What is the appropriate workup for a patient presenting with splenomegaly (enlarged spleen)?

Workup for Splenomegaly

Begin with abdominal ultrasound to confirm splenomegaly (>11cm is abnormal, >13cm requires aggressive workup), followed immediately by CBC with differential, peripheral blood smear, comprehensive metabolic panel, and LDH. 1, 2, 3

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, 3
• Document spleen size below the costal margin during physical examination with careful percussion and palpation, measuring liver span at the mid-clavicular line 1, 2
• Spleen size 11-13cm represents mild splenomegaly; >13cm is clinically significant and warrants aggressive workup 1, 2, 3
• Physical examination has 93% sensitivity but only 57% specificity for detecting splenomegaly, making imaging confirmation essential 1, 2

Essential First-Line Laboratory Testing

Complete the following tests immediately:

• Complete blood count with differential to identify cytopenias, leukocytosis, lymphocytosis, or abnormal cell populations suggesting hematologic malignancy 1, 2, 3
• Peripheral blood smear review is critical to identify blasts, atypical lymphocytes, or other abnormal cells suggestive of leukemia or lymphoma 1, 2, 3
• 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, 3
• Lactate dehydrogenase (LDH) to screen for hemolysis or malignancy 1, 3

Infectious Disease Workup

• Test for EBV, CMV, HIV, and hepatitis viruses as infectious causes are among the top three etiologies in developed countries 1, 3
• In patients with travel history to tropical regions, consider malaria and schistosomiasis testing, as these account for up to 80% of splenomegaly cases in endemic areas 4

Hematologic Malignancy Evaluation

Proceed immediately with the following if CBC or smear shows abnormalities:

• Flow cytometry of peripheral blood for immunophenotyping should be performed immediately if lymphoproliferative disorder is suspected based on CBC findings 1, 2, 3
• Testing for JAK2, CALR, and MPL mutations if myeloproliferative neoplasm is suspected, particularly with leukocytosis, thrombocytosis, or unexplained splenomegaly 1, 2, 3
• Serum tryptase and vitamin B12 levels to evaluate for myeloproliferative disorders, particularly in patients with eosinophilia 3
• Bone marrow aspiration and biopsy with immunohistochemistry, cytogenetics, and molecular testing is indicated when abnormal cells are found in peripheral blood, unexplained cytopenias are present, or myeloproliferative or lymphoproliferative disorder is suspected 1, 2, 3

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, 3
• Advanced imaging should evaluate for hepatomegaly, lymphadenopathy, and focal splenic lesions that may require tissue diagnosis 1

Additional Testing Based on Clinical Context

• Disseminated intravascular coagulation panel (D-dimer, fibrinogen, PT, PTT) in acute presentations, particularly when acute leukemia is suspected 1
• Tumor lysis syndrome panel (uric acid, potassium, phosphates, calcium) when malignancy is suspected 1
• Prothrombotic workup including JAK2 V617F mutation, paroxysmal nocturnal hemoglobinuria testing (CD55/CD59 flow cytometry), and inherited thrombophilias if portal vein thrombosis is identified 5

Critical Pitfalls to Avoid

• Do not delay bone marrow evaluation in patients with concerning peripheral blood findings such as blasts, significant cytopenias, or abnormal cell populations 1, 2, 3
• 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 1, 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 1
• Do not assume alcoholic liver disease in patients with alcohol use; other causes must be excluded through appropriate testing 1
• Platelet count <100,000/mm³ with splenomegaly serves as a surrogate measure of portal hypertension and should prompt evaluation for liver disease 2

Referral Threshold

Immediate hematology referral is warranted for:

• Peripheral smear showing blasts or abnormal lymphocytes beyond typical reactive changes 1, 2
• Presence of unexplained cytopenias 1, 2
• Symptomatic splenomegaly without clear etiology after initial workup 1, 2
• Splenomegaly ≥5cm below costal margin, particularly when exceeding 15cm, especially if considering allogeneic hematopoietic cell transplantation 6