AN APPROACH TO A CHILD WITH SPLENOMEGALY

AN APPROACH TO A CHILD WITH SPLENOMEGALY

DEFINITIONS

Splenomegaly:

 

• • •On physical examination: splenomegaly is defined as a palpable splenic edge felt >2 cm below the left costal margin. A palpable spleen tip may be a normal finding in up to 30 percent of neonates; the frequency drops to approximately 10 percent in healthy school-age children and <3 percent in young adults.
  • •On imaging studies: splenomegaly is defined as splenic length or volume that is above the upper limits of normal for age.
  • Massive splenomegaly – A spleen is massively enlarged if its lower pole is within the pelvis or if it crosses the midline.

OVERVIEW OF SPLENIC FUNCTION

 

• • The spleen as a hematopoietic organ
  • 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.
  • White pulp – The white pulp of the spleen is a major part (up to 25 percent) of the lymphoid tissue in the body. When foreign antigens are present in the circulation, the spleen plays a key role in 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 immunoglobulin G and M (IgG and IgM) antibody titers are much lower than noted in normal individuals.
  • Red pulp – The largest component of the spleen is the red pulp. It consists of the RBCs surrounding endothelial cords and interdigitating splenic sinusoids. Because of the anatomic arrangement of blood vessels, RBCs are relatively concentrated in the terminal splenic arteries, as plasma with potentially antigenic material is shunted to the white pulp. In patients with sickle cell disease (SCD), a consequence of the high RBC concentration in these arterioles and sinusoids is that relatively mild degrees of hypoxia can cause the irreversible RBC sickling, leading to splenic infarction (autosplenectomy).
  • Sinusoids – are lined with macrophages which are important 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 can remove senescent red cells, destroy or reform erythrocytes with abnormal membranes, and remove red cell inclusions such as nuclear remnants, like Howell-Jolly bodies. 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)
  • Platelet reservoir – 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 is also removed. Following splenectomy, it is common for the platelet count to temporarily exceed 1 × 10⁶/microL in a normal child, without an apparent increased risk for thrombosis.

CAUSES OF SPLENOMEGALY

In otherwise healthy individuals seen in the outpatient setting, the most common etiology of splenomegaly is infectious mononucleosis.

Infection — Infectious etiologies of splenomegaly include:

 

• • Viral infections, particularly EBV and CMV
  • Infective endocarditis
  • Malaria
  • HIV
  • Cat scratch disease
  • Babesiosis
  • Fungal infections
  • Leishmaniasis
  • Toxoplasmosis

Hematologic malignancy — Childhood leukemias and lymphomas are important causes of splenomegaly. These include:

 

• • Acute lymphoblastic leukemia (ALL), including precursor B cell ALL and precursor T cell ALL/lymphoma
  • Acute myeloid leukemia
  • Hodgkin lymphoma
  • Non-Hodgkin lymphoma

Other lymphoproliferative disorders:

 

• • Langerhans cell histiocytosis
  • Hemophagocytic lymphohistiocytosis
  • Autoimmune lymphoproliferative syndrome
  • Castleman disease and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)

Hemolytic anemia — Congenital and acquired hemolytic anemias represent a major cause of splenomegaly. In these conditions, splenomegaly results from sequestration of destroyed red blood cells (RBCs). SCD is included in this category. Splenomegaly is a clinical feature of SCD in early childhood, but, by late childhood or adulthood, the spleen is typically small and atrophic due to repeated splenic infarction.

Liver disease/portal hypertension — Splenomegaly is a feature of liver disease, particularly end-stage liver failure (cirrhosis). Cirrhosis-related splenomegaly results from congestion due to portal hypertension. Other sequelae of portal hypertension (eg, esophageal varices, gastroesophageal bleeding, ascites) may also be present. Causes of cirrhosis in children include:

 

• • Biliary atresia
  • Choledochal cysts
  • Primary sclerosing cholangitis
  • Viral hepatitis
  • Autoimmune hepatitis
  • Alpha-1 antitrypsin deficiency
  • Metabolic disease (eg, galactosemia)
  • Cystic fibrosis
  • Alagille syndrome
  • Wilson disease
  • Intestinal failure

Portal vein thrombosis — Portal vein thrombosis (PVT) is another cause of portal hypertension and splenomegaly. In neonates, PVT is most commonly associated with umbilical venous catheters. In older children, PVT may be a complication of liver transplant or may occur in children with underlying risk factors (eg, malignancy, inherited thrombophilia, antiphospholipid antibodies).

Heart failure — Hepatosplenomegaly is a common finding in patients with volume overload and systemic venous congestion due to heart failure.

Disorders of immune regulation — Splenomegaly may be noted in children with autoimmune diseases (eg, systemic lupus erythematosus, rheumatoid arthritis) and in some primary immunodeficiencies (eg, common variable immunodeficiency).

Storage disease — Splenomegaly is a prominent feature of many lysosomal storage disorders, including Gaucher disease, Niemann-Pick disease, and the mucopolysaccharidoses. These disorders are reviewed in greater detail separately.

Space-occupying lesions — Discrete space-occupying lesions that may present with splenomegaly include splenic hemangioma, hamartoma, and cysts.

Another example of a space-occupying lesion is intracapsular hematoma due to traumatic injury. In most cases, there is a clear preceding history of substantial blunt abdominal trauma. However, relatively minor trauma can cause splenic rupture in children with underlying splenomegaly due to another etiology (eg, mononucleosis).

Other — Other less common causes of splenomegaly in children include sarcoidosis and metastatic tumors (eg, neuroblastoma).

CAUSES OF MASSIVE SPLENOMEGALY

A spleen is 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:

 

• • Leukemia (lymphoid or myeloid)
  • Lymphoma, usually the more indolent variants
  • Thalassemia major
  • Acute splenic sequestration in sickle cell disease (SCD)
  • Langerhans cell histiocytosis
  • Hemophagocytic lymphohistiocytosis
  • Autoimmune lymphoproliferative syndrome
  • Castleman disease
  • Gaucher disease
  • HIV infection with Mycobacterium avium complex
  • Kala-azar
  • Hyperreactive malarial splenomegaly syndrome, also called tropical splenomegaly syndrome

EVALUATION

History

A history of recent febrile illness, pharyngitis, and fatigue suggests a viral etiology (eg, Epstein-Barr virus [EBV], cytomegalovirus [CMV], viral hepatitis).

If more pronounced constitutional symptoms are noted (eg, persistent fevers, night sweats, weight loss, decreased activity level), systemic diseases such as leukemia, lymphoma, systemic lupus erythematosus, malaria, or tuberculosis should be considered.

In some cases, the presence of an underlying condition is already known and the spleen may revert to normal size when the underlying disease is brought under control with appropriate therapy.

Physical examination

Examination of the spleen

 

• • Palpation method – Proper examination of the spleen requires relaxation of both the abdominal musculature of the patient and the examiner’s hand(s). The examiner should begin palpating low in the abdomen/pelvis and advance upward. Effectiveness in palpating the spleen can be maximized by the following:
  • •With the child supine, allow the child 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 child may be reluctant to allow the examination to continue.
  • •The examiner should be seated comfortably 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.
  • •Make sure that the child 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. Having the child slightly flex his/her the legs and neck may also help relax the abdominal musculature.
  • •If examining the child in the supine position is difficult, placing the child in the right lateral decubitus position with knees and neck flexed can improve the ability to palpate the spleen. This maneuver helps relax the abdominal musculature and rotates the spleen from its usual posterior position to a more anterior position.
  • •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.

Interpretation – A palpable spleen may represent a normal finding, splenomegaly, or massive splenomegaly:

•Normal finding – The spleen is palpable in nearly one-third of healthy neonates, 10 percent of healthy children, and approximately 3 percent of healthy adolescents and young adults. A nontender spleen that is normal or 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 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 nontender.

•Splenomegaly – A splenic edge felt >2 cm below the left costal margin is an abnormal finding. An abnormal spleen often feels hard, unlike the soft sensation of palpating a minimally enlarged spleen in a healthy child. Tenderness to palpation also suggests an abnormal finding.

•Massive splenomegaly – A spleen is considered to be massively enlarged if its lower pole is within the pelvis or if it crosses the midline. In extreme cases, the enlarged spleen may even be palpable in the right upper quadrant. Exquisite splenic tenderness suggests infarction or perisplenitis in such massively enlarged spleens.

Other examination findings — Other physical examination findings that are important to note when evaluating a child with splenomegaly include:

Lymphadenopathy – Lymphadenopathy may be a sign of infection (eg, EBV or HIV-1) or malignancy.

Jaundice – Jaundice may indicate underlying hemolytic anemia or liver disease.

Hepatomegaly and other signs of liver disease – Hepatomegaly, firm liver edge, ascites, and/or spider angiomata suggest underlying liver disease.

Rashes and/or joint swelling – Rashes and/or joint swelling suggest a systemic autoimmune disorder such as systemic lupus erythematosus or rheumatoid arthritis.

Petechiae and ecchymoses – Petechiae and ecchymoses may be present in patients with thrombocytopenia resulting from splenic enlargement. They may also be a sign of underlying malignant hematologic disease.

Initial diagnostic testing — Initial testing for children with unexplained splenomegaly includes imaging (chest radiograph and abdominal ultrasound) and laboratory testing.

Imaging

Imaging modalities

 Ultrasound accurately determines spleen size and identifies focal or diffuse pathologic changes. Doppler imaging is useful for evaluating splenic and portal blood flow. A finding of slow or reversed portal blood flow is suggestive of portal hypertension.

focal lesions on ultrasound should generally be further evaluated with computed tomography or magnetic resonance imaging.

Other imaging includes nuclear medicine liver-spleen colloid study and positron emission tomography. These imaging techniques may reveal accessory spleens (found in 30 percent of autopsies) and 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.

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

Spleen size – Splenomegaly on ultrasound is defined as splenic length or volume that is above the upper limits of normal for age. The upper limits of normal for splenic length based upon age were as follows:

 

• • •Age 3 months – 6 cm
  • •Age 12 months – 7 cm
  • •Age 6 years – 9.5 cm
  • •Age 12 years – 11.5 cm
  • •Age ≥15 years – 12 cm for girls and 13 cm for boys

Laboratory evaluation — The initial laboratory evaluation of the child with unexplained splenomegaly includes:

 

• • Complete blood count including platelet count and differential
  • Reticulocyte count
  •  peripheral blood smear
  • Liver function tests
  • Lactate dehydrogenase
  • C-reactive protein and/or erythrocyte sedimentation rate
  • EBV and CMV serologies

Additional tests may be warranted based on the clinical history (eg, tuberculin skin testing for children with relevant exposure and antinuclear antibody as a screen for autoimmune diseases for children with suggestive symptoms).

The complete blood count should be interpreted in the context of other clinical findings. Cytopenias (neutropenia, anemia, and/or thrombocytopenia) are common in children with splenomegaly and represent a nonspecific finding. Cytopenias may be due to trapping of blood cells in the enlarged spleen (termed “hypersplenism”) or may be due to other causes (eg, infection, malignancy).

The cytopenias seen with hypersplenism are not associated with morphologically abnormal circulating white or red blood cell (RBC) forms. Almost no relationship exists between the degree of splenomegaly and the presence or degree of these cytopenias

DIAGNOSTIC APPROACH   TAKE THIS REAL DEAL  الخلاصة

For most children who present with unexplained splenomegaly, a likely diagnosis (or diagnostic category) can be arrived at based upon the history, physical examination, and initial imaging and laboratory findings. In most cases, additional testing is needed to establish the specific diagnosis.

 

Initial evaluation of the child with unexplained splenomegaly includes: History and physical examinationComplete blood count including platelet count and differentialReticulocyte countReview of the peripheral blood smearLiver function testsEBV and CMV serologiesChest radiographAbdominal ultrasound In most cases, a likely diagnosis (or diagnostic category) can be arrived at based upon the findings of these tests. Additional testing may be needed to establish the specific diagnosis.
Diagnostic category	Suggestive findings	Additional evaluation*
Infectious mononucleosis	Fever, pharyngitis, fatigue, and lymphadenopathy Lymphocytosis and atypical lymphocytes on peripheral blood smear	Diagnosis is made with EBV and CMV serologies and/or heterophile antibody testing
Systemic infection TuberculosisInfective endocarditisMalariaHIVCat scratch diseaseBabesiosis	Persistent fevers, weight loss, malaise, lymphadenopathy Travel to an endemic region (malaria, tuberculosis, babesiosis) HIV risk factors (unprotected sex, IV drug use) Cat scratch (Bartonella) Tick bite (babesiosis)	Testing is guided by clinical findings and may include: TST to evaluate for TB Serial blood cultures to evaluate for IE Malaria blood smear (if relevant exposure) HIV testing (if there are relevant risk factors) Bartonella titers (if relevant exposure) Blood smear and/or PCR for babesiosis (if relevant exposure)
Hematologic malignancy Acute lymphoblastic leukemiaAcute myelogenous leukemia	Persistent fevers, anorexia, weight loss, decreased activity level, bone pain, and/or easy bruising Cytopenias (neutropenia, anemia, and/or thrombocytopenia) Abnormal immature cells (blasts) in the peripheral blood	Bone marrow aspiration/biopsy
Lymphoproliferative diseases LymphomaLangerhans cell histiocytosisHematophagocytic lymphohistiocytosisAutoimmune lymphoproliferative syndromeCastleman disease and POEMS syndrome	Lymphadenopathy (particularly if lymph nodes are massively enlarged and/or rapidly increasing in size) Chest radiograph findings of hilar adenopathy or mediastinal mass	Contrast-enhanced CT of the chest and abdomen Lymph node biopsy Bone marrow biopsy
Hemolytic anemias RBC membrane defectsRBC enzyme defectsHemoglobinopathiesAutoimmune hemolytic anemiaOther acquired hemolytic anemias	Low hemoglobin, unconjugated hyperbilirubinemia, and reticulocytosis Clues on the peripheral blood smear include polychromasia and spherocytes Certain congenial RBC disorders may have specific findings on the blood smear (eg, elliptocytes, xerocytes, sickle cells)	Serum markers of hemolysis (LDH, free hemoglobin, haptoglobin) Testing for specific causes of hemolytic anemia
Liver disease Biliary atresiaViral hepatitisWilson diseaseOther metabolic liver disease (eg, galactosemia)Primary sclerosing cholangitisAlpha-1-antitrypsin deficiencyAlagille syndromeCystic fibrosis	Jaundice, hepatomegaly, firm liver edge, ascites, and/or spider angiomata Abnormal liver function tests Abnormal findings on abdominal imaging (eg, focal or diffuse liver abnormalities; slow or reversed portal blood flow suggestive of portal hypertension)	Testing for specific causes of pediatric liver disease Liver biopsy may be warranted in some cases
Portal vein thrombosis	Patients may have abdominal pain or may be asymptomatic Underlying risk factor for thrombosis (eg, invasive catheter [UVC], liver disease, malignancy, inherited thrombophilia, antiphospholipid antibodies) Abnormal abdominal ultrasound (ie, filling defect or absence of flow Doppler images)	Diagnosis is made with Doppler ultrasound Additional evaluation may be warranted to determine cause of thrombus
Autoimmune disease SLEJIA	Rashes and/or joint swelling Laboratory findings include nonspecific markers of inflammation (eg, leukocytosis, elevated ESR or CRP)	Antinuclear antibody titers are obtained as a screening test Further evaluation is based on the clinical findings
Primary immunodeficiency Common variable immunodeficiency	History of recurrent infections and/or failure to thrive Lymphopenia may be noted on CBC	Diagnosis is based on immunoglobulin levels and antibody function studies (ie, vaccine response)
Storage disorders Gaucher diseaseNiemann-Pick diseaseMucopolysaccharidosesOther lysosomal diseases	Other organ involvement (eg, hepatomegaly, skeletal abnormalities, neurologic involvement) Plain radiographs may show bone abnormalities Focal splenic masses may be noted on abdominal ultrasound	Diagnosis is confirmed by testing for specific enzyme deficiencies and/or genetic mutations
Space-occupying lesions HemangiomaHamartomaCystsIntracapsular hematoma (trauma)	Hemangiomas: Skin hemangiomas may be noted Cysts and hamartomas: Most are asymptomatic May be noted as incidental findings on abdominal imaging studies obtained for other reasons Intracapsular hematoma: In most cases, there is a clear preceding history of substantial blunt abdominal trauma Relatively minor trauma can cause splenic rupture in children with underlying splenomegaly due to another etiology (eg, mononucleosis)	Additional imaging studies (eg, CT or MRI) may be warranted Diagnosis is based on imaging findings

CBC: complete blood count; CMV: cytomegalovirus; CRP: C-reactive protein; CT: computed tomography; EBV: Epstein-Barr virus; ESR: erythrocyte sedimentation rate; IE: infective endocarditis; IV: intravenous; JIA: juvenile idiopathic arthritis; LDH: lactate dehydrogenase; MRI: magnetic resonance imaging; PCR: polymerase chain reaction; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes; RBC: red blood cell; SLE: systemic lupus erythematosus; TB: tuberculosis; TST: tuberculin skin test; UVC: umbilical venous catheter.

Diagnostic approach to the child with unexplained splenomegaly

 

 

• • EBV: Epstein-Barr virus; CMV: cytomegalovirus; CXR: chest radiograph; LCH: Langerhans cell histiocytosis; HLH: hematophagocytic lymphohistiocytosis; ALPS: autoimmune lymphoproliferative syndrome; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes; CT: computed tomography; ALL: acute lymphoblastic leukemia; AML: acute myelogenous leukemia; CBC: complete blood count; TB: tuberculosis; IV: intravenous; SLE: systemic lupus erythematosus; ANA: antinuclear antibody; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; CVID: common variable immunodeficiency; LFTs: liver function tests; U/S: ultrasound; RBC: red blood cell; G6PD: glucose-6-phosphate dehydrogenase; LDH: lactate dehydrogenase; MRI: magnetic resonance imaging.
  • The evaluation of a child with unexplained splenomegaly generally includes history, physical examination, CBC (with platelet count and differential), reticulocyte count, review of the peripheral smear, LFTs, serologies for EBV and CMV, CXR, and abdominal U/S (with Doppler imaging). The diagnosis may be apparent from the initial evaluation (eg, physical examination may reveal clear signs mononucleosis; CBC may reveal peripheral blasts; abdominal U/S may reveal portal hypertension, portal thrombosis, or discrete splenic lesion). In most cases, additional testing is needed to confirm the specific diagnosis. If the work-up for the suspected etiology is negative, additional evaluation for other etiologies is generally warranted.