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Lymphoma - Non B cell neoplasms

T/NK cell disorders

Extranodal NK/T-cell lymphoma, nasal type


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 29 September 2011, last major update September 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● 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
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● Synonyms: angiocentric T cell lymphoma, malignant midline reticulosis, polymorphic reticulosis, lethal midline granuloma, angiocentric immunoproliferative lesion

Epidemiology
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● 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
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● 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
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● Strong association with EBV, subtype A, type II latency (EBNA1+, EBNA2-, LMP1+)
● EBV DNA titer useful to monitor disease activity (high titer–extensive disease, poor response to therapy, poor survival)
● Also occurs post-transplant or with other immunosuppressive states

Clinical features
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● Destructive sinonasal or midline facial tumors, may disseminate rapidly, sometimes associated with hemophagocytic syndromes, EBV+
● Skin–nodular, ulcerated lesions; intestine–perforation; other sites–mass lesions
● High stage at presentation
● If significant bone marrow and peripheral blood involvement, may overlap with aggressive NK-cell leukemia

Case reports
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● 34 year old man with post-treatment residual lymphoma resembling normal lymphocyte infiltration, but monoclonal by in-situ hybridization for EBV RNA (Arch Pathol Lab Med 2002;126:602)
● 37 year old man with enteropathy but no celiac disease (Hum Pathol 2004;35:639)
● 59 year old man with primary nodal presentation (J Clin Pathol 2005;58:443)
● 65 year old woman with tumor arising in pancreas (Hum Pathol 2001;32:741)
● 66 year old Korean man with testicular tumor (Arch Pathol Lab Med 2002;126:1527)
● 81 year old Japanese man with orbital tumor and metastases to lungs and heart (Hum Pathol 2003;34:290)

Treatment and prognosis
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● 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

Postulated normal counterpart
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● Activated NK cells and, less commonly, cytotoxic T lymphocytes

Gross images
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Lethal midline granuloma

Micro description
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● 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

Micro images
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Various images

Morphologic variants
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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)

Cytology description
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● Giemsa stained touch prep: azurophilic granules in the pale cytoplasm of large atypical lymphoma cells

Positive stains
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● 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%), 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
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● CD16 (positive on histiocytes only), CD20, CD57, ALK-1, TCRδ, βF1, CD16, CD57

Genetics and Molecular
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● 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 images
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Monoclonal proliferation of EBV infected cells

EM description
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● Electron-dense membrane-bound granules

Differential diagnosis
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● HSV infection of nasopharynx: CD56+, but HSV+, no angioinvasion or angiodestruction, EBV-, polyclonal (Mod Pathol 2003;16:166)
● Chronic active EBV infection
● Other inflammatory or granulomatous lesions, including Wegener granulomatosis: pulmonary involvement, c-ANCA+
● Systemic EBV+ T cell lymphoproliferative disease of childhood
● Hydroa vacciniforme-like lymphoma

Additional references
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WHO Classification of Tumours of Head and Neck, Lyon, 2005
● Review articles: Cancer 2008;112:1425, Hematol Oncol 2008;26:66

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders > Extranodal NK/T-cell lymphoma, nasal type


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