What is the differential diagnosis for a 17-year-old male with posterior cervical lymphadenopathy, night sweats, epistaxis, buccal mucosa shedding, fatigue, and hot flashes, with a normal Complete Blood Count (CBC) with differential, elevated Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) on Comprehensive Metabolic Panel (CMP), and elevated Lactate Dehydrogenase (LDH)?

Differential Diagnosis for a 17-Year-Old Male with Posterior Cervical Lymphadenopathy and Systemic Symptoms

The most likely diagnosis in this 17-year-old male with posterior cervical lymphadenopathy, B symptoms (night sweats, fatigue), elevated transaminases, elevated LDH, and a normal CBC is infectious mononucleosis (EBV infection), though lymphoma—particularly Hodgkin lymphoma or peripheral T-cell lymphoma—must be urgently excluded given the constellation of findings.

Primary Differential Diagnoses

Infectious Mononucleosis (Most Likely)

• Classic presentation: Posterior cervical lymphadenopathy with fever, pharyngitis, fatigue, and night sweats in an adolescent strongly suggests EBV infection 1
• Laboratory findings: Elevated liver enzymes (AST/ALT) increase clinical suspicion for infectious mononucleosis, even with a normal CBC 1
• Normal CBC consideration: While typical IM shows >40% lymphocytes and >10% atypical lymphocytes, the heterophile antibody test can be false-negative during the first week of illness 1
• Buccal mucosa shedding and epistaxis: These mucosal findings can occur with viral pharyngitis and oral involvement in EBV infection 1
• Elevated LDH: This nonspecific marker can be elevated in infectious mononucleosis 2

Lymphoma (Must Exclude Urgently)

Hodgkin Lymphoma

• Age and presentation: Adolescents and young adults are at peak risk; posterior cervical lymphadenopathy with B symptoms (night sweats, fatigue) is characteristic 1
• Laboratory findings: Elevated LDH is a marker for malignancy and tumor burden 3, 4
• Normal CBC: Does not exclude lymphoma, as peripheral blood involvement may be absent in early or localized disease 4
• EBV association: EBV infection is linked to Hodgkin lymphoma development, creating diagnostic overlap 1

Peripheral T-Cell Lymphoma

• Mimicry of viral illness: Acute viral lymphadenitis can histologically mimic low-grade peripheral T-cell lymphoma with pleomorphic infiltration and B symptoms 5
• Age consideration: While less common in adolescents, T-cell lymphomas can present with multicentric lymphadenopathy and constitutional symptoms 5
• Elevated LDH and transaminases: These findings occur in lymphoproliferative disorders 4

Other Infectious Etiologies

• CMV, toxoplasmosis, HIV: These can present with lymphadenopathy, elevated transaminases, and constitutional symptoms 1, 2
• HTLV-1 (Adult T-cell Leukemia/Lymphoma): Though rare in this age group and geography-dependent, it presents with lymphadenopathy and elevated LDH 6

Immediate Diagnostic Workup

First-Line Testing (Perform Immediately)

• Heterophile antibody test (Monospot): Sensitivity 87%, specificity 91% for infectious mononucleosis; cost-effective initial test 1
• Complete blood count with manual differential: Reassess for >40% lymphocytes and >10% atypical lymphocytes that may have been missed 1
• Peripheral blood smear review: Essential to identify abnormal or atypical lymphocytes suggestive of hematologic malignancy 4, 7
• EBV viral capsid antigen antibodies: More sensitive and specific than heterophile test, particularly if Monospot is negative 1
• CMV, HIV, hepatitis B/C serology: Recommended for lymphadenopathy workup 4, 7

Imaging Studies

• CT scan of chest, abdomen, and pelvis with contrast: Mandatory to document extent of lymphadenopathy, assess for mediastinal involvement, and evaluate spleen size 4, 7
• Consider PET-CT: Useful when lymphoma is suspected; however, infectious mononucleosis can show intense FDG uptake mimicking lymphoma 2

If Initial Testing Is Non-Diagnostic or Concerning

Excisional Lymph Node Biopsy (Gold Standard)

• Indication: Persistent unexplained lymphadenopathy, negative or equivocal infectious workup, or high clinical suspicion for malignancy 7
• Preferred over fine needle aspiration: Allows assessment of lymph node architecture and immunohistochemistry 3
• Timing: Should not be delayed if infectious workup is negative and symptoms persist beyond 2-3 weeks 4

Flow Cytometry of Peripheral Blood

• Indication: If lymphoproliferative disorder is suspected based on peripheral smear findings 4, 8
• Markers: Immunophenotyping for B-cell and T-cell markers 4

Bone Marrow Biopsy

• Not initial test: Reserved for cases where peripheral blood shows abnormal cells or when systemic lymphoproliferative disorder is confirmed 7
• Indication: If lymphoma is diagnosed on lymph node biopsy for staging purposes 3, 4

Critical Pitfalls to Avoid

Do Not Assume Infectious Etiology Without Confirmation

• Overlapping presentations: Viral lymphadenitis can histologically mimic peripheral T-cell lymphoma with pleomorphic infiltration, B symptoms, and multicentric lymphadenopathy 5
• False reassurance from normal CBC: Lymphoma can present with normal peripheral blood counts, particularly in early or localized disease 4

Do Not Delay Lymph Node Biopsy

• If infectious workup is negative: Proceed directly to excisional biopsy rather than prolonged observation 7
• If symptoms worsen or persist beyond 3 weeks: This suggests non-infectious etiology requiring tissue diagnosis 1

Recognize PET-CT Limitations

• Infectious mononucleosis can mimic lymphoma: Intense FDG uptake in cervical nodes, mediastinum, and spleen occurs in EBV infection, creating false-positive concerns for malignancy 2
• Clinical correlation is essential: PET-CT findings must be interpreted with serologic and hematologic data 2

Algorithmic Approach

1. Obtain heterophile antibody test and EBV serology immediately while awaiting CT imaging 1
2. Review peripheral blood smear personally for atypical lymphocytes or abnormal cells 4, 7
3. If Monospot positive and EBV IgM positive: Diagnosis is infectious mononucleosis; provide supportive care and restrict athletic activity for 3 weeks 1
4. If infectious workup is negative or equivocal: Proceed urgently to excisional lymph node biopsy within 1-2 weeks 7
5. If lymph node biopsy shows lymphoma: Complete staging with bone marrow biopsy and PET-CT 3, 4

Special Consideration for This Patient

• Buccal mucosa shedding: While this can occur with viral pharyngitis, consider oral candidiasis or other opportunistic infections if immunosuppression is present; obtain HIV testing 4
• Hot flashes: Atypical for infectious mononucleosis or lymphoma; consider thyroid dysfunction and obtain thyroid function tests 4