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Lymphoma - Non B cell neoplasms

T/NK cell disorders

Peripheral T cell lymphoma, not otherwise specified

Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 7 February 2012, last major update August 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● A heterogeneous category of nodal and extranodal mature T cell lymphomas which do not correspond to any of the specifically defined entities of mature T cell lymphoma in the current classification (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, Lyon 2008)

Differential diagnosis of nodal peripheral T cell lymphoma, not otherwise specified

Disease	Immunophenotypic features
Peripheral T cell lymphoma, not otherwise specified	CD4>CD8, antigen loss frequent (CD7, CD5, CD4/CD8, CD52), CD30-/+, CD56-/+, CD10-, BCL6-, CLCX13-, PD1-
Angioimmunoblastic lymphoma	CD4+ or mixed CD4/8, CD10+/-, BCL6+/-, CXCL13+, PD1+, hyperplasia of FDC, EBV+CD20+ B blasts
Adult T cell leukemia/lymphoma	CD4+, CD25+, CD7-, CD30-/+, CD15-/+, FoxP3+/-
Anaplastic large cell lymphoma	CD30+, ALK+/-, EMA+, CD25+, cytotoxic granules+, CD4+/-, CD3-/+, CD43+
T cell rich large B cell lymphoma	Large CD20+ blasts in background of reactive CD3+ T cells
T-zone hyperplasia	Mixed CD4/CD8, intact architecture, variable CD25 and CD30; scattered CD20+ B cells

+, nearly always positive; +/-, majority positive; -/+, minority positive; FDC, follicular dendritic cells; EBV, Epstein-Barr virus.

Terminology
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● Includes lymphoepithelioid (Lennert) lymphoma, follicular T cell, and T-zone lymphoma

Epidemiology
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● Among the most common nodal T cell lymphomas (30% of peripheral T cell lymphomas in Western countries)
● Usually adults, very rare in children
● M:F ratio 2:1

Sites
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● Peripheral lymph node involvement in most cases, but any site may be affected
● Often generalized, with infiltration of bone marrow, liver, spleen and extranodal tissues
● Peripheral blood may be involved but leukemic presentation is uncommon
● Extranodal presentation most commonly in skin and GI tract
● Less frequently involved sites: lungs, salivary glands and CNS

Clinical features
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● Usually high stage (III/IV) with skin or lung involvement, generalized lymphadenopathy, B symptoms and often pruritus
● 30-70% have marrow involvement at diagnosis
● Paraneoplastic features: eosinophilia, pruritus and rarely hemophagocytic syndrome

Case reports
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● 23 year old woman with clinical ischemic stroke (J Med Case Reports 2009;3:83)
● 25 year old woman with eyelid tumor (Clin Ophthalmol 2009;3:527)
● 54 year old man with tumor resembling Wegener granulomatosis (Intern Med 2009;48:2041)
● 57 year old woman with endometrial tumor (Am J Clin Pathol 2001;115:561)
● T cell intravascular lymphoma predominantly involving kidneys in AIDS patient (Hum Pathol 2003;34:950)

Treatment and prognosis
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● More aggressive than most B cell lymphomas; 5 year survival of 25% (20-30%)
● Treatment: chemotherapy, autologous stem cell transplant
● Usually highly aggressive with poor response to therapy and frequent relapses
● Factors consistently associated with prognosis: stage and IPI score
● Other negative prognostic factors: bone marrow involvement, EBV+, NFκB deregulation, high proliferation signature by gene expression, cytotoxic granule expression (Curr Hematol Malig Rep 2010;5:222)

Postulated normal counterpart
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● Activated mature T lymphocytes, mostly CD4+ central memory type of the adaptive immune system

Micro description
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● Paracortical or diffuse effacement by groups of atypical cells of variable sizes separated by delicate PAS+ connective tissue
● Cells often have clear cytoplasm, resemble Reed-Sternberg cells, with irregular, pleomorphic, hyperchromatic or vesicular nuclei with prominent nucleoli
● Many mitotic figures; very broad cytologic spectrum from highly polymorphous to monomorphous; eosinophils, small lymphocytes, plasma cells, epithelioid histiocytes or granulomas; often marked vascularity (high endothelial venules)
● Bone marrow: patterns are small lymphocytic, large cell/immunoblastic or mixed; diffuse or randomly distributed focal infiltrates of variable size with poorly demarcated margins that blend into remaining marrow; large cells have abundant amphophilic cytoplasm and prominent eosinophilic nucleoli resembling Reed-Sternberg cells or its mononuclear varianta; small/medium sized cells have condensed chromatin with normal or irregular nuclear contours; often associated infiltrate of histiocytes, plasma cells, eosinophils and neutrophils; often epithelioid histiocytes, increased vascularity
● Skin: dermis and subcutis involvement, often nodules with central ulceration; epidermotropism, angiocentricity and adnexal involvement
● Spleen: solitary or multiple nodules to diffuse white pulp involvement with colonization of the periarteriolar sheath; sometimes predominant red pulp infiltration; may resemble marginal zone lymphoma (Mod Pathol 2002;15:420)

Micro images
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Resembling MALT lymphoma

   
Lymph nodes

Positive stains
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● CD2, CD3, TCR β-F1; variable CD4, CD5 and CD7
● Reticulin in marrow (increased fibers in neoplastic areas that extend into adjacent marrow)
● Frequent downregulation of CD5 and CD7
● CD4+/CD8- predominantly in nodal cases; sometimes double negative or double positive
● Occasional CD56 and cytotoxic granule expression
● May be CD15+/CD30+ and resemble Hodgkin lymphoma (Am J Surg Pathol 2003;27:1513)
● Occasional aberrant CD20+ or CD79a+
● Ki67 > 70% associated with worse prognosis

Negative stains
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● CD1, TdT, CD52 (60%)
● No follicular T-helper phenotype (CD10, BCL6, PD1 and CXCL13) with the exception of the follicular variant

Genetics and molecular
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● Clonal rearrangements of T cell receptor genes; usually alpha-beta phenotype, no specific cytogenetic abnormalities
● Deletions of 5q, 10q and 12q associated with better prognosis
● EBV integration reported in some cases
● Gene expression profile distinct from normal T cells (J Clin Invest 2007;117:823)

Differential diagnosis
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● Hodgkin lymphoma: classic Reed-Sternberg cells are CD15+, CD30+, no atypia in lymphocytes
● Systemic mastocytosis: tryptase+
● Reactive lymphoid hyperplasia: usually no marked atypia, no T cell receptor clonality
● Angioimmunoblastic T cell lymphoma: follicular T-helper phenotype, different gene signature
● Follicular B cell lymphoma
● Anaplastic large cell lymphoma: different immunophenotype, different gene signature

Peripheral T cell lymphoma variants
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Lymphoepithelioid (Lennert lymphoma)
● Also called lymphoepithelioid lymphoma
● Tumor cells usually are within lymph nodes
● Mean survival 42 months
● Micro: small to large clusters of reactive epithelioid histiocytes, some resembling Reed-Sternberg cells, plus variably sized T cells with destructive infiltration and larger, more atypical proliferating blasts, diffuse or interfollicular growth

           
Various images

● Stains: CD3+, majority are CD8+, TIA1+, variable granzyme B, EBV- (Am J Surg Pathol 2000;24:1627)
● Molecular: T cell receptor gene rearrangement
● References: Am J Clin Pathol 1976;66:1

Follicular/Perifollicular growth pattern
● 9 cases of T helper neoplasm with distinctive growth pattern (Am J Surg Pathol 2000;24:117)
● Micro: prominent infiltration predominantly of marginal zones (mimicking nodal marginal zone lymphoma), but also intrafollicular (mimicking follicular lymphoma), that partially distorts lymph node structure by medium-sized cells with clear cytoplasm and significant nuclear atypia; may also form small nodular aggregates in a background of progressively transformed germinal centers (mimicking nodular lymphocyte predominant Hodgkin lymphoma)
● In the paracortical T-zone, marked proliferation of high endothelial venules; also plasmacytosis and capsular fibrosis
● Multiple images
● Stains: CD3+, CD4+, CD5+/-, CD8-, TIA1-
● Cytogenetics: t(5;9) recently reported
● DD: marginal zone lymphoma, reactive changes, angioimmunoblastic T cell lymphoma (enlarged follicular dendritic cell meshworks, high endothelial venules)

Reed-Sternberg-like cells
● 3 cases of nodal peripheral T cell lymphoma with Reed-Sternberg-like cells (Am J Surg Pathol 1999;23:1233)
● Micro: two cases had features of angioimmunoblastic T cell lymphoma (AILT); large mononuclear and binucleated cells with prominent eosinophilic nucleoli and abundant cytoplasm resembling classic Reed-Sternberg cells and mononuclear variants
● Stains: lymphoma cells: CD3, CD43, CD45RO, EBV negative
● Reed-Sternberg-like cells: CD15+, CD30+, CD20+, EBV LMP+, EBER+, negative for T cell markers
● DD: Hodgkin lymphoma

T-zone lymphoma
● Micro: peri/interfollicular growth pattern with sparing of secondary lymphoid follicles, predominantly small cells with minimal atypia
● Stains: CD3, CD4, may have loss of CD5 or CD7
● May have a more indolent course than other peripheral T cell lymphoma-NOS

Additional references
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● Review articles: Adv Hematol 2010; 2010: 624040, J Clin Pathol 2008;61:1160

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders > Peripheral T cell lymphoma, not otherwise specified

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