Lymphoma and plasma cell neoplasms
T/NK cell disorders
Extranodal NK/T-cell lymphoma, nasal type

Author: Dragos Luca, M.D. (see Authors page)

Revised: 11 January 2017, last major update September 2012

Copyright: (c) 2003-2017, PathologyOutlines.com, Inc.

PubMed Search: extranodal NK/T-cell lymphoma nasal [title]
Cite this page: Non B cell neoplasms - Extranodal NK/T cell lymphoma, nasal type . PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomanonBnasal.html. Accessed March 27th, 2017.
Definition / General
  • A predominantly extranodal lymphoma characterized by vascular damage and destruction, prominent necrosis, cytotoxic phenotype and association with EBV (WHO 2008)
  • Designated NK/T (instead of NK) because while most cases appear to be genuine NK-cell neoplasms, some cases show a cytotoxic T cell phenotype
Terminology
  • Synonyms: angiocentric T cell lymphoma, malignant midline reticulosis, polymorphic reticulosis, lethal midline granuloma, angiocentric immunoproliferative lesion
Epidemiology
  • Rare; more prevalent in Asians and native American populations of Mexico, Central America and South America
  • Adults, often Chinese (in US, of Asian/Hispanic descent, Am J Surg Pathol 2000;24:1511, Free full text)
  • More common in males than females
  • Low frequency of HLA-A*0201 allele reported in patients with EBV+ nasal NKTL (Int J Cancer 2000;87:195)
Sites
  • Almost always extranodal
  • Most common location is upper aerodigestive tract (nasal cavity, nasopharynx, paranasal sinuses, palate)
  • Non-nasal NK/T cell lymphomas are similar; often in GI tract, skin, testis, soft tissue
  • Lymph node involvement: secondary-occasional, primary-rare
  • Marrow involvement: infrequent at diagnosis, associated with early death, diagnose with EBER in-situ hybridization (Am J Clin Pathol 2001;115:266)
  • In US, paranasal sinus lymphomas are often diffuse large B cell type, EBV- in one study (Am J Surg Pathol 1999;23:1356)
  • Gynecologic tumors are rare (Arch Pathol Lab Med 2000;124:1510)
Etiology
  • Strong association with EBV, subtype A, type II latency (EBNA1+, EBNA2-, LMP1+)
  • EBV DNA titer useful to monitor disease activity (high titerextensive disease, poor response to therapy, poor survival)
  • Also occurs post-transplant or with other immunosuppressive states
  • Postulated normal counterpart: activated NK cells and, less commonly, cytotoxic T lymphocytes
Clinical Features
  • Destructive sinonasal or midline facial tumors, may disseminate rapidly, sometimes associated with hemophagocytic syndromes, EBV+
  • Skinnodular, ulcerated lesions; intestineperforation; other sitesmass lesions
  • High stage at presentation
  • If significant bone marrow and peripheral blood involvement, may overlap with aggressive NK-cell leukemia
Case Reports
Treatment
  • Unfavorable prognosis: advanced stage (III-IV), skin/bone invasion, p53 missense mutations, high LDH, large cell immunoblastoid polymorphous histology (Hum Pathol 2004;35:86), International Prognostic Index of 2 or more (Mod Pathol 2004;17:1097), high circulating EBV DNA, EBV+ cells in bone marrow
  • Historical survival rate was poor (30-40%), recently improved with more intensive therapy including upfront radiation
  • Outside the nasal cavity: highly aggressive
Micro Description
  • Atypical lymphoid cells (large and small) with abundant pale or clear cytoplasm, irregular nuclear borders and immunoblasts, granular chromatin, vesicular nuclei in large cells, inconspicuous nucleoli
  • Angiocentric and angioinvasive pattern with extensive coagulative necrosis and apoptosis
  • Perivascular and intravascular destructive infiltrates with fibrinoid changes of blood vessels even without invasion
  • Mucosal ulceration with architectural distortion and mucosal gland destruction; peculiar clear cell change of mucosal glands
  • Sometimes prominent inflammatory infiltrate may mimic an inflammatory process
  • Occasional pseudoepitheliomatous hyperplasia of the overlying epithelium

Morphologic variants
  • Cutaneous variant
    • Rare, variable EBV expression; mean survival 15 months from diagnosis (Am J Surg Pathol 1999;23:571, Am J Surg Pathol 2004;28:719)
    • Median age 57, range 43-84 years
    • Usually limited to skin, but may subsequently involve oral and nasal mucosa
    • Gross: multiple patches, plaques or nodules resembling mycosis fungoides
    • Micro: variable epidermal involvement; nodular or diffuse dermal involvement; subcutaneous involvement; variable grenz zone and interface dermatitis; tumor cells are pleomorphic, affecting adnexa, with variable rimming, tumor necrosis and angiodestruction
    • Positive stains: CD3epison, TIA1; variable CD2, CD3, CD8, CD45RO, CD56
    • Negative stains: CD4, CD7, CD57, betaF1, TdT

  • HIV associated
    • Case report of 42 year old man with AIDS, parotid and hepatic masses (Arch Pathol Lab Med 2002;126:738)
    • Micro images: Various images
    • Positive stains: CD3, UCHL-1, EBV latent membrane protein or EBER, TIA1
    • Flow cytometry: CD2, CD3, CD7 (dim), CD8, CD56; negative for CD5
    • Molecular: T cell receptor gamma gene monoclonal rearrangement, EBV RNA and HIV RNA by ISH

  • NK/T cell lymphoma, NOS
    • Case reports: 5 year old girl with EBV negative angiocentric eyelid tumor with immature (CD16+/CD56-) phenotype that spontaneously resolved (Hum Pathol 2001;32:339)
    • Aggressive NK-like CD8+, CD56+, EBV+, T cell lymphoma in previously healthy, HIV-, West African man with erythematous skin nodules, generalized lymphadenopathy, hepatosplenomegaly who died of multiple organ failure (Am J Surg Pathol 2002;26:111)
Micro Images
Images hosted on PathOut server from Case of the Week #412:

H&E (left: low power; middle / right: high power)

CD3 (left: low power; right: high power)

CD20

CD56 (high power)

EBER


Images hosted on other servers:

Various images

Cytology Description
  • Giemsa stained touch prep: azurophilic granules in the pale cytoplasm of large atypical lymphoma cells
Positive Stains
  • CD3 (cytoplasmic, not membranous, in 56%), CD56 (67-100%), TIA1, granzyme, EBER (96%); also CD2, CD5, CD7, CD4 or CD8 (20%), CD30 (focal), CD43 (96%), perforin (35%), CD43 (96%), LMP-1 (48%), p53 (56%), CD45RO, CD25, CD95, HLA-DR
  • Most typical immunophenotype: CD2+, CD56+, surface CD3-, cytoplasmic CD3ε+
  • If CD3ε+, CD56-, cytotoxic molecules+ and EBV+: extranodal NK/T-cell lymphoma
  • If CD3ε+, CD56-, cytotoxic molecules- and EBV-: peripheral T cell lymphoma NOS
  • If EBV- the diagnosis is questionable (EBER-ISH more reliable than EBV-LMP1 IHC)
  • P-glycoprotein/MDR1+ in 90% may explain poor response to therapy
Negative Stains
Molecular / Cytogenetics Description
  • Usually clonal EBV material (100%), but only rarely T cell receptor gene rearrangements (7%)
  • May have 6q- or trisomy 7 (nonspecific changes), most commonly del(6)(q21q25) o3 i(6)(p10)
Molecular / Cytogenetics Images

Monoclonal proliferation of EBV infected cells

Electron Microscopy Description
  • Electron-dense membrane-bound granules
Differential Diagnosis