How can I rule out a lymphoproliferative disorder in a patient with multiple enlarged lymph nodes on a computed tomography scan?

Ruling Out Lymphoproliferative Disorder in Multiple Lymphadenopathy

Excisional or incisional lymph node biopsy is mandatory for definitive diagnosis—fine-needle aspiration alone is inadequate except in rare inaccessible nodes. 1, 2

Initial Clinical Assessment

Begin by systematically evaluating for features that distinguish malignant lymphoproliferative disorders from reactive adenopathy:

High-Risk Historical Features

• Age >40 years increases malignancy risk and mandates aggressive workup 1
• B symptoms (fever >38°C, drenching night sweats, unintentional weight loss >10% body weight) strongly suggest lymphoma and necessitate expedited evaluation 1, 2
• Immunocompromised status (HIV, organ transplantation, immunosuppressive therapy) significantly elevates risk of lymphoproliferative disorders 3, 1
• Prior lymphoid neoplasms, particularly Hodgkin lymphoma, nodal anaplastic large cell lymphoma, or mycosis fungoides 3

Physical Examination Red Flags

• Lymph node size >1.5 cm in greatest transverse diameter is the threshold for concern 3, 1
• Firm or hard texture, reduced mobility, or matted nodes indicate possible malignancy 1
• Hepatosplenomegaly suggests systemic involvement 3, 2
• Distribution across multiple anatomical regions warrants immediate hematology-oncology referral 1

Laboratory Workup

Order the following baseline studies before proceeding to biopsy:

• Complete blood count with differential to assess for cytopenias, leukocytosis, or atypical lymphocytosis 3, 1
• Lactate dehydrogenase (LDH) as a marker of disease burden 3, 1
• Comprehensive metabolic panel including albumin 1
• Erythrocyte sedimentation rate (ESR) 1
• HIV testing, especially in younger patients or those with risk factors 1
• Hepatitis B and C serology if lymphoma is suspected 1

Imaging Strategy

For FDG-Avid Lymphomas (Most Histologies)

PET-CT is the gold standard for staging and should be obtained as baseline before therapy to increase accuracy of subsequent response assessment 3, 2. PET-CT is preferred for all nodal lymphomas except chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, mycosis fungoides, and marginal zone lymphomas 3.

For Non-FDG-Avid Histologies

Contrast-enhanced CT of chest, abdomen, and pelvis is the alternative when PET-CT is unavailable or for variably FDG-avid histologies 3, 2.

Key Imaging Findings

• Focal uptake in nodal and extranodal sites on PET-CT is considered lymphoma involvement when distribution and CT characteristics are consistent 3
• Measurable nodes must have longest diameter >1.5 cm on CT 3
• Splenomegaly >13 cm vertical length suggests splenic involvement 3

Definitive Tissue Diagnosis

Biopsy Approach

Target the most accessible enlarged cervical lymph node (>1.5 cm) for excisional biopsy before attempting mediastinal approaches 1. Excisional or incisional biopsy is mandatory because:

• Preserving nodal architecture enables accurate lymphoma subtype classification and allows essential immunohistochemistry, flow cytometry, and molecular studies 1, 2
• FNA or core-needle biopsy alone does not provide sufficient tissue for comprehensive histologic interpretation, immunophenotyping, or detection of critical markers (CD3, CD15, CD20, CD30, CD45, CD79a, PAX5) 1, 2
• The only limited exception is when a node is not easily accessible and FNA is combined with core biopsy (minimum 4mm punch) plus advanced ancillary techniques performed by an expert hematopathologist 1, 2

Essential Tissue Studies

The biopsy specimen must allow for:

• Histopathologic examination with preservation of architecture 1, 2, 4
• Immunophenotyping to determine B-cell vs T-cell lineage and detect monoclonality 1, 2, 4
• Flow cytometry for immunologic phenotyping 1, 4
• PCR-based clonality testing (IGH, TCR gene rearrangements) when diagnosis is uncertain 2, 4

Referral Pathways

Immediate Hematology-Oncology Referral Required For:

• Nodes >1.5 cm, hard or matted nodes 1
• Distribution across multiple anatomical regions 1
• B symptoms present 1
• Immunosuppression history 1

ENT/Surgical Oncology Referral For:

• Suspected head and neck primary malignancy based on symptoms 1
• Need for excisional biopsy of cervical nodes 1

Common Pitfalls to Avoid

• Do not rely on FNA alone even when cytology suggests lymphoma, because subtype classification and staging require intact nodal architecture 1, 2
• Do not perform bone marrow biopsy before establishing primary lymph node diagnosis—bone marrow should be performed after confirming lymphoma subtype to ensure appropriate staging 1
• Do not delay excisional biopsy in high-risk presentations while pursuing additional imaging or laboratory studies 1
• Do not assume normal-sized nodes exclude lymphoma—PET-CT frequently detects abnormal uptake in nodes that are not enlarged on CT 5

Post-Biopsy Staging

Once lymphoma is confirmed histologically:

• Obtain baseline PET-CT scan (skull base to mid-thigh) for initial staging and treatment planning 1
• Calculate International Prognostic Index (IPI) for diffuse large B-cell lymphoma 2
• Assess cardiac function (LVEF) before anthracycline-based therapy 2
• Consider tumor lysis syndrome prophylaxis in high tumor burden cases 2