What to evaluate and suspect in a 57-year-old female with no known comorbidities (co-existing medical conditions), presenting with a one-month history of intermittent fever, recent laboratory results showing pancytopenia, weight loss, and borderline splenomegaly?

Diagnostic Evaluation and Suspected Diagnoses

Primary Suspicion: Hematologic Malignancy

In a 57-year-old woman presenting with one month of fever, pancytopenia, weight loss, and borderline splenomegaly, the primary concern is a hematologic malignancy—specifically lymphoproliferative disorders such as lymphoma, chronic lymphocytic leukemia, or hairy cell leukemia. 1, 2

Critical Initial Evaluation

Immediate Laboratory Studies

• Complete blood count with differential to characterize the pancytopenia pattern and identify abnormal cell populations 1, 2
• Peripheral blood smear examination by a qualified hematologist or pathologist to identify abnormal cells, exclude pseudothrombocytopenia, and detect morphologic abnormalities suggesting specific diagnoses 1, 2
• Comprehensive metabolic panel including liver function tests and calcium level (hypercalcemia can occur with lymphomas) 3
• Lactate dehydrogenase (LDH) as an indicator of cell turnover in hematologic malignancies 4
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to assess inflammatory burden 5

Infectious Disease Screening

Given the fever and constitutional symptoms, infectious etiologies must be excluded:

• HIV and hepatitis C testing is recommended in adults with pancytopenia and constitutional symptoms 1, 2
• Blood cultures to exclude bacterial infections including brucellosis, which can present with fever, weight loss, splenomegaly, and pancytopenia 5
• Tuberculosis evaluation including chest imaging and tuberculin skin testing or interferon-gamma release assay, as TB can cause constitutional symptoms and pancytopenia 4
• Leishmaniasis serology if epidemiologically relevant, as visceral leishmaniasis presents with fever, weight loss, hepatosplenomegaly, and pancytopenia 6

Bone Marrow Examination

Bone marrow aspiration and biopsy are essential in this patient given her age (>60 years), constitutional symptoms (fever, weight loss), and organomegaly—all red flags suggesting underlying malignancy rather than benign causes 1, 2. The bone marrow examination should include:

• Morphologic evaluation to assess cellularity, identify infiltrative processes, and detect megaloblastic changes 7
• Flow cytometry to identify lymphoproliferative disorders and characterize cell populations 8
• Cytogenetics to detect clonal abnormalities 8
• Immunohistochemistry with markers including CD20, CD38, CD138, and light chain restriction to identify lymphoplasmacytic infiltration 8

Imaging Studies

• CT scan of chest, abdomen, and pelvis to evaluate for lymphadenopathy, assess spleen size definitively, and identify hepatomegaly or other organomegaly 8, 4
• Consider PET/CT if lymphoma is strongly suspected and biopsy sites need identification 6

Differential Diagnosis Priority

Most Likely: Lymphoproliferative Disorders

1. Waldenström's macroglobulinemia presents with constitutional symptoms (fever, night sweats, weight loss), cytopenias, and splenomegaly 8
2. Hairy cell leukemia characteristically presents with pancytopenia (39% have absolute neutrophil count <0.5 × 10⁹/L) and splenomegaly 8
3. Non-Hodgkin's lymphoma (particularly T-cell lymphomas) can present deceptively with fever, weight loss, pancytopenia, and splenomegaly without prominent lymphadenopathy 9, 3
4. Chronic lymphocytic leukemia may present with constitutional symptoms and cytopenias 8

Alternative Considerations

1. Megaloblastic anemia is the most common cause of pancytopenia in some series (74% of cases), presenting with constitutional symptoms 7
2. Aplastic anemia accounts for approximately 18% of pancytopenia cases 7
3. Myelodysplastic syndrome should be considered given the patient's age 1, 2

Red Flags Strongly Suggesting Malignancy

The constellation of findings in this patient raises serious concern for malignancy:

• Constitutional symptoms (fever, weight loss) combined with pancytopenia significantly increase concern for serious pathology 4
• Age >60 years with systemic symptoms warrants bone marrow examination 1, 2
• Splenomegaly in the context of pancytopenia suggests either infiltrative disease or hypersplenism secondary to underlying hematologic disorder 8, 2
• Absence of lymphadenopathy does not exclude lymphoma, as certain subtypes (particularly T-cell lymphomas and hairy cell leukemia) may present without prominent nodes 8, 9

Critical Pitfalls to Avoid

• Do not delay bone marrow examination in patients with this presentation—waiting for "less invasive" tests can delay diagnosis of treatable malignancies 1, 2
• Do not attribute pancytopenia to nutritional deficiency without bone marrow evaluation in patients with constitutional symptoms and organomegaly 7
• Do not miss concurrent infections in patients with hematologic malignancies, as brucellosis and other infections can coexist with leukemia 5
• Do not overlook rare presentations of lymphoma that may mimic other conditions (hepatic failure, isolated splenomegaly) 9, 3

Specific Additional Tests Based on Bone Marrow Findings

If lymphoplasmacytic infiltration is identified:

• Serum protein electrophoresis and immunofixation to detect monoclonal proteins 8
• Quantitative immunoglobulins including IgM measurement 8
• Serum viscosity if IgM is elevated 8
• Cryoglobulins and cold agglutinins 8
• MYD88 and CXCR4 mutation testing for Waldenström's macroglobulinemia 8