What is Natural Killer (NK) lymphoma?

Natural Killer (NK) Lymphoma: Characteristics and Management

Natural killer (NK) lymphoma is a rare and aggressive subtype of non-Hodgkin lymphoma originating from NK cells, characterized by Epstein-Barr virus (EBV) infection, predominantly extranodal presentation, and typically affecting the upper aerodigestive tract. 1

Definition and Classification

NK lymphoma is a distinct clinicopathological entity in the WHO classification of lymphoid neoplasms. It accounts for a small percentage of non-Hodgkin lymphomas, with higher prevalence in Asian and Latin American populations than in Western countries 1. The disease is categorized into:

• Nasal type: Most common form, affecting the nasal cavity, nasopharynx, paranasal sinuses, tonsils, hypopharynx, and larynx
• Extranasal type: Involving skin, testis, gastrointestinal tract, and other sites
• Aggressive leukemia/lymphoma type: Involving bone marrow and multiple organs 2

Pathophysiology and Diagnosis

Key Pathological Features

• Universal EBV association: EBV infection is present in virtually all cases and plays a central role in pathogenesis 3, 2
• Characteristic immunophenotype:
  • NK-cell phenotype: CD20-, CD2+, cytoplasmic CD3ε+ (surface CD3-), CD4-, CD5-, CD7-/+, CD8-/+, CD43+, CD45RO+, CD56+, TCRαβ-, TCRγδ-, EBV-EBER+ 1
  • Cytotoxic granule proteins (TIA1, perforin, granzyme B) are typically expressed 1

Diagnostic Approach

1. Tissue biopsy: Excisional or incisional biopsy is preferred

   • Include edges of lesions to increase chances of obtaining viable tissue (necrosis is common)
   • Multiple nasopharyngeal biopsies may be useful even in areas not clearly involved 1

2. Essential immunophenotyping:

   • EBV detection using EBER in-situ hybridization (EBER-ISH) is mandatory
   • A negative EBER-ISH result should prompt review for alternative diagnosis 1

3. Molecular analysis:

   • Clonal T-cell receptor gene rearrangements may be found in up to one-third of cases 1

Clinical Presentation and Staging

Common Presentations

• Nasal obstruction, epistaxis, destructive midline lesions
• B symptoms (fever, night sweats, weight loss)
• Hemophagocytic syndrome is a common complication 3

Essential Workup

• History and physical exam with attention to node-bearing areas, testicles, and skin
• ENT evaluation of nasopharynx
• Laboratory tests: CBC with differential, LDH, comprehensive metabolic panel, uric acid
• Bone marrow biopsy and aspirate
• Imaging: Chest/abdominal/pelvic CT with contrast and/or PET/CT
• Dedicated CT or MRI of nasal cavity, hard palate, anterior fossa, nasopharynx
• EBV viral load by quantitative PCR (important for diagnosis and disease monitoring) 1

Prognostic Factors

• PINK (Prognostic Index of Natural Killer Lymphoma) calculation
• Ki-67 expression (≥65% associated with shorter overall survival) 1
• EBV DNA levels (correlate with disease burden and prognosis) 2

Treatment Approaches

Stage I/II Nasal Disease

• Combined modality therapy: Non-anthracycline, asparaginase-based regimens plus sequential/concurrent radiotherapy 2
• Radiation doses are typically higher than for other lymphomas (50 Gy to initial lesion with 5-10 Gy boost to residual disease) 1

Advanced (Stage III/IV) or Relapsed/Refractory Disease

• L-asparaginase-based regimens are the backbone of therapy:

  • SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) has shown superior efficacy compared to CHOP 4, 5
  • AspaMetDex is another effective option 6

• Hematopoietic stem cell transplantation (HSCT):

  • Allogeneic HSCT should be considered for consolidation in suitable patients with advanced disease 2
  • Autologous HSCT has shown limited benefit in improving outcomes 2

Novel and Emerging Therapies

• Immune checkpoint inhibitors targeting PD-1/PD-L1
• EBV-specific cytotoxic T-cells
• Histone deacetylase inhibitors
• Targeted therapies against specific oncogenic pathways 2

Monitoring and Follow-up

• Serial plasma EBV DNA quantification (normalization indicates response; persistent elevation suggests residual disease) 1
• PET/CT for response assessment (goal: Deauville score ≤3) 2
• Close monitoring for treatment-related toxicities, particularly with L-asparaginase-based regimens (neutropenia, thrombocytopenia, nephrotoxicity) 4

Prognosis

• Localized disease: 5-year survival approximately 70%
• Advanced disease: 5-year survival approximately 40% 3
• Poor prognostic factors include advanced stage, high international prognostic index (IPI), and failure to achieve complete remission 4

Clinical Pearls and Pitfalls

• Diagnostic pitfalls: Extensive necrosis in biopsy specimens can delay diagnosis; include lesion edges in biopsies 1
• Treatment pitfalls: Conventional anthracycline-based regimens (e.g., CHOP) are ineffective due to multidrug resistance phenotype 2
• Monitoring pitfalls: Failure to normalize EBV viremia should be considered evidence of persistent disease 1
• Critical importance of complete remission: Achievement of CR is the most significant factor for improved survival 5

NK lymphoma requires specialized management at centers with expertise in treating this rare and aggressive disease 1.