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Lymphoma - Non B cell neoplasms

T/NK cell disorders - general


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 8 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
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● T/NK cell neoplasms are clonal tumors of mature and immature T cells or natural killer cells at various stages of differentiation (WHO 2008)
● T and NK neoplasms are considered together because they are closely related and share immunophenotypic and functional properties

Epidemiology
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● Precursor T lymphoid neoplasms (T-ALL/LBL): primarily diseases of children/young adults, 10-15% of acute lymphoblastic leukemia (ALL), 85-90% of lymphoblastic lymphoma (LBL), male predominance (Pediatr Blood Cancer 2008;51:489)
● Mature T/NK cell neoplasms: relatively uncommon; 15% of non-Hodgkin lymphomas in US/Western Europe; are usually aggressive with median survival of 10-30 months
● Large international study (Blood 1997;89:3909): 12% of all NHL are T/NK cell (peripheral T cell lymphoma-NOS 25.9%, angioimmunoblastic T cell lymphoma 18.5%)
● Significant geographic and racial incidence variation: generally more common in Asia or Asian populations; adult T cell leukemia/lymphoma in endemic HTLV-I areas, enteropathy-associated T cell lymphoma in those of Welsh and Irish descent
● Overall incidence of T cell neoplasms in the U.S. is 2.6 cases/100,000 persons/year (slight overall increase, mostly in the cutaneous T cell lymphoma category)

Etiology
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● EBV-associated: extranodal NK/T cell lymphoma, systemic EBV+ T cell lymphoproliferative disorder of childhood, Hydroa-vacciniforme-like T cell lymphoma
● HTLV-I: adult T cell leukemia/lymphoma

Pathophysiology
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● Cells of the innate immune system (NK cells, CD3+ CD56+ T cells or NK-like cells, and γδ T cells) first line of defense, primitive response, do not require antigen presentation
● Adaptive immune system utilizes specificity and memory
● T lymphocytes originate from a bone marrow precursor undergoing maturation in the thymus
● Cortical thymocytes: positive for TdT, CD1a, CD3, CD5, CD7 (immature T cell phenotype); initially CD4/CD8 double negative, then double positive, then either CD4 or CD8
● Medullary thymocytes: phenotype similar to mature T cells (could be αβ or γδ); associated with a complete CD3 complex (γ, δ and ε chains)
● γδ T cells: <5% of all normal T cells, CD4/CD8 double negative, usually lack CD5, a subpopulation expresses CD8, restricted distribution (splenic red pulp, intestinal epithelium, other epithelial sites)
● Two categories of CD4+ T cells: Th1 (secrete IL-2 and interferon γ) and Th2 (secrete IL-4, 5, 6 and 10)
● Unique subset of CD4+ T cells found in the germinal center: follicular T-helper cells (TFH) positive for BCL6, CD10, CD4, CD57, PD-1, CXCL13
● Regulatory CD4+ T cells (Treg) with immune suppressing function: positive for CD25, FOXP3 (adult T cell leukemia/lymphoma is associated with marked immunosuppression)
● NK cells: incomplete T cell receptor complex; positive for cytoplasmic CD3 (not surface), CD2, CD7, CD16, CD56, variably CD57, cytotoxic proteins, sometimes CD8

Sites
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● Usually mirror the distribution of their normal cellular counterparts
● Most T cell lymphomas are nodal; most NK cell lymphomas are extranodal
● Lymphomas of the innate immune system predominantly extranodal; pediatric and young adult (aggressive NK cell leukemia, systemic EBV+ T-LPD of childhood, hepatosplenic T cell lymphoma, mucosal/cutaneous γδ T cell lymphomas)
● Lymphomas of the adaptive immune system mainly nodal, usually adult patients

Micro description
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● 99% have diffuse lymphocytic infiltrate with numerous, evenly dispersed, ill-defined, small clusters of epithelioid histiocytes, but these may actually be Hodgkin lymphoma or lymphoplasmacytic lymphoma
● Peripheral T cell lymphomas are, by definition, composed of mature (not precursor) T cells; often misdiagnosed (Mod Pathol 2002;15:420)
● Most relapses of nodal disease have similar histology, pattern of nodal involvement, immunophenotype (Am J Clin Pathol 2000;114:438)
● Large B cells present in peripheral T cell disorders may be due to EBV (in immunodeficient patients) or represent clonal populations that develop into diffuse large B cell lymphoma (Am J Clin Pathol 2000;114:236, Am J Clin Pathol 2002;117:368)

Immunohistochemistry
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● Aberrant T cell phenotype (immunophenotypic clusters exhibiting altered expression of T cell antigens relative to normal) usually implies clonality
● Most common aberrant values are for CD3, CD7, CD5; CD2 is most stable; for CD7, deletion is common (Am J Clin Pathol 2001;116:512)
● Rarely express B cell markers CD20 and CD79a (Mod Pathol 2001;14:105)
● NK markers are CD11b, CD11c, CD16, CD56, CD57 and polyclonal CD3 (detects CD3 epsilon)
● Recommended immunostains include T cell markers (CD3, CD43, CD45RO) and B cell markers (CD20)
● Granzyme M (suggested role in the effector phase of the innate immune system) NK cells, CD3+ CD56+ T cells and γδ T cells (hepatosplenic T cell lymphoma, cutaneous γδ T cell lymphomas, most intestinal T cell lymphomas)
● Immunophenotypic features of common mature T cell & NK cell neoplasms:



Genetics and molecular description
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● Must first establish that process is neoplastic
● Only a few T cell neoplasms have specific genetic abnormalities: Anaplastic large cell lymphoma (ALK), HSTL (iso7q)
● Immunostaining or flow cytometry is useful for classification but usually cannot prove clonality
● Requires T cell receptor gene rearrangement studies by PCR (can use paraffin)
● Analysis of KIR receptors in NK cell proliferations is useful (NK cells do not rearrange the T cell receptor genes)

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders - General


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