Washington manual of hematology and oncology 3rd ed subspeciality consult

Library of Congress Cataloging-in-Publication Data The Washington manual hematology and oncology subspecialty consult.. — Washington manual subspecialty consult series Hematology and on

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Library of Congress Cataloging-in-Publication Data

The Washington manual hematology and oncology subspecialty consult —3rd ed / editors, Amanda Cashen, Brian A Van Tine

p ; cm — (Washington manual subspecialty consult series)

Hematology and oncology subspecialty consult

Includes bibliographical references and index

ISBN 978-1-4511-1424-9 (alk paper) — ISBN 1-4511-1424-9 (alk

paper)

I Cashen, Amanda II Van Tine, Brian A III Title: Hematology andoncology subspecialty

consult IV Series: Washington manual subspecialty consult series

[DNLM: 1 Hematologic Diseases—Handbooks 2 Diagnosis, Differential

3

The Washington Manual™ is an intent-to-use mark belonging to

Washington University in St Louis to which international legal protectionapplies The mark is used in this publication by LWW under license fromWashington University

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responsibility of the practitioner

The authors, editors, and publisher have exerted every effort to ensurethat drug selection and dosage set forth in this text are in accordance withcurrent recommendations and practice at the time of publication

However, in view of ongoing research, changes in government regulations,and the constant flow of information relating to drug therapy and drugreactions, the reader is urged to check the package insert for each drug forany change in indications and dosage and for added warnings and

precautions This is particularly important when the recommended agent is

a new or infrequently employed drug

Some drugs and medical devices presented in the publication have Foodand Drug Administration (FDA) clearance for limited use in restricted

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5

Department of Pharmacy

Barnes-Jewish Hospital

St Louis, Missouri

Amanda Cashen, MD

Assistant Professor of Medicine

Section of Leukemia and Stem Cell TransplantationWashington University School of Medicine

Department of Obstetrics and Gynecology

Washington University School of Medicine

St Louis, Missouri

Lindsay M Hladnik, PharmD, BCOP

7

Laboratory and Genomic Medicine

Washington University School of Medicine

Department of Radiation Oncology

Washington University School of Medicine

St Louis, Missouri

Department of Radiology Oncology

Washington University School of Medicine

Brian A Van Tine, MD, PhD

Assistant Professor of Medicine

Division of Medical Oncology

Washington University School of Medicine

Division of Medical Oncology

Washington University School of Medicine

St Louis, Missouri

Israel Zighelboim, MD

Assistant Professor

Department of Obstetrics and Gynecology

Division of Obstetrics and Gynecology OncologyWashington University School of Medicine

St Louis, Missouri

Imran Zoberi, MD

Assistant Professor

Department of Radiation Oncology

Washington University School of Medicine

St Louis, Missouri

11

t is a pleasure to present the new edition of The Washington Manual®Subspecialty Consult Series: Hematology/Oncology Subspecialty Consult This

pocket-size book continues to be a primary reference for medical students, interns,residents, and other practitioners who need ready access to practical clinical

information to diagnose and treat patients with a wide variety of disorders Medicalknowledge continues to increase at an astounding rate, which creates a challenge forphysicians to keep up with the biomedical discoveries, genetic and genomic

information, and novel therapeutics that can positively impact patient outcomes The

Washington Manual Subspecialty Series addresses this challenge by concisely and

practically providing current scientific information for clinicians to aid them in thediagnosis, investigation, and treatment of common medical conditions

I want to personally thank the authors, which include house officers, fellows,and attendings at Washington University School of Medicine and Barnes-JewishHospital Their commitment to patient care and education is unsurpassed, and theirefforts and skill in compiling this manual are evident in the quality of the final

product In particular, I would like to acknowledge our editors, Drs Amanda Cashenand Brian A Van Tine, and the series editors, Drs Katherine Henderson and Tom

De Fer, who have worked tirelessly to produce another outstanding edition of thismanual I would also like to thank Dr Melvin Blanchard, Chief of the Division ofMedical Education in the Department of Medicine at Washington University School

of Medicine, for his advice and guidance I believe this Subspecialty Manual willmeet its desired goal of providing practical knowledge that can be directly applied

at the bedside and in outpatient settings to improve patient care

Victoria J Fraser, MD

Dr J William Campbell ProfessorInterim Chairman of MedicineCo-Director of the Infectious Disease DivisionWashington University School of Medicine

e are pleased to present the third edition of The Washington Manual™

Hematology and Oncology Subspecialty Consult The field of medical oncology

continues to advance at a remarkable pace Every year, new indications are foundfor existing therapies and new anti-cancer drugs are approved Staging systems,classifications, and prognostic models are in flux, reflecting the discovery of newbiomarkers, changes in treatment algorithms, and the general improvement in patientoutcomes Therapeutic advances have also been made in benign hematology,

particularly with the introduction of novel anticoagulants

This edition has been updated to include new standards in the treatment of

malignancies and hematologic disorders, mechanisms of action of new therapeuticagents, and current use of molecular prognostic factors The information in eachchapter is now presented in a consistent format, with important references cited Ourgoal is to provide a concise, practical reference for fellows, residents, and medicalstudents rotating on hematology and oncology subspecialty services Most of theauthors are hematology–oncology fellows or internal medicine residents, the

physicians who have recent experience with the issues and questions that arise in thecourse of training in these subspecialties Primary care practitioners and other healthcare professionals also will find this manual useful as a quick reference source inhematology and oncology

As the practice of hematology and oncology continues to evolve, changes indosing and indications for chemotherapy and targeted therapies will occur, and

staging systems will be modified We recommend a handbook of chemotherapy

regimens and an oncology staging manual to complement the information in this

book And of course, clinical judgment is imperative when applying the principlespresented here to the care of individual patients

We appreciate the effort and expertise of everyone who contributed to this

edition of the Hematology and Oncology Subspecialty Consult In particular, we

would like to thank the authors for their enthusiastic efforts to distill volumes ofmedical advances into a concise, useable format We also recognize the faculty inthe divisions of hematology, oncology, bone marrow transplantation, radiation

oncology, and gynecologic oncology at Washington University for their mentorshipand commitment to education.

—A.C and B.A.V.T

15

4 Platelets: Thrombocytopenia and Thrombocytosis

Gregory H Miday and Paul Mehan

5 Introduction to Coagulation and Laboratory Evaluation of Coagulation

George Ansstas

10 Transfusion Medicine

Ronald Jackups and Tzu-Fei Wang

11 Sickle Cell Disease

PART II ONCOLOGY

14 Introduction and Approach to Oncology

17 Introduction to Radiation Oncology

Daniel J Ma, Parag J Parikh, and Imran Zoberi

22 Malignant Melanoma

Gregory H Miday and Yee Hong Chia

23 Head and Neck Cance

Amie Jackson and Kristen M Sanfilippo

31 Introduction to Hematopoietic Stem Cell TransplantationArmin Ghobadi

32 Human Immunodeficiency Virus–Related MalignanciesXiaoyi Hu

33 Cancer of Unknown Primary

Gayathri Nagaraj

34 Supportive Care in Oncology

Brian A Van Tine

35 Oncologic Emergencies

Michael Ansstas

Index

19

GENERAL PRINCIPLES

Approach to the Hematology Patient

Hematologic diseases are a heterogeneous group of diseases that can have

multiple clinical and laboratory manifestations that mimic nonhematologic diseases.History, physical exam, labs, peripheral smear, and bone marrow biopsy are critical

in making the correct diagnosis The diseases can be approached by identifying theprimary hematologic component that is affected: RBCs, WBCs, platelets, or thecoagulation system The major abnormalities in hematology are quantitative in

nature, with either excessive or deficient production of one of the hematopoieticconstituents (e.g., leukemias, anemias) Qualitative abnormalities that can be

inherited (e.g., sickle cell disease) or acquired also occur

DIAGNOSIS

Clinical Presentation

History

The medical history is, of course, the first step in hematology diagnostic

assessment Table 1-1 offers some general questions for evaluation of a hematologicdisorder

Physical Exam

The physical exam is also an important part of the diagnostic process Alongwith the history, it can suggest a diagnosis, guide lab testing, and aid in the

differential diagnosis Table 1-2 offers some general physical exam findings that areuseful in the hematology patient

Diagnostic Testing

Laboratories

The clinician should be comfortable using the complete blood count (CBC) andperipheral smear to evaluate patients for possible hematologic disorders Patientsmay be referred to a hematologist based on a lab abnormality that is drawn for areason other than the diagnosis of a primary hematologic disorder There are certainlimiting values in hematology that can help exclude or confirm the need for furthertesting or warn us of the possibility of potential physiological consequences (seeTable 1-3)

The Peripheral Smear The visual study of peripheral blood is

necessary to diagnose hematologic and nonhematologic diseases, forexample, thrombotic thrombocytopenic purpura or malaria In thesecases, as in others, automated hematology analyzers are able to provide

a large number of data regarding all the blood cells but will not be able

to detect subtle anomalies critical in the diagnosis

21

Slides for a peripheral smear are typically prepared either by automated

methods or by qualified technicians in a specialized laboratory This step is criticalsince poorly processed samples can lead to incorrect diagnoses Smears may be

prepared on glass slides or coverslips Ideally, blood smears should be prepared from uncoagulated blood and from a sample collected from a finger stick In

practice, most slides are prepared from blood samples containing anticoagulants andare thus prone to the introduction of morphologic artifacts Blood smears are

normally stained using Wright or May–Grünwald–Giemsa stain

Examination of the Peripheral Smear Examination of the smearshould proceed systematically and begin under low power to identify aportion of the slide with optimal cellular distribution and staining, whichnormally corresponds to the thinner edge of the sample As a general

rule, the analysis starts with RBCs, continues with leukocytes, and finishes with platelets Under low power (×10 to ×20) it is

possible to analyze general characteristics of RBCs to discover, for

example, the presence of Rouleaux associated with multiple myeloma,estimate the WBC and platelet counts, and determine the presence ofabnormal populations of cells, such as blasts, by scanning over the entire

23

smear Under high power (×100), each of the cell lineages is examinedfor any abnormalities in number or morphology.

Red Blood Cells Quantitative analysis of RBCs is difficult on a

peripheral smear Automated analyzers are used to calculate:

MCHC, the mean cell Hgb concentration, expressed as grams per

deciliter;

MCH, the mean corpuscular Hgb, expressed as picograms; and

MCV, the mean corpuscular volume, expressed as femtoliters (10−15 L)

Qualitative analysis of RBCs should demonstrate uniform round cells with

smooth membranes and a pale central area with a round rim of red Hgb Variations

in size are called anisocytosis, and variations in shape, poikilocytosis The

following abnormalities may be observed:

Hypochromia corresponds to a very thin rim of Hgb and a larger

central pale area These red cells are often microcytic and are seen iniron deficiency, thalassemias, and sideroblastic anemia

Microcytosis (<6 μm): Differential diagnosis includes iron-deficiency

anemia, anemia in chronic disease, thalassemias, and sideroblasticanemia These cells are usually hypochromic and have prominent centralpallor

Macrocytosis (>9 μm in diameter): Differential diagnosis includes liverdisease, alcoholism, aplastic anemia, and myelodysplasia Megaloblasticanemias (B12 and folate deficiencies) have macro-ovalocytes (large oval

c e l l s ) Reticulocytes are large immature red cells withpolychromatophilia

Schistocytes (fragmented cells) are caused by mechanical disruption ofcells in the microvasculature by fibrin strands or by mechanical prostheticheart valves Differential diagnosis includes thrombotic thrombocytopenicpurpura/hemolytic uremic syndrome, disseminated intravascularcoagulation, hemolysis/elevated liver enzymes/low platelet count(HELLP) syndrome, and malignant hypertension

Acanthocytes (spiculated cells with irregular projections of varying

length) are seen in liver disease

Burr cells (cells with short, evenly spaced cytoplasmic projections) may

be an artifact of slide preparation or found in renal failure and uremia Bite cells (cells with a smooth semicircle extracted) are due to spleenphagocytes that have removed Heinz bodies consisting of denaturedHgb They are found in hemolytic anemia due to glucose-6-phosphatedehydrogenase deficiency

Spherocytes (round, dense cells with absent central pallor) are seen inimmune hemolytic anemia and hereditary spherocytosis

Sickle cells (sickle-shaped cells) are due to polymerization of Hgb Theyare found in sickle cell disease but not in sickle cell trait

Target cells (cells with extra Hgb in the center surrounded by a rim ofpallor; bull’s-eye appearance) are due to an increase in the ratio of cellmembrane surface area to Hgb volume within the cell These have acentral spot of Hgb surrounded by a ring of pallor from the redundancy incell membrane They are found in liver disease, postsplenectomy, in

25

hemoglobinopathies, and in thalassemia.

Teardrop cells/dacryocytes (teardrop-shaped cells) are found in

myelofibrosis and myelophthisic states of marrow infiltration

Ovalocytes (elliptical cells) are due to the abnormal membrane

cytoskeleton found in hereditary elliptocytosis

Polychromatophilia (blue hue of cytoplasm) is due to the presence ofRNA and ribosomes in reticulocytes

Howell–Jolly bodies (small, single, purple cytoplasmic inclusions)

represent nuclear remnant DNA and are found after splenectomy or withfunctional asplenism

Basophilic stippling (dark-purple inclusions, usually multiple) arises

from precipitated RNA found in lead poisoning and thalassemia

Nucleated red cells are not normally found in peripheral blood Theyappear in hypoxemia and myelofibrosis or other myelophthisicconditions, as well as with severe hemolysis

Heinz bodies (inclusions seen only on staining with violet crystal)

represent denatured Hgb and are found in glucose-6-phosphatedehydrogenase after oxidative stress

Parasites, including malaria and babesiosis, may be seen within red

cells

Rouleaux (red cell aggregates resembling a stack of coins) is due to

the loss of normal electrostatic charge–repelling red cells due to coatingwith abnormal paraprotein, such as in multiple myeloma

Leukoerythroblastic smear (teardrop cells, nucleated red cells, and

immature white cells) is found in marrow infiltration or fibrosis(myelophthisic conditions)

White Blood Cells WBCs normally seen on the peripheral smear

include mature granulocytes (neutrophils, eosinophils, and basophils)and mature agranulocytes (lymphocytes and monocytes) Under normalconditions, immature myeloid and lymphoid cells are not seen and theirpresence is related to conditions such as infections and hematologic

neoplasias

Neutrophils Neutrophils comprise 55% to 60% of total WBCs (1.8 ×

109 to 7.7 × 109/L) They have nuclei containing three or four lobes andgranular cytoplasm The normal size is 10 to 15 μm Hypersegmentedneutrophils contain more than five lobes and are found in megaloblasticanemias The cytoplasmic granules correspond to enzymes that are used

during the acute phase of inflammation Increased prominence ofcytoplasmic granules is indicative of systemic infection or therapy withgrowth factors and is known as toxic granulation Neutrophils developfrom myeloblasts through promyelocyte, myelocyte, metamyelocyte, andband forms and progress to mature neutrophils Only mature neutrophilsand bands are normally found in peripheral blood Metamyelocytes andmyelocytes may be found in pregnancy, infections, and leukemoidreactions The presence of less mature forms in the peripheral blood isindicative of hematologic malignancy or myelophthisis.

Lymphocytes Lymphocytes comprise 25% to 35% (1 × 109 to 4.8 ×

109/L, or thousands per cubic millimeter) of total WBCs They contain adark, clumped nucleus and a scant rim of blue cytoplasm Thedifferentiation of T and B cells using light microscopy is very difficult The

normal size is 7 to 18 μm Atypical (or reactive) lymphocytes seen

in viral infections contain more extensive, malleable cytoplasm that mayencompass surrounding red cells

Eosinophils Eosinophils comprise 0.5% to 4% of total WBCs (0.2

×109/L, or thousands per cubic millimeter) These are large cellscontaining prominent red/orange granules and a bilobed nucleus Thenormal size is 10 to 15 μm Increased numbers are found in parasiticinfections and allergic disorders

Monocytes Monocytes comprise 4% to 8% of total WBCs (0 to 0.3 ×

109/L, or thousands per cubic millimeter) These are the biggercirculating cells with an eccentric U-shaped nucleus They contain bluecytoplasm and are the precursors of the mononuclear phagocyte system(macrophages, osteoclasts, alveolar macrophages, Kupfer cells, andmicroglia) The usual size is 12 to 20 μm

Basophils Basophils comprise 0.01% to 0.3% of total WBCs (0 to 0.1

×109/L, or thousands per cubic millimeter) Their cytoplasm containslarge dark-blue granules and a bilobed nucleus They are involved ininflammatory reactions and increased numbers are also seen in chronicmyeloid leukemia As for eosinophils, the normal size is 10 to 15 μm

WBC Abnormalities Quantitative anomalies result in leukopenia and

leukocytosis Main causes of leukopenia include bone marrow failure(aplastic anemia), myelophthisis (acute leukemia), drugs(immunosuppressive drugs, propylthiouracil), and hypersplenism (portalhypertension) Main causes of leukocytosis are infection, inflammation,

27

malignancies, and allergic reactions.

Pelger–Huet anomaly (neutrophils have a bilobed nucleus connected

by a thin strand and decreased granulation) is seen in myelodysplasticsyndromes

Hypersegmented neutrophils (more than four nuclear lobes) are

found in megaloblastic anemias (vitamin B12 and folate deficiency)

Blast cells (myeloblasts or lymphoblasts; large cells with large nuclei

and prominent nucleoli) are seen in acute leukemia

Auer rods (rodlike granules in blast cytoplasm) are pathognomonic for

acute myelogenous leukemia, especially acute promyelocytic leukemia(M3)

Hairy cells (lymphoid cells with ragged cytoplasm) are seen in hairy cell

leukemia

Sézary cells (atypical lymphoid cells with cerebriform nuclei) are seen

in cutaneous T cell lymphoma

Platelets Platelets appear as small (1- to 2-μm-diameter), purplishcytoplasmic fragments without a nucleus, containing red/blue granules.Derived from bone marrow giant cells called megakaryocytes, they areinvolved in the cellular mechanisms of primary hemostasis leading to theformation of blood clots Normal counts are 150,000 to 400,000 per cubicmillimeter of peripheral blood The number of platelets per high-powerfield multiplied by 20,000 usually estimates the platelet count per

microliter Alternatively, one should find 1 platelet for every 10 to 20 redcells

Numbers of platelets can decrease due to bone marrow disease(myelophthisic bone marrow), consumption (disseminated intravascularcoagulation), or drugs An increase in numbers can be seen in bonemarrow overproduction (myeloproliferative syndromes) or in a normal

response to massive bleeding Pseudo-thrombocytopenia represents

clumping of platelets in blood samples collected in EDTA, resulting inspuriously low platelet counts This phenomenon can be avoided byusing citrate to anticoagulate blood samples sent for blood counts

Diagnostic Procedures

Bone Marrow Evaluation For many hematologic diseases that affectthe bone marrow, evaluation of the peripheral blood smear does notprovide sufficient information, and a direct examination of the bone

marrow is required to establish the diagnosis The bone marrow biopsycan be done at the bedside under local anesthesia alone or in

combination with low doses of anxiolytics or opioids Despite advances inthe bone marrow biopsy and aspiration techniques, they are still

commonly considered painful procedures, but with expertise, they can beperformed safely and with minimal discomfort to the patient

Indications and Contraindications The most common indications forbone marrow evaluation are workup of bone marrow malignancies;

staging of marrow involvement by metastatic tumors; assessment ofinfectious diseases that may involve the bone marrow (i.e., HIV,

tuberculosis); determination of marrow damage in patients exposed toradiation, drugs, and chemicals; and workup of metabolic storage

diseases There are a few absolute contraindications for the procedure,including infection, previous radiation therapy at the site of biopsy, andpoor patient cooperation Thrombocytopenia is not a contraindication tobone marrow biopsy, although it may be associated with more

procedure-related bleeding Patients who have a coagulopathy requirefactor replacement or withholding of anticoagulation to minimize

bleeding complications

Technique In adults, the most common places to do the procedure arethe posterior and anterior iliac crests Other potential biopsy sites arethe sternum and tibia The posterior iliac crest is the preferred site, as itallows collection of both aspirate and biopsy specimens and is associatedwith minimal morbidity or complications Usually, a Jamshidi bone

marrow aspiration and biopsy needle is used Additional aspirate is oftenobtained for studies such as flow cytometry, cytogenetics, and cultures

In some instances, marrow cannot be aspirated and only a biopsy is

obtained (a “dry tap”) This can be due to the technique or may signalmyelofibrosis or previous local radiotherapy In such cases, touch

preparations of the biopsy can be made to allow for a cytologic exam.The biopsy specimen is embedded in a buffered formaldehyde-basedfixation for further processing

Complications Bleeding at the site of puncture is the most commoncomplication It is easily controlled with compression, but some

thrombocytopenic patients will require platelet transfusions Other

uncommon complications are infections, tumor seeding in the needletrack, and needle breakage

29

Bone Marrow Examination

The examination of the bone marrow aspirate begins under low power

to obtain an impression of overall cellularity, an initial scan for anyabnormal populations of cells or clumps of cells, and an evaluation of thepresence or absence of bone marrow spicules Megakaryocytes arenormally seen under low power as large multinucleated cells The overallcellularity of the marrow is difficult to estimate from the aspiratebecause of contamination with peripheral blood

The myeloid-to-erythroid (M:E) ratio is also determined under low

power and is normally 3:1 to 4:1 The ratio is increased in chronicmyeloid leukemia due to an increase in granulocyte precursors and isincreased in pure red cell aplasia due to a decrease in red cellprecursors The ratio is decreased in hemolytic disorders in whichincreased erythroid precursors are present or in agranulocytic conditionssecondary to chemotherapeutic agents or other drugs

Under high power, the aspirate should contain a variety of cells

representative of various stages of myeloid and erythroid maturation.Myeloid cells progress from myeloblasts to promyelocytes, myelocytes,metamyelocytes, band forms, and then mature neutrophils As thesecells mature, their nuclear chromatin condenses, with a resultantdecrease in the nuclear-tocytoplasmic ratio Their cytoplasm graduallydevelops granules seen in mature neutrophils

Erythroid precursors progress from proerythroblasts through varying

stages of normoblasts known as basophilic, chromatophilic, andorthochromic The nucleus gradually condenses, and the cytoplasmgradually takes on the pinkish hue of Hgb found in mature red cells

Bone marrow core biopsies are fixed in a buffered

formaldehyde-based solution and then embedded in paraffin or plastic Biopsies areused to assess the cellularity of the bone marrow and the presence ofneoplasias, infections, or fibrosis Cellularity is estimated by observingthe ratio of hematopoietic cells to fat cells Cellularity is usually 30% to60% but typically declines with advancing age

Abnormalities in the Bone Marrow Evaluation Listed below aresome of the more common abnormal findings of the bone marrow

Acute leukemia: The presence of >20% blasts in the bone marrow

establishes the diagnosis of acute leukemia

Myelodysplastic syndrome is a heterogeneous group of diseases

characterized by the presence of immature erythroid precursors with loss

of synchrony between nuclear and cytoplasmic maturation Maturemyeloid cells have decreased lobes (Pelger–Huet cells) Iron stainingmay reveal ring sideroblasts with iron granules surrounding the nucleus

Chronic myeloid leukemia: Findings include a hypercellular marrow

with an increased M:E ratio Myeloblasts represent <5% of cells, withthe marrow containing predominantly myelocytes, metamyelocytes, andmature neutrophils

Chronic lymphocytic leukemia is marked by hypercellular marrow

with small, round, mature lymphocytes with a thin rim of blue cytoplasm

Myelofibrosis is often the cause of a “dry tap.” Bone marrow biopsy

will reveal marrow infiltration with collagen and fibrous tissue

Essential thrombocytosis: Megakaryocyte hyperplasia is a common

finding

Polycythemia vera is characterized by a hypercellular marrow.

Multiple myeloma: The marrow is replaced by large numbers of

abnormal, often immature plasma cells with eccentric nuclei containing acartwheel pattern of nuclear chromatin Flame cells contain pink,flamelike cytoplasm and are associated with an IgA paraprotein

Megaloblastic anemia: Findings include hypercellular marrow with

abnormalities in myeloid and erythroid precursors Megaloblasts areerythroid cells that are larger than normal, with more nuclear chromatin.There is loss of synchrony between nuclear and cytoplasmic maturation

Storage diseases: Patients with Gaucher disease may have

macrophages with striated cytoplasm due to accumulation ofcerebrosides Individuals with Niemann–Pick disease may havemacrophages with a foamy cytoplasm secondary to containedsphingomyelin

31

General Principles

The normal white blood cell (WBC) count varies with gender and

ethnicity but, in general, ranges from 4 × 109 to 11 × 109 cells/L (Table2-1) and is composed of those cells committed to the leukocyte lineage:granulocytes (neutrophils, eosinophils, and basophils), monocytes, andlymphocytes Neutrophils make up about 60% of the peripheral bloodnucleated cells A person’s gender and ethnic background should be

taken into consideration when determining normal ranges

Leukopenia is defined as a WBC count <3.8 × 10 9 cells/L This

lower limit of normal varies with age (infants have lower absolute

neutrophil counts [ANCs] than adults) and race (lower ANCs in persons ofAfrican ancestry, West Indians, Arab Jordanian, and Yemenite Jews),1and 5% of thenormal population may fall outside of the normal referencerange Leukopenias can be divided according to clinically relevant celllineages: neutrophils and lymphocytes

NEUTROPENIA

General Principles

Definition

The ANC is obtained by taking the percentage of neutrophils identified on a cell differential or by the Coulter counter and multiplying by the total WBC count.

100-Neutropenia is classified as mild (ANC, <1.5 × 109 to 1 × 109 /L), moderate (ANC,

1 × 109 to 0.5 × 109/L), or severe (ANC, <0.5 × 109 /L) Agranulocytosis is the

total absence of granulocytes

obtained by analyzing blood several hours old and in the presence of

paraproteinemia and certain anticoagulants that can cause clumping Lower ANCsoccur in African Americans as a result of defective release of neutrophils from themarrow, a poor marrow reserve, or an increased marginated pool of neutrophils.2

33

Neutropenia results from decreased production, ineffective granulopoiesis,increased margination to peripheral pools, or increased peripheral destruction.Acquired neutropenias are usually a result of infection, toxins/drugs, or immunedisorders Viral, parasitic, or bacterial infections may cause neutropenia, and this isusually short lived The underlying mechanism involves increased margination,sequestration, and increased destruction by circulating antibodies Drug and toxinexposure usually follows a temporal course, with neutropenia developing aftercontinued drug exposure of days to months The mechanism of drug-induced

neutropenia is either antibody-mediated or direct toxic effects on the marrow.

Certain drugs at higher risk of causing neutropenia are highlighted in Table 2-3.Primary immune disorders mediate neutropenia through antibody-mediated

neutrophil destruction

Diagnosis

Clinical Presentation

Neutropenia is often incidentally discovered on a complete blood count

(CBC) but may present with fever or infection Signs of infection, such

as purulence, may be less evident, given the low neutrophil count Therisk of infection is directly related to the degree and duration of

neutropenia The risk of infection increases at an ANC <1 × 109/L, butclinical symptoms usually do not become manifest until the ANC fallsbelow 0.5 × 109/L.3

The initial evaluation should include a complete history and physical

exam The history should focus on systemic symptoms of infection,

recent exposures or new medications, history of neutropenia, and family

history of neutropenia The physical exam may suggest the cause of

neutropenia, and attention should be paid to vital signs that would

suggest sepsis or infection, oral cavity exam for gingivitis or tooth

abscess, macroglossia to suggest vitamin deficiency, lymphadenopathy

to suggest malignancy or infection, skin and joint changes suggesting arheumatologic disorder, and splenomegaly (sequestration and Felty’ssyndrome)

Diagnostic Testing

Initial laboratory evaluation starts with the CBC with complete differential and

review of the peripheral blood smear Additional testing to consider includes

nutritional studies of vitamin B12, folate, and possibly copper If a clonal process issuspected, lymphocyte immunophenotyping by flow cytometry and T-cell receptorgene rearrangement studies may be useful Antinuclear antibody and antineutrophilantibody testing can be sent to evaluate for autoimmune neutropenia HIV and EBVserologies start the initial infectious workup If anemia or thrombocytopenia occurs

in combination with neutropenia, direct examination of the bone marrow via bonemarrow biopsy is usually warranted unless a cause is obvious In cases of

asymptomatic mild neutropenia, serial CBC examination to rule out cyclic

35

neutropenia may be considered In mild cases of neutropenia that do not improve in acouple of months with observation, a bone marrow biopsy should be considered.

Treatment

Treatment is guided by the underlying etiology and severity of

neutropenia This can range from close observation in patients with

benign neutropenia to growth factor support and antibiotics in patientswith neutropenic fevers

Growth factors can be used to speed count recovery in drug-induced

neutropenia The major complication associated with neutropenia isinfection

Supportive care with broad-spectrum antibiotics in the ill or febrile

patient is an essential part of initial care while the workup for a cause ofneutropenia is under way Common sites of infection include mucousmembranes, skin, perirectal and genital areas, bloodstream, and lungs.Most commonly, endogenous bacterial flora is the pathogen

(Staphylococcus from skin or gram-negative organisms from the gut).Antibiotics should be continued until the ANC is >500/L for 2 days andthe fever subsides If fever and neutropenia persist, empiric antifungalcoverage should be considered

Cases caused by drug toxicity should improve, with removal of the drugwithin 1 to 3 weeks Drug-related neutropenia can be confirmed by

testing antineutrophil-associated drug antibodies Infectious etiologiesresolve with treatment of the infection or shortly after a viral infectionhas subsided Autoimmune diseases can be treated by

immunosuppression with corticosteroids and can be confirmed by testingantineutrophil antibodies Congenital etiologies are often supported withgrowth factors such as granulocyte colony-stimulating factor (G-CSF).The involvement of other blood cell lineages (RBCs and platelets)

suggests aplastic anemia, leukemia, myelodysplastic syndromes, or

megaloblastic anemia

LYMPHOPENIA

General Principles

Definition

Lymphopenia is defined as an absolute lymphocyte count <1.2 10 9 /L The

absolute lymphocyte count is 80% T cells and 20% B cells Sixty-six percent of theT-cell population is CD4+ cells and the remaining is mainly CD8+ cells

Etiology

Lymphopenia is most often acquired, but congenital causes should also be

37

considered Etiologies of lymphopenia are listed in Table 2-4 and are mainly

acquired Patients who appear to have low or absent CD4 cells should be evaluatedfor OKT4 epitope deficiency This condition is found in 8% of individuals of

African descent Individuals with OKT4 epitope deficiency usually have normalCD4+ number and do not develop infections.4

causes predispose to recurrent and opportunistic infections, and detailed discussion

of management is beyond the scope of this text In general, prophylactic antibioticscan be used, as well as best supportive care

LEUKOCYTOSIS

General Principles

An elevated WBC most commonly reflects a normal bone marrow response toinflammation or infection Occasionally leukemia or myeloproliferative disordersare to blame The maturation of WBCs is influenced by G-CSFs, interleukins (ILs),tumor necrosis factor, and complement components

Definition

Leukocytosis is defined as a WBC count >10 × 109 cells/L

Leukocytosis should be divided into granulocytosis, monocytosis, and

lymphocytosis to guide the workup and differential diagnosis

Etiology

Most cases of leukocytosis are a result of the bone marrow reacting to

inflammation or infection A leukemoid reaction is an excessive WBC response

(usually >50,000) associated with a cause outside of the bone marrow (growth

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factors, infection, or differentiating agents such as all-trans retinoic acid [ATRA]).Leukocytosis may also be caused by physical and emotional stress and usually

resolves in hours once the stress is eliminated In postsplenectomy patients, a

transient leukocytosis can be seen, lasting for weeks to months secondary to thedemargination of leukocytes typically stored in the spleen Other etiologies includemedications, but leukocytes should not rise above 20,000 to 30,000 in this case Theleukocytosis seen in hemolytic anemias (sickle cell and autoimmune types) is related

to the nonspecific effects of increased erythropoiesis and inflammation

Nonhematopoietic malignancy can also cause a leukocytosis that is multifactorial inetiology Finally, acute and chronic leukemias and myeloproliferative disordersusually present with a leukocytosis

remainder in circulation This large storage pool allows for a rapid increase inWBCs (mostly neutrophils) In addition, a percentage of circulating WBCs is