What initial lab work is recommended for a patient presenting with splenomegaly (enlargement of the spleen)?

Initial Laboratory Workup for Splenomegaly

The initial laboratory workup for splenomegaly should include a complete blood count with differential, peripheral blood smear review, comprehensive metabolic panel, lactate dehydrogenase, and flow cytometry if lymphoproliferative disorder is suspected, with additional infectious disease testing (EBV, CMV, HIV, hepatitis) based on clinical context. 1, 2

Essential First-Line Laboratory Tests

Core Hematologic Evaluation

• Complete blood count (CBC) with differential is mandatory to identify cytopenias, leukocytosis, lymphocytosis, thrombocytosis, or abnormal cell populations that suggest hematologic malignancy 1, 2
• Peripheral blood smear review must be performed to identify blasts, atypical lymphocytes, or other abnormal cells suggestive of leukemia or lymphoma—this is critical and should not be delayed 1, 2
• Lactate dehydrogenase (LDH) serves as a screening marker for hemolysis or malignancy 1, 2

Hepatic and Metabolic Assessment

• Comprehensive metabolic panel including liver function tests (AST, ALT, alkaline phosphatase, GGT, total bilirubin) is essential since liver disease is one of the three most common causes of splenomegaly in the United States 3, 1, 2
• Platelet count should be included as part of the CBC, as it helps calculate fibrosis indices (APRI, FIB-4, GPR) that can detect advanced fibrosis and portal hypertension 3

Infectious Disease Screening

• Viral studies for EBV, CMV, HIV, and hepatitis should be obtained as infectious causes are among the top three etiologies of splenomegaly in developed countries 1, 2
• This testing is particularly important given that infectious mononucleosis is one of the most apparent causes of splenomegaly 4

Advanced Testing Based on Initial Findings

When Hematologic Malignancy is Suspected

• Flow cytometry of peripheral blood for immunophenotyping should be performed immediately if the CBC or peripheral smear suggests lymphoproliferative disorder 1, 2
• JAK2, CALR, and MPL mutation testing is indicated if myeloproliferative neoplasm is suspected, particularly with leukocytosis, thrombocytosis, or unexplained splenomegaly 1, 2
• Bone marrow aspiration and biopsy is warranted when abnormal cells are found in peripheral blood, unexplained cytopenias are present, or myeloproliferative/lymphoproliferative disorder is suspected 1, 2

Coagulation Assessment

• Disseminated intravascular coagulation panel (D-dimer, fibrinogen, PT, PTT) should be obtained in acute presentations, particularly in acute leukemia 3
• Tumor lysis syndrome panel (uric acid, potassium, phosphates, calcium) is indicated when malignancy is suspected 3

Imaging Confirmation

• Abdominal ultrasound is the first-line imaging modality to confirm splenomegaly, assess for focal lesions, evaluate hepatomegaly, and identify lymphadenopathy 1, 2
• Spleen size of 11-13 cm represents mild splenomegaly, while >13 cm is clinically significant and warrants aggressive workup 1, 2
• 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

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
• Do not miss lymphoma-associated hemophagocytic lymphohistiocytosis (HLH), as approximately 40-70% of adult HLH cases are malignancy-associated, particularly with Hodgkin lymphoma, diffuse large B-cell lymphoma, and T-cell lymphomas 2
• Do not assume alcoholic liver disease in patients with alcohol use—other causes must be excluded through appropriate testing 3
• Do not overlook the need for HIV testing in patients with unexplained lymphadenopathy or splenomegaly 5

Physical Examination Specifics

• Perform careful percussion and palpation of the entire liver and spleen with measurement of the liver span at the mid-clavicular line 3, 1
• Document exact spleen size below the costal margin 2
• Assess for hepatomegaly, which has a sensitivity of 60% and specificity of 44% for detecting advanced liver disease, while splenomegaly has a sensitivity of 93% and specificity of 57% 3

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 2