Initial Workup for Splenomegaly
Begin with abdominal ultrasound to confirm splenomegaly (>13 cm is clinically significant) and obtain complete blood count with differential, peripheral blood smear, comprehensive metabolic panel, and lactate dehydrogenase immediately. 1, 2
Confirming Splenomegaly
- Abdominal ultrasound is the first-line imaging modality to confirm splenomegaly, assess for focal lesions, evaluate liver size and appearance, and identify lymphadenopathy 1, 2
- Spleen size 11-13 cm represents mild splenomegaly, while >13 cm is clinically significant and warrants aggressive workup 1, 2
- Physical examination should document the exact spleen size below the costal margin with careful percussion and palpation, measuring liver span at the mid-clavicular line 1, 2
Essential Laboratory Testing (First-Line)
- Complete blood count with differential to identify cytopenias, leukocytosis, lymphocytosis, or abnormal cell populations suggesting hematologic malignancy 1, 2
- Peripheral blood smear review is critical to identify blasts, atypical lymphocytes, or other abnormal cells suggestive of leukemia or lymphoma 1, 2
- Comprehensive metabolic panel to assess liver function, as liver disease is one of the three most common causes of splenomegaly in the United States 1, 2
- Lactate dehydrogenase (LDH) to screen for hemolysis or malignancy 1, 2
Infectious Disease Workup
- Test for EBV, CMV, HIV, and hepatitis viruses as infectious causes are among the top three etiologies in developed countries 1, 2
- This is particularly important given that the most common causes of splenomegaly in the United States are liver disease, malignancy, and infection 3
Hematologic Malignancy Evaluation (Based on Initial Findings)
- Flow cytometry of peripheral blood for immunophenotyping should be performed immediately if lymphoproliferative disorder is suspected based on CBC findings 1, 2
- Testing for JAK2, CALR, and MPL mutations if myeloproliferative neoplasm is suspected (particularly with leukocytosis, thrombocytosis, or unexplained splenomegaly) 1, 2
- Bone marrow aspiration and biopsy is indicated when abnormal cells are found in peripheral blood, unexplained cytopenias are present, or myeloproliferative or lymphoproliferative disorder is suspected 1, 2
Advanced Imaging Considerations
- CT or MRI of the abdomen should be obtained if ultrasound findings are equivocal, lymphadenopathy needs characterization, or focal splenic lesions are present 1, 2
- Advanced imaging should evaluate for hepatomegaly, lymphadenopathy, and focal splenic lesions that may require tissue diagnosis 2
Common Etiologies to Consider
The differential diagnosis should focus on the three most common causes in developed countries:
- Lymphoproliferative disorders (lymphomas, leukemias) suggested by abnormal cell populations on CBC 1, 4
- Myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, myelofibrosis, chronic myeloid leukemia) 1, 4
- Liver disease with portal hypertension 2, 3
- Infectious causes including viral infections (EBV, CMV, HIV) 2, 3
Critical Pitfalls to Avoid
- Do not delay bone marrow evaluation in patients with concerning peripheral blood findings (blasts, significant cytopenias, or abnormal cell populations) 2
- Do not miss lymphoma-associated hemophagocytic lymphohistiocytosis (HLH): approximately 40-70% of adult HLH cases are malignancy-associated, particularly with Hodgkin lymphoma, diffuse large B-cell lymphoma, and T-cell lymphomas 2
- Consider PET-guided imaging and repetitive tissue sampling if lymphoma is suspected but initial biopsies are negative, as tumor-infiltrating reactive lymphocytes can mask underlying lymphoma 2
Referral Threshold
- Immediate hematology referral is warranted for peripheral smear showing blasts or abnormal lymphocytes beyond typical reactive changes, presence of cytopenias, or symptomatic splenomegaly without clear etiology after initial workup 1, 2
- Lymph node biopsy should be performed if lymphadenopathy is present and lymphoma is suspected 1