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    Peripheral T Cell Lymphoma Unspecified

    Definition

    • Morphologically and immunophenotypically heterogeneous group of nodal T cell lymphomas that do not meet the diagnostic criteria of one of the other WHO-defined T-cell lymphoma categories

    Alternate/Historical Names

    • Lymphoepithelioid cell lymphoma / Lennert lymphoma / T cell lymphoma with high content of epithelioid lymphocytes
    • Pleomorphic T-cell lymphoma
    • T cell lymphoma, NOS and diffuse small cleaved cell, diffuse mixed small and large cell, diffuse large cell, and immunoblastic types
    • T-zone lymphoma

    Diagnostic Criteria

    • Morphologic features are highly variable
      • Cell size usually medium to large, but can be small
      • Pattern of infiltration usually diffuse
        • T-zone variant
          • Malignant infiltrate spares follicles
          • Cytologic atypia is subtle
          • Vascular/mixed inflammatory background
      • Cytologically malignant features usually present
        • Nuclear pleomorphism and irregular nuclear contour
        • Vesicular or hyperchromatic chromatin pattern
        • Prominent nucleoli
      • Background often vascular with admixed plasma cells, eosinophils, histiocytes, immunoblasts
        • Lymphoepithelioid cell variant (“Lennert lymphoma”)
          • Clusters of epithelioid histiocytes
          • Malignant infiltrate with subtle cytologic atypia
    • Accompanying B cell proliferation in ~20%
      • Diagnosis of diffuse large B cell lymphoma requires sheets of monoclonal large B cells
      • Diagnosis of plasmacytoma requires sheets of monoclonal plasma cells
      • Molecular evidence of B cell clonality is NOT sufficient for diagnosis of B cell lymphoma/plasmacytoma

    Dita Gratzinger MD PhD
    Yasodha Natkunam MD PhD

    Department of Pathology
    Stanford University School of Medicine
    Stanford CA 94305-5342

    Initial posting : October 8, 2007

    Supplemental studies

    Immunohistology

    • Non-lineage specific markers
      • CD30+ 30-60%
      • Cytotoxic marker ~10%
        • TIA-1 and/or granzyme
      • CD56+ ~10%
    • T lineage markers:
      • Loss of T cell markers is common and is helpful in diagnosis
        • CD3+ 80-90%
        • CD5+ 50-60%
        • CD4+ 50%
        • CD8+ 20%
        • CD4/CD8 double negative ~30%

    Genetic analysis

    • Most cases show T cell gene rearrangement
    • ~1/3 show clonal immunoglobulin gene rearrangement
    • Complex cytogenetic abnormalities often present and are highly variable
      • Help establish clonality but are not prognostically significant
    • In situ hybridization for EBV early region RNA (EBER):
      • ~60% of cases positive; EBV+ cells correspond to CD20+ B immunoblasts

    Differential Diagnosis

    Angioimmunoblastic T Cell Lymphoma Peripheral T Cell Lymphoma Unspecified
    Characteristic morphology with vascular proliferation, follicular dendritic cell proliferation, and polymorphic infiltrate including immunoblasts Morphology varies widely but does onot show all of the features of AITL
    Germinal center T cell phenotype (CD10+, CXCL13+) ini 60-90% Usually not germinal center phenotype (only in 10-30% of cases)
    Infrequent T cell antigen loss Frequent T cell antigen loss (CD5, CD7)
    Characteristic clinical presentation with pruritic rash, immune dysregulation Rash and immune dysregulation uncommon
    Both are clinically aggressive nodal T cell lymphomas arising in similar patient populations

     

    Peripheral T Cell Lymphoma Unspecified Primary Systemic Anaplastic Large Cell Lymphoma
    T cell immunophenotype T cell or null cell immunophenotype
    Often CD30+ Always CD30+
    ALK1 negative >60% of cases ALK1 positive*
    Variety of large pleomorphic cells including hallmark-type cells may be present Hallmark cells present
    Both may show large pleomorphic T cells with abundant cytoplasm and be CD30+.  *Cases currently classified as anaplastic large cell lymphoma which are ALK negative are clinically indistinguishable from peripheral T cell lymphoma, unspecified and will likely be merged with this category in the future.

     

    Peripheral T Cell Lymphoma Unspecified Extranodal NK/T Cell Lymphoma, Nasal Type
    Predominantly nodal, but commonly involves extranodal sites Predominantly extranodal, but may secondarily involve lymph nodes
    T-cell receptor rearrangement usually present T-cell receptor usually in germline configuration
    Admixed B immunoblasts EBV+ in 1/3 NK/T cell population EBV+
    Rare cases CD56+ (~10%) Most cases CD56+
    Both are aggressive CD3+ lymphomas which may be CD56+ and show EBV reactivity.

     

    Peripheral T Cell Lymphoma Unspecified T Cell / Histiocyte Rich Diffuse Large B Cell Lymphoma
    May show monomorphous or polymorphous B cell proliferation, scattered or in sheets <10% scattered large B lymphocytes; morphology varies, but is generally uniform within a case
    Monoclonal immunoglobulin gene rearrangement sometimes present (~1/3) Monoclonal immunoglobulin gene rearrangement usually present
    T cells usually monoclonal T cells polyclonal
    T cell population usually overtly cytologically malignant Background of small T lymphocytes, sometimes with numerous epithelioid histiocytes
    Aberrant loss of T cell markers common No aberrant loss of T cell markers
    Both show large B cell population in a background of T cells and are clinically aggressive

     

    Peripheral T Cell Lymphoma Unspecified Nodular Lymphocyte Predominance Hodgkin Lymphoma
    Spectrum of B cells usually present including immunoblasts and Reed-Sternberg-like cells. Scattered L&H cells with “popcorn” nuclei, smaller B cells.
    Lymph node usually diffusely effaced; T-zone variant preserves germinal centers Large nodules and sometimes diffuse areas efface the lymph node.
    T cell population cytologically malignant T cell population cytologically bland
    Aberrant loss of T cell markers common No aberrant loss of T cell markers
    T cells usually monoclonal or oligoclonal T cells polyclonal
    Monoclonal immunoglobulin gene rearrangement sometimes present (~1/3) Monoclonal immunoglobulin gene rearrangement may be detectable
    Aggressive clinical course Generally indolent with localized lymphadenopathy; but may coexist with or recur as diffuse large B cell lymphoma.
    Both show scattered large atypical B cells in a T cell rich background

     

    Peripheral T Cell Lymphoma Unspecified Classical Hodgkin Lymphoma
    Spectrum of B cells usually present including immunoblasts and Reed-Sternberg-like cells. B cells are predominantly large mononuclear and multinucleated Reed-Sternberg variants
    Lymph node usually diffusely effaced; T-zone variant preserves germinal centers Broad bands of fibrosis present in the most common (nodular sclerosis) variant
    T cell population cytologically malignant T cell population cytologically bland
    Aberrant loss of T cell markers common No aberrant loss of T cell markers
    T cells usually monoclonal or oligoclonal T cells polyclonal
    Monoclonal immunoglobulin gene rearrangement sometimes present (~1/3) Monoclonal immunoglobulin gene rearrangement rarely detectable
    Both may show CD30+, CD15+, EBV+, CD20+ large cells with Reed-Sternberg morphology and polymorphic background infiltrate including plasma cells, histiocytes, and eosinophils; generalized lymphadenopathy with constitutional symptoms.

     

    Peripheral T Cell Lymphoma Unspecified Reactive T Zone Hyperplasia: Viral (e.g. Infectious Mononucleosis)
    Necrosis generally absent Necrosis may be present
    EBV often positive in B cells EBV positive in T cells in infectious mononucleosis
    Immunoblasts/Reed-Sternberg-like cells B lineage Immunoblasts/Reed-Sternberg-like cells T lineage
    T cells usually monoclonal or oligoclonal T cells polyclonal
    Aberrant loss of T cell markers common No aberrant loss of T cell markers
    1/3 also show B cell clonality EBV-associated monoclonal B-cell proliferations rarely develop (especially with immunodeficiency/immunosuppression).
    Aggressive clinical course with generalized lymphadenopathy or mass lesions. Localized lymphadenopathy, viral syndrome, viral serologies.
    Both may show paracortical expansion with numerous immunoblasts and sometimes Reed-Sternberg-like cells, residual germinal centers, increased vascularity

     

    Peripheral T Cell Lymphoma Unspecified Reactive T Zone Hyperplasia: Anticonvulsant-associated
    Necrosis generally absent Necrosis may be present
    EBV often positive in B cells EBV negative
    Immunoblasts/Reed-Sternberg-like cells B lineage Immunoblasts/Reed-Sternberg-like cells T lineage
    Aberrant loss of T cell antigens common No aberrant loss of T cell antigens
    T cells usually monoclonal or oligoclonal T cells polyclonal
    1/3 also show B cell clonality B cells polyclonal
    Aggressive clinical course despite chemotherapy. History of anticonvulsant exposure; symptoms resolve with drug withdrawal.
    Both may show paracortical expansion with numerous immunoblasts, sometimes Reed-Sternberg-like cells, residual germinal centers, increased vascularity.

     

    Peripheral T Cell Lymphoma Unspecified Reactive T Zone Hyperplasia: Dermatopathic Lymphadenopathy
    No increase in interdigitating reticulum cells/Langerhans histiocytes Pale-staining S100+/CD1a+ interdigitating reticulum cells, Langerhans histiocytes
    Histiocytes increased but not pigment-laden Hemosiderin and pigment-laden histiocytes
    Cytologically malignant T cell population Cytologically bland*
    Aberrant loss of T cell antigens common No loss of T cell antigens*
    T cells usually monoclonal; 1/3 also show B cell clonality T cells polyclonal*
    Follicular dendritic cell proliferation outside germinal centers No follicular dendritic cell proliferation outside germinal centers
    Aggressive clinical course. Clinically indolent*.
    Both may show paracortical expansion with admixed histiocytes, plasma cells, and eosinophils, increased vascularity, reactive or atretic follicles.
    *Except in cases with concomitant lymph node involvement by cutaneous T cell lymphoma.

     

    Peripheral T Cell Lymphoma Unspecified Reactive T Zone Hyperplasia: Toxoplasma Lymphadenitis
    Pale-staining cells, if present, are T cells Pale-staining cells are monocytoid B cells.
    Cytologically malignant T cell infiltrate with sparing of germinal centers Characteristic triad of reactive germinal centers, perifollicular clusters of epithelioid histiocytes, and islands of monocytoid cells
    Aberrant loss of T cell antigens common No loss of T cell antigens
    T cells usually monoclonal; 1/3 also show B cell clonality B and T cells polyclonal
    Aggressive clinical course with generalized lymphadenopathy or mass lesions. Localized lymphadenopathy, positive Toxoplasma serology.
    Both may show paracortical expansion with patches of pale-staining cells, admixed histiocytes.

     

    Peripheral T Cell Lymphoma Unspecified Granulomatous Disease
    Cytologically atypical lymphoid population Cytologically bland lymphoid population
    Effacement of lymph node architecture Preservation of lymph node architecture
    Cytologically malignant T cell infiltrate Cytologically bland
    Aberrant loss of T cell antigens common No loss of T cell antigens
    T cells usually monoclonal; 1/3 also show B cell clonality B and T cells polyclonal
    Aggressive clinical course with generalized lymphadenopathy or mass lesions. Clinical/serologic findings of granulomatous infection, sarcoidosis, etc.
    Both may show clusters of epithelioid histiocytes in a lymphocyte-rich background.

     

    Peripheral T Cell Lymphoma Unspecified Autoimmune Lymphoproliferative Syndrome
    Lymph node usually effaced; follicle centers may be spared Paracortical expansion with florid reactive follicular hyperplasia
    Aberrant loss of T cell antigens common Characteristic T cell immunophenotype: CD4/CD8 double negative, CD45RO–
    Cytologically malignant T cell population Medium-large T cells with abundant cytoplasm, T immunoblasts
    T cells usually monoclonal
    1/3 show B cell clonality    		 T cells polyclonal
    B cells usually polyclonal*
    Aggressive clinical course with generalized lymphadenopathy or mass lesions, rare in children. Generalized lymphadenopathy, splenomegaly, autoimmune phenomena, usually presents in childhood.  FAS mutation present.
    Both may show paracortical expansion by atypical T cell population, generalized lymphadenopathy.
    *Lymphoma may develop in this setting, most commonly B cell non-Hodgkin type.

     

    Peripheral T Cell Lymphoma Unspecified Kikuchi-Fujimoto Disease, Proliferative Phase
    Cytologically malignant T cell population Sheets of T immunoblasts
    Necrosis rare Prominent non-suppurative necrosis
    Histiocytes lack crescentic nuclei, MPO Crescentic histiocytes (MPO+)
    Aberrant loss of T cell antigens common No loss of T cell antigens
    T cells usually monoclonal
    1/3 show B cell clonality    		 T cells polyclonal
    B cells usually polyclonal
    Aggressive clinical course with generalized lymphadenopathy or mass lesions. Cervical lymphadenopathy, flu-like symptoms, spontaneous resolution.
    Both may show diffuse effacement by atypical T cell population.

    Clinical

    • Most common T cell lymphoma category in non-EBV-endemic populations (North America/Europe)
    • Predominantly nodal presentation
      • Extranodal involvement common
        • skin, gastrointestinal tract, liver, bone marrow
    • Generally aggressive lymphomas with poor response to therapy
    • Category likely comprises heterogeneous clinical entities which cannot be reliably distinguished
      • Morphologic categories not prognostically useful
    • Cytotoxic marker (granzyme and/or TIA-1) positivity has been proposed as a poor prognostic factor in a Japanese study; however the poor outcome could also have been due to concomitant EBV positivity, and it is not clear whether this is true in non-EBV endemic populations

    Grading / Staging / Report

    Grading not applicable

    Ann Arbor Staging System

    • Stage I
      • I if involvement of a single lymph node region
      • IE if involvement of a single extralymphatic organ or site
    • Stage II
      • II if two or more lymph node regions on same side of diaphragm
      • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
    • Stage III
      • III if Involvement of lymph node regions on both sides of the diphragm
      • IIIS if spleen involved
      • IIIE if extralymphatic site involved
    • Stage IV
      • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
    • Systemic Symptoms in 6 months preceding admission
      • Fever, night sweats, 10% weight loss
      • A = absent
      • B = present
    • Extranodal sites are also designated
      • M+ = marrow
      • L+ = lung
      • H+ = liver
      • P+ = pleura
      • O+ = bone
      • D+ = skin and subcutaneous tissue
    • Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

    The pathology report should contain the following information:

    • Diagnosis in the World Health Organization (WHO) classification
      • Equivalent diagnosis in other classifications used by relevant clinicians
    • Results of supplementary studies if performed
    • Relationship to other specimens from the same patient
    • Information relevant to staging if available

     

    Lists

    Mature T and NK cell neoplasms (WHO classification)

    Bibliography

    • Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF . Tumors of the Lymph Nodes and Spleen, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 14, 1995
    • Jaffe ES, Harris NL Stein H, Vardiman JW . Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
    • Ioachim HL, Ratech H. Ioachim’s Lymph Node Pathology.  Lippincott Williams and Wilkins, 3rd Edition, 2002.
    • Tan BT, Warnke RA, Arber DA. The frequency of B- and T-cell gene rearrangements and epstein-barr virus in T-cell lymphomas: a comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations. J Mol Diagn. 2006 Sep;8(4):466-75.
    • Asano N, Suzuki R, Kagami Y, et al. Clinicopathologic and prognostic significance of cytotoxic molecule expression in nodal peripheral T-cell lymphoma, unspecified. Am J Surg Pathol. 2005;29:1284-1293.
    • Savage KJ Blood Rev. Peripheral T-cell lymphomas. 2007 Jul;21(4):201-16.
    • Warnke RA, Jones D, Hsi ED. Morphologic and immunophenotypic variants of nodal T-cell lymphomas and T-cell lymphoma mimics. Am J Clin Pathol. 2007 Apr;127(4):511-27.
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