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    Primary Systemic Anaplastic Large Cell Lymphoma

    Definition

    • Systemic CD30+ T cell lymphoma usually composed of cohesive large cells witih abundant cytoplasm and pleomorphic nuclei; half or more express anaplastic lymphoma kinase (ALK1)

    Alternate/Historical Names

    • Anaplastic large cell lymphoma (T/null cell type)
    • Ki-1 lymphoma (included some cases of diffuse large B cell lymphoma)

    Diagnostic Criteria

    • Cohesive large cells with abundant cytoplasm and pleomorphic nuclei
      • Hallmark cells (“horseshoe cells”)
        • Characteristic large cells with U-shaped or C-shaped nuclei surrounding a brightly eosinophilic Golgi area
        • Most frequent in the common variant
        • Scattered hallmark cells usually also found in small cell, lymphohistiocytic and other variants
      • Cohesive growth pattern
        • Intrasinusoidal growth in lymph nodes (if lymph node is not effaced)
      • Numerous histological variants have been described, and may coexist
        • Common variant
          • large anaplastic cells with abundant eosinophilic cytoplasm and pleomorphic nuclei
        • Small cell variant
          • Smaller cells with less irregular nuclei than common variant
          • Hallmark cells in perivascular location
        • Lymphohistiocytic variant
          • Predominance of histiocytes
          • Hallmark cells in perivascular location
        • Less common subtypes: neutrophil-rich, giant cell rich, signet ring, sarcomatoid, Hodgkin-like with nodular sclerosis
    • T cell or “null cell” immunophenotype
      • Lack of B cell or classical Hodgkin immunophenotype
    • ALK1 immunopositivity/ALK1 translocation is definitional in this setting, but is absent in up to 40% of cases
    • May involve multiple lymph node and soft tissue sites, including skin, but must not be limited to the skin
      • See primary cutaneous anaplastic large cell lymphoma

      Dita Gratzinger MD PhD
      Yasodha Natkunam MD PhD

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

      Initial posting : September 29, 2007

    Supplemental studies

    Immunohistochemistry and flow cytometry

    • Non-lineage specific markers
      • ALK1
        • 60-85% of cases overall
        • 91% of pediatric cases positive
      • CD30 >95%
        • In small cell and lymphohistiocytic variants, strongest CD30 staining is present in larger cells in perivascular location
      • EMA >95%
        • Keratin reported in some older studies
      • clusterin > 90%
      • CD45 >90%
      • CD56 (NCAM) 15%
    • T lineage-associated markers
      • T cell antigen loss is common, but most cases express at least one
        • Rare cases with “null-cell” phenotype by immunohistochemistry
      • CD43, CD45RO commonly positive (~2/3 positive)
        • CD43 is also expressed in monocytes, acute myeloid leukemia, and some B cell lymphomas
      • CD2, CD4, LAT sometimes positive (40-50%)
        • LAT is also expressed in megakaryocytes, mast cells
      • CD3, CD5, CD7, CD8 commonly negative (<25% positive)
    • Cytotoxic proteins
      • TIA-1, granzyme B, or perforin (80-90% positive)
        • > 90%  positive for one or more

    Genetic analysis

    • Gene translocation involving ALK is definitional if present and correlates with ALK1 expression pattern by immunohistochemistry
      • t(2;5) translocation (ALK-nucleophosmin)
        • most common (70-80 %)
        • cytoplasmic and nuclear ALK1 by immunohistochemistry
      • t(1;2) translocation (tropomyosin3-ALK)
        • 10-20%
        • cytoplasmic ALK1 by immunohistochemistry
      • a variety of other less common translocations involving ALK predominantly show cytoplasmic ALK1 by immunohistochemistry
    • Most cases show T cell receptor gene rearrangements (but are negative for immunoglobulin gene rearrangements)
      • May be useful in cases with a “null-cell” phenotype by immunohistochemistry

    Differential Diagnosis

    Primary Systemic Anaplastic Large Cell Lymphoma Carcinoma
    Usually CD45+ and/or CD45RO+ CD45 and CD45RO negative
    ALK positive 60-85% ALK negative
    Usually T cell antigen positive T cell antigen negative
    ALCL may be EMA and infrequently keratin positive (mostly older reports)

    Primary Systemic Anaplastic Large Cell Lymphoma Anaplastic Variant Large B Cell Lymphoma ALK Positive Large B Cell Lymphoma
    Marked anaplasia Marked anaplasia Monomorphic with round nuclei
    Frequently sinusoidal Frequently sinusoidal Frequently sinusoidal
    CD30 >90% CD30 variable CD30 negative
    EMA 60% EMA 33% EMA positive
    T lineage B lineage B lineage
    ALK immunohistology 60-85% positive ALK immunohistology negative ALK immunohistology 100% positive
    Majority of ALK positive cases show ALK translocation such as t(2;5) or t(1:2) Lack ALK translocation Rare cases reported with clathrin-ALK t(2:17) gene rearrangement
    ALCL may lack T markers and require genetic analysis to determine lineage

    Primary Systemic ALCL Classical Hodgkin Lymphoma
    PAX5 negative Usually PAX5 positive
    Rarely CD15 positive Usually CD15 positive
    Usually clusterin positive Rarely clusterin positive
    Usually positive for T cell antigens Rarely positive for T cell antigens
    Usually T cell receptor gene rearrangement positive Usually T cell receptor gene rearrangement negative
    Hallmark cells usually present Reed Sternberg cells usually present
    Lacks conspicuously large nucleoli Very large nucleoli

     

    Both share anaplastic cytology, T lineage and CD30 reactivity
    Primary Systemic ALCL Primary Cutaneous ALCL
    Most under age 30 Adult, rare in children
    Primary nodal involvement Primary cutaneous involvement
    ALK+ 60-85% of cases ALK negative to rare
    EMA+ 60% of cases EMA negative to rare
    Majority of ALK positive cases show ALK translocation such as t(2;5) or t(1;2) Usually negative for t(2;5) and t(1;2)
  • Secondary nodal involvement may be seen in primary cutaneous cases in the presence of widespread cutaneous disease
  • Secondary cutaneous involvement may be seen in primary systemic cases

    • Clinical

    • Commonly presents with widespread systemic involvement
      • lymph nodes
      • extranodal sites
        • especially skin, bone, soft tissues
        • rarely gastrointestinal tract, CNS
      • bone marrow
        • immunohistochemistry for CD30, EMA or ALK1 may be required to recognize minimal involvement
    • ALK1 positive cases:
      • Predominance of children and young adults, male > female
      • Better prognosis than ALK1 negative cases
    • ALK1 negative cases:
      • Older adults
      • Poorer prognosis than ALK1 positive cases (similar to other peripheral T-cell lymphoma, NOS)

    Grading / Staging / Report

    Grading not applicable

    • Originally considered a high grade lymphoma, but responds well to therapy

    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
      • Results of ALK1 staining are clinically important
    • 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 R . 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 eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001.
    • d'Amore ES, Menin A, Bonoldi E, Bevilacqua P, Cazzavillan S, Donofrio V, Gambini C, Forni M, Gentile A, Magro G, Boldrini R, Pillon M, Rosolen A, Alaggio R. Anaplastic large cell lymphomas: a study of 75 pediatric patients. Pediatr Dev Pathol. 2007 May-Jun;10(3):181-91. 
    • Benharroch D, Meguerian-Bedoyan Z, Lamant L, et al. ALK-positive lymphoma: a single disease with a broad spectrum of morphology. Blood. 1998;91:2076–2084
    • Kesler MV, Paranjape GS, Asplund SL, McKenna RW, Jamal S, Kroft SH. Anaplastic large cell lymphoma: a flow cytometric analysis of 29 cases. Am J Clin Pathol. 2007 Aug;128(2):314-22.
    • Medeiros LJ and KSJ Elenitoba-Johnson.  Anaplastic Large Cell Lymphoma. Am J Clin Pathol 2007;127:707-722
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