What is the next step in evaluating a 15-year-old male with splenomegaly (enlarged spleen) and negative mononucleosis (mono) testing?

Evaluation of a 15-Year-Old Male with Splenomegaly and Negative Monospot

Proceed immediately with complete blood count with differential, peripheral blood smear review, comprehensive metabolic panel, and abdominal ultrasound to confirm splenomegaly and evaluate for hematologic malignancy or other serious causes. 1

Confirm and Characterize the Splenomegaly

• Obtain abdominal ultrasound to confirm splenomegaly (normal spleen length <11 cm; mild splenomegaly 11-13 cm; clinically significant >13 cm) and assess for focal lesions or hepatomegaly. 1, 2
• Physical examination should document the exact spleen size below the costal margin, as pediatric patients with hematologic disorders frequently present with larger spleens than adults. 3

Essential Laboratory Workup

First-Line Blood Tests

• Complete blood count with differential to identify cytopenias, leukocytosis, lymphocytosis, or abnormal cell populations that suggest hematologic malignancy. 1
• Peripheral blood smear review is critical to identify atypical lymphocytes (>10% suggests infectious mononucleosis despite negative monospot), blasts, or other abnormal cells suggestive of leukemia or lymphoma. 1, 4
• Comprehensive metabolic panel including liver function tests, as elevated transaminases can occur with infectious mononucleosis even when heterophile antibody is negative, and hepatomegaly suggests hematologic disorders. 1, 4
• Lactate dehydrogenase (LDH) to screen for hemolysis or malignancy. 1

Additional Testing Based on Clinical Context

• EBV viral capsid antigen (VCA) IgM and IgG antibodies should be obtained since the heterophile antibody test has a sensitivity of only 87% and can be falsely negative in the first week of illness or in younger patients. 4
• The presence of IgM antibody to EBV viral capsid antigen is the most valuable serologic finding during acute primary EBV infection. 5
• Flow cytometry of peripheral blood for immunophenotyping if lymphoproliferative disorder is suspected based on CBC findings. 1

Critical Differential Diagnoses to Exclude

Hematologic Malignancies (Highest Priority)

• Lymphoproliferative disorders (lymphoma, leukemia) are suggested by anemia, leukocytosis with lymphocytosis, and hepatosplenomegaly in this age group. 2
• Chronic myeloid leukemia (CML) should be considered, as pediatric CML-CP presents with high leukocyte counts, splenomegaly (often larger than in adults), and mild anemia. 3
• Bone marrow aspiration and biopsy should be performed if abnormal cells are found in peripheral blood, unexplained cytopenias are present, or myeloproliferative/lymphoproliferative disorder is suspected. 1

Infectious Causes Beyond EBV

• Test for CMV, HIV, hepatitis, and toxoplasmosis as these can cause mononucleosis-like syndromes with splenomegaly. 1, 6
• In the United States, infection is one of the three most common causes of splenomegaly alongside liver disease and malignancy. 7

Other Hematologic Conditions

• Myeloproliferative neoplasms should be considered; testing for JAK2, CALR, and MPL mutations is recommended if this is suspected. 1, 2
• Sickle cell disease with splenic sequestration presents with rapidly enlarging spleen and hemoglobin decrease >2 g/dL below baseline, though this typically occurs in younger children. 3

Imaging Considerations

• CT or MRI of the abdomen should be considered if ultrasound findings are equivocal or if lymphadenopathy needs further characterization. 1
• Advanced imaging can help identify focal splenic lesions, assess for lymphadenopathy, and evaluate liver involvement. 1

When to Escalate Care

• Immediate hematology referral is warranted if peripheral smear shows blasts, abnormal lymphocytes beyond typical reactive changes, or if cytopenias are present. 1
• Lymph node biopsy should be performed if lymphadenopathy is present and lymphoma is suspected. 1
• For suspected CML, conventional cytogenetics, FISH, and/or RT-PCR to detect tyrosine kinase fusion gene rearrangements is recommended. 1

Common Pitfalls to Avoid

• Do not rely solely on a negative monospot test to exclude EBV infection; the test can be falsely negative early in illness, and EBV-specific antibody testing is more sensitive and specific. 4
• Do not delay bone marrow evaluation in patients with concerning peripheral blood findings such as blasts, severe cytopenias, or unexplained leukocytosis. 1
• Assess for signs of splenic complications including acute splenic sequestration (rapid enlargement with hemoglobin drop) or impending rupture (abdominal pain, left shoulder pain). 3, 8
• Advise against contact sports until splenomegaly resolves, as spontaneous splenic rupture occurs in 0.1-0.5% of infectious mononucleosis cases and is potentially life-threatening. 8, 4