This category includes following disorders:

• Extranodal NK/T-cell lymphoma
• EBV-positive nodal T- and NK-cell lymphoma

Extranodal NK/T-cell lymphoma

Introduction:

• Presents as lethal midline granuloma of nose. 

Epidemiology: 

• Common in Asians and native Americans 
• Increased association with haplotypes: HLA-DPB1, HLA-DRB1 and IL18RAP

Etiology: 

• Most are associated with EBV infection 
• Immunosuppressed state

Clinical Features: 

• Facial edema 
• Nasal obstruction/ epistaxis 
• Midfacial destruction with extension into orbits, sinuses and oral cavity 
• Systemic symptoms- Fever, malaise, weight loss 
• Some cases- Hemophagocytic syndrome 
• Regional lymph nodes may be involved

Investigations: 

• Tissue biopsy 
  • Biopsy has to be taken from the edge of the lesion and from apparently uninvolved site, as there is often extensive necrosis. 
  • Mucosal sites show extensive ulceration 
  • Diffuse lymphomatous infiltrate 
  • Angiocentric&angiodestructive growth pattern is usually present 
  • Fibrinoid changes may be seen in vessel walls
  • Coagulative necrosis and apoptotic bodies are very common 
  • Tumor cells show wide spectrum of morphology– small / medium / large / anaplastic 
  • Tumor cells have irregular or elongated nuclei with granular chromatin and iinconspicuous nucleoli. Cytoplasm is moderate and pale to clear .
  • They may show heavy admixture of inflammatory cells including small lymphocytes, plasma cells, histiocytes and eosinophils (so also called as polymorphic reticulosis) 
• Immunophenotyping by immunohistochemistry
  • Positive – CD56, CD2,  Cytoplasmic CD3ε, Cytotoxic granule associated protein CD43, CD45RO, HLA-DR, IL2 receptor, fas&fasligand 
  • Negative – Surface CD3 and other T & NK cell associated antigens (CD4, CD5, CD8, TCRb, TCRd, CD16, CD57) 
  • In situ hybridization for EBER- Positive 
• Molecular studies
  • T Cell receptor & immunoglobulin genes are in germ line configuration
  • EBV can be demonstrated (Clonal episomal form) 
  • Mutation of TP53, beta catenin, K-RAS, c-KIT 
• Cytogenetics
  • del (6)  (q21 q25) 
  • i(6) (p10) 
  • Gain of 2q and loss of 1p, 6p and 4q 
• MRI- To note the extension of disease
• PET-CT
  • To identify occult disease 
  • This is must, as, if tumor is localized it is curable by radiotherapy 
  • EBV PCR (Viral load)-  
  • Helpful in monitoring of disease 
  • May have prognostic relavance 

Prognosis: 

• Poor 
• With disseminated disease overall survival is few months 
• With sequential chemo-radiotherapy 5 year survival- >70% with early stage disease 
• Prognostic index of Natural Killer Lymphoma: Risk factors include
  • Age >60 years 
  • Stage III or IV disease 
  • Distant lymph node involvement 
  • Non-nasal type disease 

• Other unfavorable prognostic markers: 
  • B Symptoms 
  • Elevated LDH 
  • Bone/ skin involvement 
  • Expression of p19 
  • Ki67- >50% 
  • Raised CRP level 
  • Anemia 
  • Thrombocytopenia 
  • High serum EBV levels 
  • EBV positive cells in bone marrow

Pretreatment Work-up:  

• History 
  • B-Symptoms 
• Examination 
  • LN: 
  • Spleen: 
  • ENT- Includingnasopharynx: 
  • Complete Skin exam: 
  • Testicles 
• WHO P. S. 
• BSA 
• IHC 
• BMA and Bx 
• CT (CAP)/ PET 
• MRI+/-CT Nose/PNS/Palate 
• Stage 
• Hemoglobin 
• TLC, DLC 
• Platelet count 
• LFT: Bili- T/D   SGPT:   SGOT: Albumin:     Globulin: 
• Creatinine 
• Electrolytes: Na:     K:    Ca: Mg:      PO4: 
• Uric acid: 
• LDH 
• HIV:
• HBsAg:
• HCV: 
• EBV Viral load 
• UPT 
• PINK score 
• ECHO (If anthracyclines planned)- LVEF-               % 
• RT Consulation for Pre-Rx Evaluation
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment Plan: 

• Nasal
  • Limited disease (Stage 1 and 2)
    • If fit for chemotherapy treat like advanced stage of disease
    • If not fit for chemotherapy- RT and observe

Radiotherapy: 

• Involved field radiotherapy 
• 50Gy 

Related Disorders: 

• Extranasal NK T cell lymphoma 
  • Involves skin, testes, GIT 
  • Careful ENT evaluation is must, to rule out occult primary 
  • Tumor cells are EBV positive 

EBV-positive nodal T- and NK-cell lymphoma

• It is an EBV-positive lymphoma of cytotoxic T- or NK-cell lineage, presenting primarily with nodal disease
• Presents with lymphadenopathy, B symptoms and thrombocytopenia
• Rare
• Median age: 60-64 years
• Micro: Architectural effacement by a diffuse infiltrate of medium to large lymphoid cells (centroblastic)
• IHC: 
  • Positive: pan T-cell markers (such as CD3 and CD2), cytotoxic molecules (TIA1, granzyme B, and perforin), CD8 and CD56
  • Negative: CD4 and CD5
  • EBER- Postive in most of tumor cells
• Median survival: 2-8 months

Recent advances:

Efficacy of a short sandwich protocol, methotrexate, gemcitabine, L-asparaginase and dexamethasone chemotherapy combined with radiotherapy, in localised newly diagnosed NK/T-cell lymphoma

A retrospective multi-centre study evaluated the efficacy of the MGAD regimen combined with radiotherapy in 35 patients with localized extranodal NK/T-cell lymphoma. 91% of patients achieved complete remission, with progression-free and overall survival rates at 2 and 5 years of 71%, 80%, and 53%, 73%, respectively. About one third of patients experienced relapse within 14.5 months. Manageable side-effects included cytopenias, mucositis, and infection. Asparaginase activity monitoring showed drug inactivation in 54% of patients. These findings suggest that the sandwich MGAD chemoradiotherapy is a tolerable and effective treatment option for localized extranodal NK/T-cell lymphoma.

https://doi.org/10.1111/bjh.18689