13/1/2557 Approach to the child with an enlarged spleen

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Approach to the child with an enlarged spleen

Authors Section Editor Deputy Editor

Kenneth L McClain, MD, PhD Donald H Mahoney, Jr, MD Alison G Hoppin, MD
Stephen A Landaw, MD, PhD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2013. | This topic last updated: พ.ย. 20, 2556.

INTRODUCTION — Diagnostic criteria for various disease states (eg, the presence of splenomegaly in juvenile idiopathic arthritis or subacute bacterial endocarditis) historically have
been built on long experience with the physical examination, whereas scanning procedures have been available for only a relatively short time. Thus, the clinical or diagnostic
significance of a spleen that is modestly enlarged on scan but is not palpable is uncertain and requires other findings to establish its importance.

This topic review discusses the approach to a child whose spleen is enlarged on physical examination or is more than minimally enlarged on ultrasound, x-ray, nuclear medicine liver-
spleen colloid study, computerized tomography scan (CT), or magnetic resonance imaging (MRI).

OVERVIEW OF SPLENIC FUNCTION — The spleen is a hematopoietic organ, which, at various times during gestation and/or extrauterine life, is capable of supporting elements of
the erythroid, myeloid, megakaryocytic, lymphoid, and monocyte-macrophage (ie, reticuloendothelial) systems. In certain disease states (eg, beta thalassemia major, primary
myelofibrosis), it may become the site of extramedullary hematopoiesis and contain developing erythroid, myeloid, and megakaryocytic precursors. (See "Clinical manifestations and
diagnosis of the thalassemias".)

● The white pulp of the spleen is a major part (up to 25 percent) of the lymphoid tissue in the body. Like lymph nodes, it has germinal centers where early B-lymphocytes
predominate, along with plasma cells. T-lymphocytes are the major population around periarteriolar sheaths. When antigens are present in the circulation, the spleen plays a
key role in providing an environment for the immunologic response. Thus, in the absence of the spleen, antibody production may be significantly diminished. As an example,
when pneumococcal vaccine is given intramuscularly to asplenic individuals, the IgG and IgM antibody titers are less than those noted in normal individuals [1]. Likewise, the
titers of pneumococcal antibodies decline more rapidly in asplenic patients [2].

● The largest component of the spleen is the red cell mass known as the "red pulp." It consists of the red blood cells surrounding endothelial cords of Billroth and interdigitating
splenic sinusoids, which are lined with macrophages. Because of the anatomic arrangement of blood vessels, red cells are relatively concentrated in the terminal splenic
arteries, as plasma with potentially antigenic material is shunted to the white pulp. The high concentration of red cells in these arterioles and sinusoids explains how relatively
mild degrees of hypoxia can cause transformation of sickle cells to the irreversibly hardened variety and promote infarction in this organ (autosplenectomy). (See "Overview of
the clinical manifestations of sickle cell disease".)

● In the splenic sinusoids, which course through white and red pulp, macrophages line the vascular spaces. These macrophages are important parts of the immune system in
presenting antigens to lymphocytes in the white pulp as well as in destroying antibody-coated bacteria or hematopoietic cells. When red cells squeeze through these sinusoids,
the surrounding macrophages are able to remove senescent red cells, destroy erythrocytes with abnormal membranes, and remove red cell inclusions such as nuclear
remnants. As a result, when the spleen is absent, many of these abnormal red cells may circulate, along with red cells containing nuclear remnants (ie, Howell-Jolly bodies),
(picture 1 and picture 2). (See "Hereditary spherocytosis: Mechanism of hemolysis and pathogenesis", section on 'Splenic conditioning' and "Pathogenesis of autoimmune
hemolytic anemia: Warm agglutinins and drugs".)

● The spleen acts as a reservoir for platelets; one-third of the circulating platelet mass is temporarily sequestered within a normal sized spleen, and up to 90 percent may be found
within a markedly enlarged spleen. When the spleen is removed, this reservoir function also is removed, and a common occurrence is for the platelet count to temporarily
exceed 1 x 106/microL after splenectomy in a normal child, without an increased risk for thrombosis [3].

As a result of these many functional components within the spleen, the etiology of splenomegaly may relate to an increase in a normal splenic process (eg, hemolysis) or may be
due to infiltrative, infectious, or vascular disorders. Similarly, removal of a spleen may alleviate disease by more than one mechanism. As an example, thrombocytopenia may be
alleviated in immune thrombocytopenia (ITP, previously known as idiopathic thrombocytopenic purpura) through the loss of a large number of antiplatelet antibody-producing
lymphocytes, as well as through the removal of splenic macrophages capable of destroying antibody-coated platelets. (See "Immune thrombocytopenia (ITP) in children: Management
of chronic disease", section on 'Splenectomy'.)

SPLEEN SIZE — The spleen weighs 11 g at birth, 55 g at six years of age, and 125 g (range 100 to 250 g) at puberty [4]. It is palpable below the left costal margin in nearly one-third
of neonates, 10 percent of normal children, and more than 2 percent of normal 19-year-olds. However, a splenic edge felt more than 2 cm below the ribs definitely is an abnormal
finding.

Ultrasound measurements of the normal spleen length (from the dome to the tip) have been published [5]. The upper limits of splenic length for various ages include 6 cm at 3 months,
7 cm at 12 months, 9.5 cm at 6 years, 11.5 cm at 12 years, 12 cm for girls 15 or older, and 13 cm for boys ≥15 years of age. In this study, the authors showed that in all patients
with splenomegaly by clinical exam who had a defined illness, the splenic length exceeded these normal limits.

Splenic imaging — Imaging of the spleen with radioactive (Tc-99m) sulfur colloid scintigraphy or denatured red cells, ultrasonography, CT, or MRI can be an important adjunct to the
physical exam in defining pathologic changes in this organ. However, one must be aware of some artifacts with these technologies to avoid an erroneous reading of an abnormality
[6]. Imaging techniques may reveal the existence of accessory spleens (found in 30 percent of autopsies), which are more common in females, as well as polysplenia associated with
congenital heart disease, biliary atresia, or situs inversus. A "wandering spleen," resulting from a lack of ligamentous attachment can be found anywhere in the abdomen. (See
"Differential diagnosis of abdominal pain in adults", section on 'Wandering spleen syndrome'.)

Causes of splenomegaly that may be elucidated by imaging techniques include portal hypertension (eg, due to cirrhosis or portal vein thrombosis), isolated cysts, hemangioma,
lymphangioma, or hamartomas. Multiple focal abnormalities could result from trauma to the spleen (eg, subcapsular hematoma, splenic rupture), abscesses, granulomas,
lymphoproliferative disease, Langerhans cell histiocytosis, Gaucher disease, Niemann-Pick disease, or sarcoidosis.

PHYSICAL EXAMINATION OF THE SPLEEN — Numerous studies have shown wide interobserver variability in the ability to appreciate an enlarged spleen, which generally is not
associated with the level of clinical experience [7].

Of note, a palpable spleen may be detected in healthy adolescents and young adults. This was illustrated in a study of 2,200 entering college freshmen, of whom 3 percent (63
students) had palpable spleens detected by one of three examiners [8]. Only six students had an identified underlying condition including four with infectious mononucleosis. Three
years later, 19 subjects (30 percent of those with palpable spleen initially) still had palpable spleens.

Palpation method — The most frequent errors made in examination of the spleen involve incomplete relaxation of the abdominal musculature of the patient and the musculature of
the examiner's hand(s). Effectiveness in palpating the spleen can be maximized by paying attention to the following:

● With the patient supine, allow the patient to feel the examining hand on the abdomen and to become adjusted to its presence before pressing down. Do not suddenly increase
pressure during palpation, as an enlarged spleen may be quite tender (particularly if it has enlarged quickly) and the patient may be reluctant to allow the examination to
continue.

● Make sure that the patient is relaxed, with arms at the sides of the abdomen. If the arms are raised, this may stiffen the abdominal musculature and make examination more
difficult.

● Relaxation of the patient can be improved if the legs and neck are slightly flexed. Relaxation of the examiner can be improved by being comfortably seated in a chair alongside
the patient's bed or examining table, with the examiner on the patient's right side, the right hand doing the palpation and the left hand underneath and supporting the patient's left
lower rib cage.

A spleen that is only minimally enlarged will be quite movable with respiration and may be palpable only at the end of inspiration. Using a light touch, with the skin depressed under

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the left costal margin, one can feel a minimally enlarged spleen as a rounded edge with the consistency of normal liver, which slips under the examiner's fingers at the end of
inspiration and back on expiration. A normal spleen is soft and non-tender.

Because the spleen normally is a posterior structure, increased sensitivity occasionally can be obtained by placing the patient in the right lateral decubitus position, with knees and
neck flexed. This maneuver also increases relaxation of the abdominal musculature and rotates the spleen to a more anterior position. However, one study suggested that this
additional maneuver was not useful when it followed examination of the patient in the supine position [9].

With greater degrees of enlargement, the spleen rotates to a more anterior and rightward position and may extend downward into the pelvis. Under these circumstances, the lower
pole of the spleen may not be felt easily because it is well below the left costal margin. In such cases, splenomegaly is appreciated either by palpating at successively lower levels on
the left side of the abdomen or by palpating the medial edge of the spleen. The presence of a notch or indentation on the medial splenic edge is a further indication that the mass is
spleen and not the left kidney or a pancreatic pseudocyst.

In more extreme cases, the enlarged spleen extends across the midline and may even be palpable in the right upper quadrant. The presence of exquisite splenic tenderness suggests
the presence of infarction or perisplenitis in such massively enlarged spleens.

CAUSES OF AN ENLARGED SPLEEN — The causes of an enlarged spleen are multiple and most often reflect the presence of hepatic or hematologic disease, infection, or
inflammation (table 1). An interesting mnemonic to help remember the general causes of splenomegaly is S-P-L-E-E-N, as follows [10]:

● Sequestration of red blood cells, as in congenital spherocytosis or other congenital or acquired hemolytic anemias

● Proliferation secondary to chronic inflammation or infection, as in systemic lupus erythematosus, rheumatoid arthritis, and infective endocarditis

● Lipid deposition disorders such as Gaucher or Niemann-Pick disease

● Endowment as in congenital causes for splenomegaly, including splenic hemangioma, hamartoma, or cysts

● Engorgement caused by splenic trauma with intracapsular hematoma formation, sequestration crisis in sickle cell disease, chronic heart failure, or portal hypertension. In
children, portal vein thrombosis is a relatively common cause of portal hypertension [11]. (See "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and
management", section on 'Clinical manifestations' and "Pathogenesis and clinical manifestations of venous thrombosis and thromboembolism in infants and children", section on
'Portal vein thrombosis'.)

● iNvasion with granulomatous, histiocytic, lymphoproliferative, or malignant hematologic disease

In children, splenomegaly most commonly is the result of an exuberant response of the immune system to infections by many different agents, disorders of immune regulation, or
abnormal destruction of red blood cells. However, infiltration with neoplastic or storage disease cells, abnormal splenic blood flow as in portal hypertension, and space-occupying
lesions also must be considered.

In children with hereditary spherocytosis, sickle cell anemia (SCA), thalassemia, infections, or malignant diseases, serial assessment of splenic size is important in order to define
the need for, or the response to, appropriate therapeutic interventions. As an example, in the child with SCA, a rapidly enlarging spleen with a falling hematocrit suggests the
presence of a splenic sequestration crisis, which is a medical emergency associated with a mortality rate as high as 10 to 15 percent. (See "Overview of the clinical manifestations of
sickle cell disease", section on 'Acute severe anemia'.)

The most common causes for an enlarged spleen will vary from country to country, according to prevailing incidences of infection and genetic disorders. As an example, in a study of
22 children with splenomegaly from Pakistan, causes included [12]:

● Beta thalassemia – 55 percent

● Hematologic malignancy – 18 percent
● Hemolytic anemia other than thalassemia – 14 percent
● Storage disorders – 9 percent
● Congenital sideroblastic anemia – 4 percent

We can find no case series describing the relative frequency of causes of splenomegaly in children in Western countries. Three case series summarize a large number of patients
from California with splenomegaly, most of whom were adults [13-15].

Causes of a massively enlarged spleen — A spleen is considered to be massively enlarged if its lower pole is within the pelvis or if it crosses the midline. Only a few diseases
cause this degree of splenic enlargement. These include the following disorders, each of which is discussed elsewhere on the appropriate topic reviews:

● Leukemia (lymphoid or myeloid, usually chronic, as in chronic myeloid leukemia)

● Thalassemia major

● Lymphoma, usually the more indolent variants

● Langerhans cell histiocytosis (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

● Autoimmune lymphoproliferative syndrome (Canale Smith syndrome) [16] (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

● Castleman's disease [17] (See "Castleman's disease".)

● Gaucher disease (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)

● AIDS with Mycobacterium avium complex [13] (See "Mycobacterium avium complex (MAC) infections in HIV-infected patients".)

● Kala-azar (See "Clinical manifestations and diagnosis of visceral leishmaniasis".)

● Hyperreactive malarial splenomegaly syndrome, also called tropical splenomegaly syndrome (See "Overview of non-falciparum malaria", section on 'Hyperreactive malarial
splenomegaly'.)

● Hemophagocytic lymphohistiocytosis/familial erythrophagocytic lymphohistiocytosis [18]. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

CLINICAL EVALUATION — The history may provide valuable clues as to the possible cause of splenomegaly (table 1).

In children with a recent viral syndrome including fever, pharyngitis, and malaise, one would naturally include common viral infections (eg, infectious mononucleosis, cytomegalovirus,
hepatitis) as an etiology. (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Cytomegalovirus infection and disease in newborns, infants, children and
adolescents".)

In the patient with systemic complaints such as fever, night sweats, malaise, and/or weight loss, an enlarged spleen may reflect activity of a systemic disease, such as lymphoma,
AIDS, systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, malaria, tuberculosis, or hematologic disorders (eg, acute or chronic leukemias), that may already have been
diagnosed. In such cases, the spleen may revert to normal size when the underlying disease is brought under control with appropriate therapy.

The problem often confronting the examining physician is that the child presents with splenomegaly for which no prior diagnosed or evident condition can be considered responsible. A
reasonable and standard approach to such patients is outlined in the algorithm (algorithm 1). The evaluation begins with a focused history (including recent travel information),
physical examination, complete blood count with white blood cell differential and platelet count, liver function studies, urinalysis, chest x-ray, and abdominal ultrasound. If the initial
evaluation does not provide a diagnosis to explain the splenomegaly, additional evaluation for other disorders may be considered, depending on the clinical context. This may include
testing for the presence of antibodies to Epstein-Barr virus, cytomegalovirus, parvovirus, or HIV-1 or measurement of glucocerebrosidase activity in peripheral leukocytes, to evaluate
for Gaucher disease. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)

Complete blood count and examination of the peripheral smear — The complete blood count and white blood cell differential, along with a careful examination of the peripheral
smear, often are of utmost importance in determining the cause of an enlarged spleen. The peripheral smear may yield sufficient clues to suggest an immediate diagnosis. (See

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"Evaluation of the peripheral blood smear".) Examples are:

● A leukemic blast cell containing Auer rods immediately indicates the diagnosis of acute myeloid leukemia (picture 3).

● The presence of hypochromic, microcytic red cells, along with target cells and basophilic stippling, in an iron-replete child suggests the diagnosis of thalassemia (picture 4 and
picture 5).

● Circulating LE cells occasionally can be seen in systemic lupus erythematosus (picture 6).

Cytopenias — Neutropenia, anemia, and/or thrombocytopenia may be present, as these formed elements can be trapped in an enlarged spleen, giving the nonspecific picture
termed "hypersplenism." Only a minimally predictable relationship exists between the degree of splenomegaly and the presence or degree of these cytopenias [19]. (See "Extrinsic
nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and hypersplenism".)

The cytopenias seen with hypersplenism are not associated with abnormal circulating white blood cell or red blood cell forms. However, cytopenias are nonspecific, as multiple other
causes, including certain infections, can provoke these changes in a patient with splenomegaly.

Congenital hemolytic anemias — The spleen may be enlarged in congenital red cell disorders associated with shortened red cell lifespan and increased splenic sequestration.
Clues to the presence of these disorders include:

● Spherocytes (picture 7)
● Elliptocytes (picture 8)
● Xerocytes (picture 9)
● Sickle cells (picture 2)
● Stomatocytes (picture 10).
● Severe degrees of hypochromia associated with increased numbers of target cells in the thalassemic syndromes (picture 5).

Evidence for infection — The presence of neutrophilia (ie, an absolute neutrophil count greater than age-specific normal values) with or without increased numbers of band and
metamyelocyte forms ("left shift") suggests the presence of infection. On occasion, invading organisms may be seen on the peripheral smear, either free in the plasma as in
overwhelming sepsis, within neutrophils or monocytes (eg, bacteria, ehrlichiae), or within red blood cells (eg, bartonellosis, babesiosis (picture 11), and malaria (picture 12)). (See
"Approach to the patient with neutrophilia".)

Patients with overwhelming bacterial sepsis may show other abnormalities on smear, including microangiopathic changes in red blood cells (picture 13) and toxic granulation,
vacuoles, and Dohle bodies in neutrophils (picture 14). (See "Approach to the patient with neutrophilia", section on 'Evaluation of the complete blood count'.)

Certain infectious organisms are associated with relatively specific changes, such as red blood cell agglutination caused by the presence of cold agglutinins (picture 15) in infections
with Mycoplasma pneumoniae or infectious mononucleosis, and the atypical lymphocytes seen in the latter infection (picture 16). (See "Pathogenesis of autoimmune hemolytic
anemia: Cold agglutinin disease" and "Infectious mononucleosis in adults and adolescents".)

The combination of sepsis, profound anemia with hemoglobinemia, hemoglobinuria, and the presence of microspherocytes suggests infection with a phospholipase-producing
Clostridial organism. (See "Clostridial myonecrosis", section on 'Clinical manifestations'.)

Evidence for widespread bone marrow invasion — The presence of early white cells (cells less mature than metamyelocytes) and red cell forms (nucleated red cells) on the
peripheral smear, along with teardrop-shaped red cells (ie, a leukoerythroblastic blood picture) (picture 17A-B), suggests the presence of widespread bone marrow invasion. This
picture may be seen in marrow invasion with tumor; infection such as tuberculosis; hematologic diseases including thalassemia, osteopetrosis, erythroblastosis fetalis; and in
myeloproliferative disorders including myelofibrosis, polycythemia vera, and Down syndrome with transient myeloproliferative disease.

Evidence for malignant disease — The presence of increased numbers of abnormal cells in the peripheral blood suggests the presence of a hematologic malignancy, such as
follicular lymphoma (picture 18), hairy cell leukemia (picture 19), acute lymphocytic leukemia (picture 20), or myeloid leukemia (picture 3). Morphologic evaluation of the bone marrow,
coupled with special staining and immunocytochemical techniques, can help to establish the correct diagnosis [20]. (See "Evaluation of bone marrow aspirate smears".)

Additional studies — If no abnormalities are suggested by the above workup, CT examination of the chest and abdomen should be performed to evaluate the patient for
disseminated or intraabdominal malignancy, such as lymphoma or neuroblastoma, advanced liver disease, or portal hypertension.

An alternative approach is to biopsy tissue depending upon the clinical suspicion. Thus, if infection is suspected, a lymph node or bone marrow biopsy may be indicated, or a liver
biopsy if liver disease is suspected [13]. Without a specific organ or tissue to biopsy, a reasonable approach would be performance of a bone marrow aspiration with biopsy and
culture. Conditions such as lipid storage diseases (picture 21 and picture 22), disseminated mycobacterial or granulomatous disease, hemophagocytic syndrome (picture 23), and
occult tumors (picture 24) may be diagnosed in this way.

SUMMARY

● When splenomegaly is included among diagnostic criteria for a disease state, it is usually based on whether splenomegaly was detected on the physical examination. Thus, the
clinical or diagnostic significance of a spleen that is modestly enlarged on scan but is not palpable is uncertain and requires other findings to establish its importance. (See
'Introduction' above.)

● The spleen has an important role in the immune response, because it provides an environment for antigen presentation by macrophages and antibody response by lymphocytes.
In addition, splenic macrophages remove senescent red cells from the circulation and the spleen acts as a reservoir for platelets. (See 'Overview of splenic function' above.)

● The spleen is palpable below the left costal margin in nearly one-third of neonates, 10 percent of normal children, and more than 2 percent of normal 19-year-olds. However, a
splenic edge felt more than 2 cm below the ribs definitely is an abnormal finding. The upper limits of splenic length for range from 6 cm at 3 months, to 12 cm for girls 15 or
older, and 13 cm for boys ≥15 years of age. (See 'Spleen size' above.)

● To detect a spleen that is only minimally enlarged, the patient should be examined while in the supine position, with the arms down and abdominal musculature relaxed. The
spleen will be quite movable with respiration and may be palpable only at the end of inspiration. With greater degrees of enlargement, the spleen rotates to a more anterior and
rightward position and may extend downward into the pelvis, and splenomegaly is appreciated either by palpating at successively lower levels on the left side of the abdomen or
by palpating the medial edge of the spleen. (See 'Palpation method' above.)

● In children, splenomegaly most commonly is the result of an exuberant response of the immune system to infections by many different agents, disorders of immune regulation,
or abnormal destruction of red blood cells. However, infiltration with neoplastic or storage disease cells, abnormal splenic blood flow as in portal hypertension, and space-
occupying lesions must also be considered (table 1). (See 'Causes of an enlarged spleen' above.)

● The evaluation of a child with unexplained splenomegaly begins with a focused history (including recent travel information), physical examination, complete blood count with
white blood cell differential and platelet count, liver function studies, urinalysis, chest x-ray and abdominal ultrasound (algorithm 1). The complete blood count and examination of
the peripheral blood smear should detect evidence of cytopenias (eg, neutropenia, anemia, and/or thrombocytopenia), congenital hemolytic anemias (including sickle cell
disease), infection, bone marrow invasion, or malignant disease. (See 'Clinical evaluation' above and 'Complete blood count and examination of the peripheral smear' above.)

● If the initial evaluation does not provide a diagnosis to explain the splenomegaly, additional evaluation for other disorders may be considered, depending on the clinical context.
This may include testing for the presence of antibodies to Epstein-Barr virus, cytomegalovirus, parvovirus, or HIV-1, or measurement of glucocerebrosidase activity in peripheral
leukocytes, to evaluate for Gaucher disease. In some cases, CT examination of the chest and abdomen may be considered to evaluate the patient for disseminated or
intraabdominal malignancy, such as lymphoma or neuroblastoma, advanced liver disease, or portal hypertension. (See 'Clinical evaluation' above and 'Additional studies' above.)

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GRAPHICS

Howell-Jolly bodies following splenectomy

This peripheral blood smear shows two red blood cells (RBC) that
contain Howell-Jolly bodies (black arrows). Howell-Jolly bodies are
remnants of RBC nuclei that are normally removed by the spleen.
Thus, they are seen in patients who have undergone splenectomy (as
in this case) or who have functional asplenia (eg, from sickle cell
disease). Target cells (blue arrows) are another consequence of
splenectomy.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Peripheral blood smear in sickle cell anemia

Peripheral blood smear from a patient with sickle cell anemia. This
smear shows multiple sickle cells (blue arrows). There are also findings
consistent with functional asplenia, including a nucleated red blood
cell (upper left), a red blood cell containing a Howell-Jolly body (black
arrow), and target cells (red arrow).

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Major causes of splenomegaly

Congestive
Cirrhosis

Heart failure

Thrombosis of portal, hepatic, or splenic veins

Malignancy
Lymphoma, usually indolent variants

Acute and chronic leukemias

Polycythemia vera

Multiple myeloma and its variants

Essential thrombocythemia

Agnogenic myeloid metaplasia

Primary splenic tumors

Metastatic solid tumors

Infection
Viral - hepatitis, infectious mononucleosis, cytomegalovirus

Bacterial - salmonella, brucella, tuberculosis

Parasitic - malaria, schistosomiasis,toxoplasmosis, leishmaniasis

Infective endocarditis

Fungal

Inflammation
Sarcoid

Serum sickness

Systemic lupus erythematosus

Rheumatoid arthritis (Felty syndrome)

Infiltrative, nonmalignant
Gaucher's disease

Niemann-Pick disease

Amyloid

Glycogen storage disease

Langerhans cell histiocytosis

Hemophagocytic lymphohistiocytosis

Rosai-Dorfman disease

Hematologic (hypersplenic) states

Acute and chronic hemolytic anemias, all etiologies

Sickle cell disease (children)

Following use of recombinant human granulocyte colony-stimulating factor

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Evaluation of splenomegaly in a child

If the initial evaluation does not provide a diagnosis to explain the splenomegaly, additional
evaluation for other disorders may be considered, depending on the clinical context. These
include rheumatologic diseases; sarcoid; common variable immunodeficiency (CVID); autoimmune
lyphoproliferative syndrome (ALPS) (evaluate with immunoglobulins and T and B lymphocyte
subset analysis); porphyria, Wilson disease; schistosomiasis; familial mediterranean fever;
typhoid; and glucosidase abnormalities (eg, glycogen storage diseases including Pompe disease).

CBC: complete blood count; LFTs: liver function tests (aspartate aminotransferase and alanine
aminotransferase); EBV: Epstein-Barr virus; CMV: cytomegalovirus; HHV6: human herpesvirus 6; Tb:
tuberculosis; CT: computed tomography; ALPS: autoimmune lymphoproliferative syndrome; LCH:
Langerhans cell histiocytosis.
​* If the peripheral smear shows sickle cells, target cells, nucleated RBC, or cell fragments: obtain
hemoglobin electrophoretic profile or evaluate for dyserythropoietic anemias. If the smear shows
elliptocytes or spherocytes: measure osmotic fragility. If inclusions in neutrophils are seen: consider
Chediak Higashi Syndrome. If there is a suggestive travel history, look for malaria parasites in red
blood cells.
• Evaluate for leukemia, Gaucher, or Nieman Pick diseases, myeloproliferative/myelodysplastic
syndromes, and mastocytosis.
​Δ Important infectious considerations include sepsis, bartonella, and brucellosis.

Courtesy of Kenneth McClain, MD, PhD.

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Myeloblasts with Auer rod in acute myeloid leukemia

Peripheral smear from a patient with acute myeloid leukemia. There

are two myeloblasts, which are large cells with high nuclear-to-
cytoplasmic ratio and nucleoli. Each myeloblast has a pink/red rod-like
structure (Auer rod) in the cytoplasm (arrows).

From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Beta thalassemia trait

Peripheral smear from a patient with beta thalassemia trait. The field
shows numerous hypochromic and microcytic red cells (thin arrows),
some of which are also target cells (blue arrows).

Courtesy of Stanley Schrier, MD

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Peripheral blood smear in beta thalassemia

intermedia

Peripheral smear from a patient with beta thalassemia intermedia

post-splenectomy. This field shows target cells, hypochromic cells,
microcytic cells, red cell fragments, red cells with bizarre shapes, and
a single nucleated red cell (arrow).

Courtesy of Stanley Schrier, MD.

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CIrculating "LE Cell" in systemic lupus

erythematosus

Blood smear from a patient with systemic lupus erythematosus

showing a classical LE cell in which a viable neutrophil has ingested
nuclear material. Note the nuclear debris and an adjacent normal
neutrophil and the nuclear debris.

Courtesy of the American College of Rheumatology.

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Spherocytes

Peripheral blood smear shows multiple spherocytes which are small,

dark, dense hyperchromic red cells without central pallor (arrows).
These findings are compatible with hereditary spherocytosis or
autoimmune hemolytic anemia.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Elliptical red cells in hereditary elliptocytosis

Peripheral blood smear from a patient with hereditary elliptocytosis

shows multiple elliptocytes.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Xerocytosis

Peripheral smear from a patient with hereditary xerocytosis shows

many hyperchromic red cells with hemoglogin puddled at the periphery
of the cell (eccentrocytes, arrows). There is also marked
anisocytosis, poikilocytosis, and target cells.

Courtesy of Carlo Brugnara, MD.

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Stomatocytosis

Peripheral blood smear showing multiple stomatocytes characterized

by a mouth-shaped area of central pallor.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Babesia microti parasites in red blood cells

Panel A) Babesia microti [1] . This thin peripheral blood smear (Giemsa stain;
x1000) shows Babesia microti. Several erythrocytes contain multiple parasites,
including a diagnostic tetrad form (arrow). Panel B) Malaria (for comparison)
[2] . Peripheral smear from a patient with malaria shows intraerythrocytic ring

forms (trophozoites) (arrows). Panel C) Normal [2] . High power view of a

normal peripheral blood smear. Several platelets (black arrows) and a normal
lymphocyte (blue arrow) can also be seen. The red cells are of relatively
uniform size and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte; central pallor (red
arrow) should equal one-third of its diameter.

Courtesy of:
1. Harriet Provine
2. Carola von Kapff, SH (ASCP).

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Malaria: Red cell containing intraerythrocytic ring

forms (trophozoites)

Peripheral smear from a patient with malaria shows intraerythrocytic

ring forms (trophozoites) (arrows).

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Peripheral smear in microangiopathic hemolytic

anemia showing presence of schistocytes

Peripheral blood smear from a patient with a microangiopathic

hemolytic anemia with marked red cell fragmentation. The smear
shows multiple helmet cells (small black arrows), other fragmented red
cells (large black arrow); microspherocytes are also seen (blue
arrows). The platelet number is reduced; the large platelet in the
center (red arrow) suggests that the thrombocytopenia is due to
enhanced destruction.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Toxic granulations and Döhle bodies in

infection/inflammation

Left panel: Peripheral blood smear shows neutrophils with toxic granulations,
which are dark coarse granules. A Döhle body is also seen (arrow). Right
panel: A neutrophil with toxic granulations, vacuoles (another toxic change),
and a Döhle body (arrow). These abnormalities are characteristic of toxic
systemic illnesses.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Red blood cell agglutination due to a cold agglutinin

Peripheral blood smear from a patient with cold agglutinin hemolytic

anemia shows marked red blood cell agglutination into irregular clumps.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Atypical lymphocytes in infectious mononucleosis

Peripheral smear from a patient with infectious mononucleosis shows

three atypical lymphocytes with generous cytoplasm.

Courtesy of Carola von Kapff, SH (ASCP).

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Leukoerythroblastic peripheral blood smear

Leukoerythroblastic peripheral blood smear showing the presence of

nucleated red cells and immature white cells. This pattern occurs with
marrow replacement, usually due to fibrosis that may be idiopathic
(eg, primary myelofibrosis) or reactive to conditions such as
metastatic cancer.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Teardrop-shaped red blood cells (dacrocytes)

This peripheral smear from a patient with bone marrow fibrosis shows
numerous teardrop-shaped red cells (arrows). Note that the teardrops
are pointed in several different directions, ruling out an artifact due to
preparation of the smear.

Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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13/1/2557 Approach to the child with an enlarged spleen

Circulating lymphoma cells in follicular lymphoma

Two fields of a peripheral blood smear from a patient with follicular

lymphoma are shown here. Several cells with a "notched nucleus"
(centrocytes) are seen; nuclei are partially or completely divided by a
characteristic cleft (arrows). The chromatin stains intensely and is
compactly clumped. These cells have also been called "buttock" cells.

From Warnke, RA, Weiss, LM, Chan, JK, Cleary, ML, Dorfman, RF. Tumors of
the lymph nodes and spleen. Atlas of tumor pathology (electronic fascicle),
Third series, fascicle 14, 1995, Washington, DC. Armed Forces Institute of
Pathology.

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Abnormal circulating lymphocytes in hairy cell

leukemia

Peripheral smear from a patient with hairy cell leukemia. Panel A:

normal view of five hairy cells. The cells have abundant, irregularly
distributed cytoplasm. The nuclei vary from round to oval to slightly
lobulated. Panel B: same view but with the contrast adjusted to show
the irregular cytoplasmic outlines, giving the cells their "hairy"
appearance (arrows). Wright-Giemsa stain.

From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

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Lymphoblasts in acute lymphoblastic leukemia FAB L-

1 morphologic type

Blood smear showing small lymphoblasts with rare nucleoli and

vacuoles, as seen in acute lymphocytic leukemia (ALL) of the French
American British (FAB) L-1 morphologic type.

Courtesy of Robert Baehner, MD.

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Gaucher cells on bone marrow aspirate

Bone marrow aspirate showing a number of large macrophages laden

with cerebrosides (Gaucher cells, arrows) in a patient with Gaucher
disease and concomitant multiple myeloma. The cytoplasm has a
pattern which has been likened to wrinkled silk or crumpled
newspaper.

Courtesy of David S Rosenthal, MD and William C Moloney, MD.

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Niemann Pick Cells on bone marrow aspirate

Bone marrow aspirate from a patient with Niemann Pick disease,

showing two large macrophages laden with sphingomyelin, giving the
cytoplasm a "foamy" appearance (arrows).

Courtesy of David S Rosenthal, MD and William C Moloney, MD.

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Infection-associated hemophagocytic syndrome

Bone marrow from a child with hemophagocytic syndrome, secondary

to Epstein-Barr virus infection. Reactive histiocytes show
phagocytosis of nucleated red blood cells (red arrows) and platelets
(black arrows). Wright-Giemsa stain.

From: Brunning RD, McKenna RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

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Neuroblastoma cells within the bone marrow

Bone marrow aspirate from a patient with metastatic neuroblastoma

shows a clump of cells forming a rosette. Note the indistinct borders
between cells in this clump of tumor cells.

Courtesy of David S Rosenthal, MD and William C Moloney, MD.

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