What is the recommended management for secondary laryngeal involvement by non‑Hodgkin lymphoma in an adult patient with systemic disease?

Management of Secondary Laryngeal Involvement by Non-Hodgkin Lymphoma

Secondary laryngeal involvement by non-Hodgkin lymphoma requires systemic chemotherapy with rituximab-based regimens (R-CHOP for 6-8 cycles) as the primary treatment, not local radiation therapy alone, since this represents disseminated disease requiring systemic control. 1

Critical Diagnostic Distinction

Secondary laryngeal involvement must be distinguished from primary laryngeal lymphoma, as the treatment approach differs fundamentally:

• Secondary involvement indicates systemic disease and mandates complete staging workup including PET-CT scan for whole-body disease assessment, bone marrow biopsy, and comprehensive laboratory evaluation 1
• Deep biopsies with comprehensive immunophenotyping are mandatory to confirm B-cell versus T-cell lineage, as this determines the chemotherapy regimen 1
• For B-cell lymphomas, CD20 positivity confirms eligibility for rituximab-based therapy 1, 2

Standard Systemic Treatment Approach

For B-Cell Non-Hodgkin Lymphoma (Most Common)

R-CHOP chemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) for 6-8 cycles is the standard first-line treatment for diffuse large B-cell lymphoma, the most common subtype causing secondary laryngeal involvement 3, 1, 2:

• Rituximab is FDA-approved for CD20-positive B-cell NHL in combination with CHOP or other anthracycline-based chemotherapy regimens 2
• Treatment should be administered every 21 days with appropriate premedication to prevent infusion reactions 2
• Dose reductions due to hematological toxicity should be avoided; febrile neutropenia justifies prophylactic use of hematopoietic growth factors 3

Role of Radiation Therapy

• Consolidation radiotherapy to the larynx has not proven benefit in the setting of systemic disease and should not be considered standard 3
• Involved-field radiation may be considered only after systemic chemotherapy in select cases with residual local disease 1

Treatment for Refractory or Relapsed Disease

If the patient has primary refractory or early relapsed disease after initial R-CHOP:

• CAR T-cell therapy (axicabtagene ciloleucel or lisocabtagene maraleucel) is now recommended as second-line therapy for fit patients with relapsed/refractory DLBCL 1
• Alternative salvage regimens include gemcitabine-based regimens with rituximab, bendamustine with rituximab, or lenalidomide with rituximab (particularly for non-germinal center B-cell subtype) 1

Special Considerations for T-Cell/NK-Cell Subtypes

If immunophenotyping reveals T-cell or NK/T-cell lymphoma:

• These subtypes require different treatment protocols than standard DLBCL regimens and should not receive R-CHOP 1
• NK/T-cell lymphomas are often EBV-associated and require protocols specific for extranodal NK/T-cell lymphoma 1
• Immunophenotyping must include CD2, CD3 (surface and cytoplasmic), CD4, CD5, CD7, CD8, CD56, and EBV-EBER 1

Response Evaluation and Monitoring

• Adequate radiological assessment should be performed after 2-4 cycles and after the last cycle of chemotherapy 3
• PET-CT is preferred over CT alone for response assessment when available 3
• Patients with incomplete or lacking response should be evaluated immediately for early salvage regimens 3

Common Pitfalls to Avoid

• Do not treat secondary laryngeal lymphoma like squamous cell laryngeal carcinoma with surgery or definitive chemoradiation—this represents a fundamental misdiagnosis that will result in inappropriate therapy 1
• Do not use radiation therapy alone for secondary laryngeal involvement, as this represents systemic disease requiring systemic chemotherapy 1, 4
• Do not delay systemic chemotherapy to pursue local therapies, as secondary involvement indicates disseminated disease with poor prognosis if not treated systemically 4
• Screen all patients for hepatitis B virus (HBsAg and anti-HBc) before initiating rituximab, as HBV reactivation can result in fulminant hepatitis and death 2

Multidisciplinary Team Requirements

The treatment team must include medical oncology/hematology (primary), radiation oncology, pathology with expertise in lymphoma immunophenotyping, and otolaryngology for airway management if needed 1