In a patient with lymphoma presenting with left leg pain, how should I evaluate and manage possible deep‑vein thrombosis, chemotherapy‑induced neuropathy, or compressive lymphadenopathy?

Evaluation and Management of Left Leg Pain in a Patient with Lymphoma

In a lymphoma patient presenting with left leg pain, immediately evaluate for deep vein thrombosis (DVT) using compression ultrasound of the proximal veins, as lymphoma—particularly high-grade non-Hodgkin lymphoma—confers markedly elevated VTE risk, most commonly from tumor-related venous compression. 1, 2

Immediate Diagnostic Priorities

1. Rule Out Deep Vein Thrombosis First

DVT represents the most urgent life-threatening cause and must be excluded immediately:

• Perform compression ultrasound (CUS) of the proximal deep veins (common femoral and popliteal) as the initial diagnostic test 3
• Position the patient with the lower extremity dependent to facilitate vein distension 3
• If proximal CUS is positive, initiate anticoagulation immediately without confirmatory venography 3
• If proximal CUS is negative, obtain D-dimer testing; if D-dimer is also negative, DVT is effectively ruled out 3
• Consider whole-leg ultrasound or iliac vein imaging if extensive unexplained leg swelling persists despite negative proximal CUS 3

Lymphoma-specific VTE risk factors to assess:

• High-grade non-Hodgkin lymphoma carries the highest DVT risk among hematologic malignancies, predominantly due to compressive lymphadenopathy 1, 2
• Active chemotherapy amplifies VTE risk approximately 6.5-fold 2
• Immunomodulatory agents (lenalidomide, thalidomide) dramatically increase thrombotic risk, especially when combined with dexamethasone or multi-agent chemotherapy 1, 2
• The first 3 months after cancer diagnosis represent peak thrombotic risk 2
• Distant metastases confer an adjusted odds ratio of ~19.8 for VTE 2

2. Evaluate for Compressive Lymphadenopathy

After excluding acute DVT, assess for direct tumor compression:

• Obtain CT imaging of the abdomen/pelvis and affected leg to identify bulky lymph nodes (>5 cm) compressing the iliac or femoral vessels 1
• Disease-related venous compression is the most common cause of VTE in high-grade lymphoma patients 1
• Urgent spinal MRI is indicated if any neurologic symptoms suggest spinal cord compression from epidural lymphoma 1
• Compressive lymphadenopathy may cause pain, swelling, and venous congestion even without frank thrombosis 4

3. Consider Chemotherapy-Induced Peripheral Neuropathy (CIPN)

If DVT and compression are excluded, evaluate for neuropathic pain:

• CIPN presents with numbness, tingling, and pain in a stocking-glove distribution, typically starting distally in toes and progressing proximally 1
• Pain descriptors include burning, shooting, or pins-and-needles sensations; numbness and tingling appear earlier than pain 1
• Diagnosis is clinical: new or worsening numbness/tingling/pain in hands or feet during or after neurotoxic chemotherapy (platinum compounds, taxanes, vinca alkaloids, bortezomib) without alternative explanation 1
• Physical examination may reveal decreased sensation, diminished reflexes, or motor weakness 1
• Electromyography (EMG) is not routinely necessary but can confirm demyelination if diagnosis is uncertain 1

4. Assess for Neurolymphomatosis

Consider direct lymphomatous nerve infiltration, especially if pain is severe and disruptive:

• Neurolymphomatosis causes spontaneous pain that significantly disrupts daily activities, often presenting as multiple mononeuropathies or asymmetric neuropathy 5
• FDG-PET imaging showing positive signals along peripheral nerves strongly suggests neurolymphomatosis 5
• Electrophysiological findings may paradoxically show demyelinating patterns mimicking chronic inflammatory demyelinating polyneuropathy (CIDP), leading to frequent misdiagnosis 5
• Nerve biopsy reveals lymphomatous cell invasion more prominent in proximal nerve trunks, causing demyelination and subsequent distal axonal degeneration 5
• Vinca alkaloids (commonly used in lymphoma treatment) cause peripheral neuropathy and must be distinguished from neurolymphomatosis 6

Diagnostic Algorithm

Step 1: Compression ultrasound of proximal leg veins 3

• Positive → Treat DVT with anticoagulation 3, 7
• Negative → Proceed to Step 2

Step 2: D-dimer testing 3

• Negative → DVT excluded; proceed to Step 3
• Positive → Consider whole-leg ultrasound or repeat proximal CUS in 1 week 3

Step 3: CT abdomen/pelvis to assess for compressive lymphadenopathy 1

• Bulky nodes compressing vessels → Treat underlying lymphoma; consider anticoagulation if venous stasis present 1
• No compression → Proceed to Step 4

Step 4: Clinical assessment for neuropathy 1

• History of neurotoxic chemotherapy + distal sensory symptoms → Diagnose CIPN 1
• Severe spontaneous pain + asymmetric distribution → Consider neurolymphomatosis; obtain FDG-PET 5

Management Considerations

DVT Treatment in Lymphoma Patients

• Direct oral anticoagulants (DOACs: apixaban, rivaroxaban, edoxaban) or low-molecular-weight heparin (LMWH) are preferred over warfarin 7
• Evaluate drug-drug interactions carefully, as many lymphoma therapies interact with anticoagulants 7
• Bleeding risk assessment is critical given thrombocytopenia risk from chemotherapy 7

CIPN Management

• No Grade A or B therapies exist for CIPN prevention or treatment 1
• Acetyl-L-carnitine is contraindicated (Grade H) as it worsens CIPN symptoms 1
• Duloxetine is the only agent with guideline support for CIPN treatment 1
• Pain management requires multimodal pharmacologic and non-pharmacologic approaches 1

Neurolymphomatosis Management

• Treatment of underlying lymphoma is the primary intervention, though neurologic recovery is rare 6
• Some patients initially respond to immunomodulatory treatments (IVIG, steroids), but this does not exclude neurolymphomatosis 5

Critical Pitfalls to Avoid

• Do not assume leg pain is "just neuropathy" without excluding DVT—lymphoma patients have 4- to 7-fold increased VTE risk 1
• A negative proximal leg ultrasound does not rule out pulmonary embolism; maintain clinical suspicion 3
• Do not misdiagnose neurolymphomatosis as CIDP based solely on demyelinating electrophysiology—lymphoma patients can meet CIDP criteria yet have direct nerve invasion 5
• Radiation plexopathy does not develop until ≥6 months post-irradiation; earlier symptoms suggest tumor infiltration 6
• Lymphedema from lymphoma treatment can mimic DVT; ultrasound is essential to differentiate 1