What is the differential diagnosis for a 30-year-old patient with multiple painless lymphadenopathies (lymph node enlargements), anemia, and no fever (afebrile)?

Differential Diagnosis: 30-Year-Old with Multiple Painless Lymphadenopathy, Anemia, and Afebrile

The most critical diagnoses to exclude immediately are lymphoma (Hodgkin and non-Hodgkin), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and Waldenström's macroglobulinaemia, as these malignancies directly impact mortality and require urgent tissue diagnosis. 1

Primary Malignant Considerations (Highest Priority)

Lymphoproliferative Malignancies

• Lymphoma (Hodgkin and non-Hodgkin) is the foremost concern in a 30-year-old with painless, multiple lymphadenopathies and anemia, particularly given the absence of fever which makes infection less likely 1, 2
• CLL/SLL should be strongly considered, as diagnosis can be established by immunophenotyping of peripheral blood showing monoclonal B lymphocytes with characteristic CD5+/CD20+/CD23+ pattern 1
• Waldenström's macroglobulinaemia presents with lymphadenopathy and anemia, requiring bone marrow biopsy showing lymphoplasmacytic infiltration and detection of monoclonal IgM protein 1
• The absence of B symptoms (fever, night sweats, weight loss) does NOT exclude lymphoma, though their presence would mandate immediate PET/CT imaging 3, 2

Key Diagnostic Actions for Malignancy

• Excisional lymph node biopsy is the gold standard and should be performed urgently, as fine-needle aspiration alone is insufficient for initial lymphoma diagnosis 1, 3
• Obtain complete blood count with differential to evaluate for circulating lymphocytes (>5×10⁹/L suggests CLL if monoclonal) 1
• Flow cytometry of peripheral blood with kappa/lambda, CD19, CD20, CD5, CD23, CD10 is essential if CLL/SLL suspected 1
• Bone marrow biopsy is indicated if peripheral blood shows abnormalities or if Waldenström's is considered 1

Infectious Etiologies (Secondary Priority)

Chronic Viral Infections

• Epstein-Barr virus (infectious mononucleosis) commonly causes cervical lymphadenopathy but typically presents with fever; however, atypical presentations occur 3, 2
• HIV-related lymphadenopathy must be excluded with serologic testing, as it can present with painless generalized lymphadenopathy and anemia 2, 4
• Viral syndromes can be excluded if symptoms persist beyond 3 months 1

Mycobacterial Infections

• Tuberculosis should be considered, especially in adults where >90% of mycobacterial lymphadenitis is due to M. tuberculosis 3, 4
• Non-tuberculous mycobacterial (NTM) infection typically presents as unilateral, non-tender nodes (80% due to MAC), making this less likely given multiple sites 3, 4
• Tuberculin skin testing should be performed to help distinguish tuberculous from non-tuberculous disease 3, 4

Autoimmune/Inflammatory Disorders (Tertiary Priority)

Histiocytic Disorders

• Rosai-Dorfman-Destombes disease (RDD) classically presents with bilateral, massive, painless cervical lymphadenopathy with or without B symptoms; mediastinal, axillary, and inguinal nodes may be involved 1, 3, 4
• Diagnosis requires biopsy showing characteristic large pale histiocytes with emperipolesis, S100+/CD68+/CD1a- immunophenotype 1

Rheumatologic Conditions

• Systemic lupus erythematosus (SLE) and Sjögren's disease can present with lymphadenopathy and anemia, though typically with other systemic manifestations 5, 6
• Kikuchi-Fujimoto disease presents with cervical lymphadenopathy in young adults (average age 21.5 years) with anemia and leukopenia in 50% of cases; self-limited but requires biopsy for diagnosis 7
• IgG4-related disease should be considered, requiring lymph node biopsy showing characteristic histopathology 5, 6

Adult-Onset Still's Disease (AOSD)

• AOSD can present with lymphadenopathy and anemia, but the absence of fever makes this diagnosis unlikely, as quotidian fever pattern is characteristic 1
• Neoplastic disorders including leukemia, lymphoma, and angioblastic lymphadenopathy must be excluded before diagnosing AOSD 1

Critical Decision Algorithm

Immediate Workup (Within 1-2 Weeks)

1. Complete blood count with differential to assess for circulating lymphocytes, anemia pattern, and thrombocytopenia 1, 8
2. Peripheral blood flow cytometry if lymphocytosis present (kappa/lambda, CD19, CD20, CD5, CD23, CD10) 1
3. Comprehensive metabolic panel, LDH, serum immunoglobulins (elevated LDH suggests malignancy or hemolysis) 1, 5
4. Viral serologies: HIV, HBV, HCV, EBV 1, 2, 4
5. Tuberculin skin test to evaluate for mycobacterial disease 3, 4

Imaging Studies

• CT chest/abdomen/pelvis with IV contrast to assess extent of lymphadenopathy and identify organomegaly 1, 3
• Lymph nodes >1.5 cm in short axis require workup for malignancy 3, 2
• Loss of fatty hilum, round shape, heterogeneous echogenicity, or central necrosis on imaging strongly suggests malignancy 3, 2

Tissue Diagnosis (Urgent)

• Excisional lymph node biopsy is mandatory for definitive diagnosis, with >95% diagnostic yield 1, 3, 4
• Biopsy should include immunohistochemistry panel: CD3, CD5, CD10, CD20, CD23, cyclin D1, S100 1
• Flow cytometry and cytogenetics/FISH should be performed on biopsy tissue 1
• Do NOT empirically treat with antibiotics in the absence of acute bacterial infection signs (rapid onset, fever, tenderness, erythema), as this delays diagnosis 3

Common Pitfalls to Avoid

• Do not rely on node size alone: nodes ≤15 mm can harbor malignancy in immunocompromised patients, while reactive hyperplasia can cause enlargement >25 mm 2
• Do not delay biopsy waiting for "watchful waiting": painless lymphadenopathy persisting >4 weeks with anemia warrants immediate tissue diagnosis 3, 8
• Do not use fine-needle aspiration as sole diagnostic method for suspected lymphoma; excisional biopsy is required 1, 3
• Do not assume absence of fever excludes serious disease: many lymphomas and chronic infections present without fever 1, 2
• Do not start corticosteroids before biopsy, as they can mask histologic diagnosis of lymphoma 8