If a pretracheal biopsy is not feasible, and considering either metastasis (spread of cancer) vs a reactive process from an abscess, should immunotherapy be continued, dual immunotherapy be considered, chemotherapy be added on top of immunotherapy, or a repeat positron emission tomography (PET) scan be performed?

Management Approach When Pretracheal Biopsy is Not Feasible

I would strongly recommend obtaining tissue diagnosis through alternative biopsy methods before making any treatment changes, as distinguishing metastasis from reactive/infectious processes is critical for appropriate management and directly impacts survival outcomes.

Priority: Establish Definitive Diagnosis

The fundamental issue is diagnostic uncertainty between malignant disease progression and benign reactive changes from an abscess. This distinction is absolutely critical because:

• Continuing immunotherapy in the setting of an undiagnosed abscess could worsen outcomes by suppressing the immune response needed to control infection 1
• Escalating to dual immunotherapy or adding chemotherapy without confirming malignancy exposes patients to significant toxicity without proven benefit 1
• Treatment decisions for cancer versus infection are diametrically opposed 1

Recommended Diagnostic Algorithm

Step 1: Pursue Alternative Biopsy Approaches

Since pretracheal biopsy is not amenable, consider these alternatives in order of preference:

• Mediastinoscopy - provides access to pretracheal and paratracheal nodes (stations 1-4) with high diagnostic yield 1
• Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) - less invasive alternative for mediastinal lymph nodes 1
• CT-guided percutaneous needle biopsy if the lesion is accessible - has high diagnostic success with acceptable morbidity 1
• Video-assisted thoracoscopic surgery (VATS) - allows multiple large biopsies from different sites 1

The decision to proceed with biopsy should be based on careful risk-benefit analysis, considering the suspected diagnosis, anatomic distribution, and availability of interventional expertise 1.

Step 2: If Biopsy Truly Cannot Be Obtained

Only if tissue diagnosis is genuinely impossible after exhausting all biopsy options:

Option A: Repeat PET Scan (Preferred in this scenario)

I recommend repeat PET scan as the next step because:

• PET scanning is the most accurate imaging modality for distinguishing malignant from benign mediastinal processes (sensitivity 88%, specificity 93%) 1
• Timing matters: Perform PET scan at least 6 weeks after any recent treatment to reduce false-positives 1
• Sarcoid-like granulomatous reactions can occur with immunotherapy and mimic disease progression on imaging, requiring differentiation 1
• Serial imaging can help distinguish infection (which should improve with antibiotics) from malignancy 2

If PET scan shows:

• High FDG uptake with SUV progression → strongly suggests malignancy; proceed with treatment intensification
• Low/stable uptake or improvement → suggests reactive/infectious process; continue current immunotherapy with close monitoring
• Equivocal findings → must pursue tissue diagnosis before treatment changes

Option B: Clinical Trial of Antibiotics with Close Monitoring

If abscess is strongly suspected clinically:

• Treat presumed infection with appropriate antibiotics for 2-4 weeks 2
• Repeat imaging in 4-6 weeks to assess response 2
• Hold immunotherapy temporarily if infection is the leading diagnosis 1
• Clinical improvement and radiographic resolution support infectious etiology; can resume immunotherapy
• Lack of improvement or progression mandates tissue diagnosis before any treatment escalation

What NOT to Do Without Tissue Diagnosis

Do Not Continue Current Immunotherapy Unchanged

• Continuing immunotherapy without knowing if this represents progression versus infection is inappropriate 1
• If this is an abscess, immunotherapy could impair infection control 1
• If this is progression, continuing the same regimen delays effective treatment

Do Not Escalate to Dual Immunotherapy

• Dual immunotherapy (e.g., ipilimumab + nivolumab) significantly increases toxicity (10% vs 3% severe adverse events for combination vs monotherapy) 1
• Adding CTLA-4 blockade without confirmed malignancy exposes patients to unnecessary risk of severe immune-related adverse events including pneumonitis, colitis, and endocrinopathies 1
• No evidence supports empiric escalation without documented progression 1

Do Not Add Chemotherapy Empirically

• Adding chemotherapy to immunotherapy increases toxicity and discontinuation rates 3, 4
• Chemo-immunotherapy combinations are indicated for specific tumor types with confirmed malignancy, not for diagnostic uncertainty 1
• Chemotherapy in the setting of undiagnosed infection could worsen outcomes 5

Critical Pitfalls to Avoid

• Do not assume radiographic progression equals malignant progression - immune-related reactions, sarcoid-like changes, and infections can all mimic cancer progression on imaging 1
• Do not rely on PET scan alone if performed too soon after treatment - wait at least 6 weeks to avoid false-positives 1
• Do not escalate therapy based on imaging alone when tissue diagnosis is potentially obtainable 1
• Do not continue immunotherapy if infection is the primary concern - temporary hold is appropriate while establishing diagnosis 1

Summary Algorithm

1. Exhaust all biopsy options first (mediastinoscopy, EBUS, CT-guided biopsy, VATS) 1
2. If biopsy truly impossible: Repeat PET scan (≥6 weeks from last treatment) 1
3. If abscess strongly suspected clinically: Trial of antibiotics with hold on immunotherapy, repeat imaging in 4-6 weeks 2
4. Never escalate treatment (dual immunotherapy or add chemotherapy) without tissue confirmation of malignancy 1