What is the initial workup for a patient presenting with splenomegaly of unknown etiology?

Initial Workup for Splenomegaly of Unknown Etiology

Begin with abdominal ultrasound to confirm splenomegaly (>11cm is abnormal, >13cm is clinically significant), followed immediately by complete blood count with differential, peripheral blood smear, comprehensive metabolic panel, and lactate dehydrogenase to screen for the three most common causes in developed countries: hematologic malignancy, liver disease, and infection. 1, 2, 3

Confirming Splenomegaly

• Abdominal ultrasound is the first-line imaging modality to confirm splenomegaly and assess for focal lesions, hepatomegaly, and lymphadenopathy 1
• Spleen size 11-13cm represents mild splenomegaly, while >13cm is clinically significant and warrants aggressive workup 1, 2
• Physical examination should document exact spleen size below the costal margin with careful percussion and palpation, measuring liver span at the mid-clavicular line 1

Essential Laboratory Testing (Order Immediately)

Complete blood count with differential to identify cytopenias (anemia, thrombocytopenia), 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, 3

Lactate dehydrogenase (LDH) to screen for hemolysis or malignancy 1

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 tropical regions, consider malaria and schistosomiasis testing, as these account for up to 80% of splenomegaly cases in endemic areas 3

Hematologic Malignancy Evaluation (High Priority)

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 1, 2
• Unexplained cytopenias are present 1, 2
• Myeloproliferative or lymphoproliferative disorder is suspected 1, 2
• Initial workup fails to reveal a diagnosis, as malignancy is the most common cause of unexplained splenomegaly 3, 4

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

Tissue Diagnosis for Persistent Diagnostic Uncertainty

Lymph node biopsy if lymphadenopathy is present and lymphoma is suspected 1

Diagnostic splenectomy should be considered when extensive workup fails to yield a diagnosis, as studies show a high diagnostic yield (95% in one series) with malignancy being the most common finding 5, 4

• In patients with isolated splenomegaly and no diagnosis after comprehensive workup, splenectomy typically reveals malignancy (most commonly intermediate-grade B-cell lymphoma), though benign neoplasms and reactive disorders account for 25% of cases 4
• For patients with HLH of unknown cause and splenomegaly, splenectomy may detect lymphomas hiding in the spleen or perisplenic tissue 6

Critical Pitfalls to Avoid

• Do not delay bone marrow evaluation in patients with concerning peripheral blood findings (blasts, significant cytopenias, or abnormal cell populations) 1
• Do not miss lymphoma-associated HLH: approximately 40-70% of adult HLH cases are malignancy-associated, particularly with Hodgkin lymphoma, diffuse large B-cell lymphoma, and T-cell lymphomas 6
• 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 6
• Patients with splenomegaly should refrain from contact sports due to rupture risk 3

Referral Threshold

Immediate hematology referral is warranted for:

• Peripheral smear showing blasts or abnormal lymphocytes beyond typical reactive changes 7
• Presence of cytopenias 7
• Symptomatic splenomegaly without clear etiology after initial workup 1