poikilocytes, , 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- – disorders • • Hemoglobinopathies Hb S, C, D and E

Hgb SC disease with C crystals, Taco cells and sickle cells

“Washington Monument crystals”

Microangiopathic hemolytic anemia

DIC, TTP, HUS Rouleoux and Clumping

RBC Clumping: cold agglutinin

Rouleaux: monoclonal gammopathy vs. polyclonal gammopathy 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 (, 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

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 -

Pappenheimer bodies

Small, dense basophilic granules (mitochondrial remnant that contains Fe)

Seen in: - - Post-splenectomy

The Malignant Mimicker: Leukemoid Reaction

• Precursor 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, , 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 • 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

Plasmacytoid

Atypical/reactive 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 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 with 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

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

Type of CGB Immunochemical Associated Diseases Comments composition

Type II: IgM-IgG B- Cell dyscasias: Circulating Myeloma immune Mixed IgG-IgG complexes W. Macroglobulinaemia Monoclonal CGB con. IgA-IgG CLL /Polyclonal IG usually(5mg/ml) HCV

CRYOGLOBULIN TYPES & ASSOCIATED DISEASES

Type of CGB Immunochemical Associated Diseases Comments composition Type III : IgM-IgG Autoimmune disease: Circulating Rheumatoid arthritis immune complexes Mixed in response to Ig IgM-IgG-IgA SLE 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 • 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 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 • 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 • 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)