What is the appropriate management for a patient with systemic non‑Hodgkin lymphoma who develops secondary involvement of the larynx?

Management of Secondary Non-Hodgkin's Lymphoma of the Larynx

Treat secondary laryngeal involvement from systemic non-Hodgkin's lymphoma with systemic chemotherapy directed at the underlying lymphoma subtype, not with laryngeal-directed surgery or radiation therapy alone. 1

Critical Diagnostic Distinction

Secondary laryngeal lymphoma must be distinguished from primary squamous cell carcinoma of the larynx, as these require fundamentally different treatment approaches. 1 The NCCN head and neck cancer guidelines 2 address squamous cell carcinoma management (surgery, radiation, or chemoradiation), which is not applicable to lymphoma patients. 1

Essential Diagnostic Steps

• Deep biopsies including edges of lesions to maximize diagnostic yield, as necrosis commonly delays diagnosis. 2
• Comprehensive immunophenotyping is mandatory to distinguish B-cell from T-cell/NK-cell lineage, as treatment differs substantially. 1
• For B-cell lymphomas: Confirm CD20 positivity. 2
• For T/NK-cell lymphomas: Typical immunophenotype includes CD2+, surface CD3-, cytoplasmic CD3ε+, CD56+, with EBV-EBER positivity. 2, 1
• Multiple biopsies may be required when initial samples are inadequate. 3

Systemic Staging Workup (Mandatory)

Complete systemic staging is required before treatment, as laryngeal involvement represents disseminated disease. 1

• PET-CT scan for whole-body disease assessment. 1
• Bone marrow biopsy and aspirate (lymphoid aggregates are considered involved if EBER-1 positive). 2
• Complete laboratory evaluation including LDH, comprehensive metabolic panel, uric acid. 2
• EBV viral load by quantitative PCR (particularly important for NK/T-cell types). 2
• Chest/abdominal/pelvic CT with contrast. 2
• Dedicated CT or MRI of the nasal cavity and nasopharynx for NK/T-cell types. 2

Treatment Algorithm by Lymphoma Subtype

For B-Cell Lymphomas (Most Common)

Primary treatment is systemic chemotherapy with rituximab-based regimens, typically R-CHOP for 6-8 cycles. 1, 3 This represents the standard approach for diffuse large B-cell lymphoma, the most common laryngeal lymphoma subtype. 1

• R-CHOP regimen: Rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone. 3
• Involved-field radiation therapy may be added after 3 courses of R-CHOP in selected cases. 3
• For elderly patients (>80 years) or those with cardiac dysfunction, consider dose-reduced R-COP (omitting doxorubicin). 3

For relapsed/refractory disease after initial therapy:

• CAR T-cell therapy (axicabtagene ciloleucel or lisocabtagene maraleucel) is now recommended as second-line therapy for fit patients. 1
• Alternative salvage regimens include gemcitabine-based regimens with rituximab, bendamustine with rituximab, or lenalidomide with rituximab. 1

For T-Cell and NK/T-Cell Lymphomas

NK/T-cell lymphomas require different protocols than standard DLBCL regimens, as they are predominantly extranodal and often EBV-associated. 1 These should be treated according to extranodal NK/T-cell lymphoma protocols, not standard B-cell regimens. 1

• Diagnosis is particularly challenging and often delayed for T/NK-cell types. 1
• Treatment should occur at centers with expertise in managing these rare subtypes. 2
• Calculate the Prognostic Index of Natural Killer Lymphoma (PINK). 2
• Concurrent referral to radiation therapy for pre-treatment evaluation. 2

For Marginal Zone Lymphoma (Less Common)

For secondary laryngeal involvement from marginal zone lymphoma, systemic treatment with Ibrutinib 520mg daily plus Rituximab 375 mg/m² every 28 days is appropriate. 4

Multidisciplinary Team Requirements

The treatment team must include:

• Medical oncology/hematology (primary treatment coordinator). 1
• Radiation oncology. 1
• Pathology with expertise in lymphoma immunophenotyping. 1
• Otolaryngology for airway management and biopsy. 1

Critical Pitfalls to Avoid

Do not treat secondary laryngeal lymphoma with total laryngectomy or primary radiation therapy alone, as this addresses only the local manifestation of systemic disease. 1 The prognosis of secondary laryngeal involvement by systemic lymphoma is generally poor and depends on the underlying systemic disease burden. 5

Do not apply squamous cell carcinoma treatment algorithms (such as concurrent cisplatin/radiation or laryngectomy) to lymphoma patients, as these approaches are inappropriate and potentially harmful. 1

Ensure adequate tissue sampling, as insufficient biopsies frequently delay diagnosis in laryngeal lymphomas. 3

Prognosis Considerations

Secondary involvement of the larynx by systemic lesions is usually associated with very poor prognosis, unlike primary laryngeal lymphomas which tend to remain localized and respond well to treatment. 5 The overall prognosis depends on the stage and subtype of the systemic lymphoma rather than the laryngeal involvement itself. 5