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The 2016 revision of the World Health Organization classification of lymphoid neoplasms

Steven H. Swerdlow, Elias Campo, Stefano A. Pileri, Nancy Lee Harris, Harald Stein, Reiner Siebert, Ranjana Advani, Michele Ghielmini, Gilles A. Salles, Andrew D. Zelenetz and Elaine S. Jaffe

Data supplements

Article Figures & Data

Figures

  • Figure 1

    New provisional B-cell lymphoma entities. (A-D) LBCL with IRF4 rearrangement. (A) Note the very large abnormal-appearing follicles in the central portion of this tonsil. (B) The neoplastic follicles have numerous transformed cells that are (C) IRF4/MUM-1+ and (D) BCL6+. (E-H) Burkitt-like lymphoma with 11q aberration. (E) The touch imprint demonstrates a monotonous population of transformed cells with basophilic cytoplasm that are (F) CD20+, (G) have a very high MIB1/Ki-67 proliferation fraction, and are (H) BCL6+. (A-B) Hematoxylin and eosin stain; (C,D-H) immunoperoxidase stains as specified; (E) Romanowsky-type stain.

  • Figure 2

    Proposed model of molecular pathogenesis in the development and progression of major subtypes of MCL. Precursor B cells usually with but sometimes without a CCND1 rearrangement mature to abnormal naïve B cells which may initially colonize, often the inner portion of the mantle zones, representing ISMCN. These cells already have additional molecular genetic abnormalities, such as inactivating ATM mutations. They may progress to classical MCL which most frequently is SOX11+, has no evidence of transit through the germinal center, and is genetically unstable acquiring additional abnormalities related to cell cycle dysregulation, the DNA damage response pathway, cell survival, and other pathways. Ultimately, progression to blastoid or pleomorphic MCL may occur. A smaller proportion of neoplastic mantle cells may undergo somatic hypermutation, presumably in germinal centers, leading to SOX11 MCL that are more genetically stable for long periods of time and which preferentially involve the PB, bone marrow (BM), and sometimes the spleen. Even these MCL, however, may undergo additional molecular/cytogenetic abnormalities, particularly TP53 abnormalities, leading to clinical and sometime morphological progression. Adapted from Jares et al31 and Swerdlow et al.2 Professional illustration by Patrick Lane, ScEYEnce Studios.

  • Figure 3

    NOTCH1 mutation detected by NGS and Sanger sequencing. (A) NOTCH1 p.P2514fs*4 (NP_060087.3) (c.7541-7542delCT, NM_017617.3) mutation detected by NGS (MiSeq, Illumina) as visualized in the Integrative Genomics Viewer (IGV, www.broadinstitute.org/igv, human reference genome GRCh37/hg19) (left, mutated case) and the same region of a NOTCH1 unmutated sample (right, unmutated case). In each case, the nucleotide coverage as well as a few representative NGS reads are shown. A deletion of AG (CT if considering the reverse strand) is observed in the mutated case. By NGS, each read is represented by a gray horizontal bar and the deletion is represented as a black line within those reads carrying the mutation. A decrease in 50% of the coverage can be observed for the 2 nucleotides affected showing that the mutation is present in half of the reads. (B) Sanger sequencing results are shown under the reference nucleotide and amino acid sequences.

  • Figure 4

    Diagnostic approach to HBCLs. Lymphomas that potentially fall into the HGBL categories can morphologically resemble B-lymphoblastic leukemia/lymphoma (B-LBL), BL, and DLBCL as well as lymphomas that are intermediate between DLBCL and BL (DLBCL/BL). These distinctions can be very subjective. The orange arrows indicate cases with a BL phenotype and a MYC rearrangement without BCL2 or BCL6 rearrangements (“single hit”). The red arrows indicate cases with MYC and BCL2 and/or BCL6 rearrangements (“double or triple hit”). Neither MCLs, subtypes of LBCLs, nor Burkitt-like lymphoma with 11q aberration are indicated in this diagram. Adapted from Kluin et al89 with permission. Professional illustration by Patrick Lane, ScEYEnce Studios.

  • Figure 5

    Cytologic spectrum of HGBL, with MYC and BCL2 and/or BCL6 rearrangements. (A-B) This HGBL with MYC and BCL6 rearrangements closely resembles a BL including a starry sky with tingible body macrophages and many intermediate-sized transformed cells although there are some subtle cytologic differences from a classic BL. (C) This HGBL with MYC, BCL2, and BCL6 rearrangements appears more blastoid but was TdT. (D) This HGBL with MYC and BCL2 rearrangements would otherwise have been considered a DLBCL that included many immunoblastic-type cells with single prominent central nucleoli. (A-D) Hematoxylin and eosin stain.

  • Figure 6

    TCLs. (A) ALK ALCL with DUSP22 rearrangement. There is a relatively monotonous proliferation of large transformed cells and classic “Hallmark” cells. (B) Breast implant–associated ALCL. The seroma cavity demonstrates numerous very large anaplastic-appearing lymphoid cells. (C-D) Primary cutaneous acral CD8+ TCL. (C) Nodule on the ear. (D) There is a diffuse monotonous infiltrate of CD8+ T cells. (E) EATL. The somewhat pleomorphic intestinal infiltrate extends into the epithelium and would be associated with enteropathic changes elsewhere in the intestine. (F) MEITL. The monotonous intestinal infiltrate is very epitheliotropic. (G-H) Primary cutaneous CD4+ small/medium T-cell LPD. (G) Small nodule on scalp. (H) Although the infiltrate is dense and lymphoma-like, this is now to be considered a lymphoproliferative disorder rather than a “lymphoma.” (A,E,F,H) Hematoxylin and eosin stain; (B) Romanowsky-type stain; (D) CD8 immunoperoxidase stain.

Tables

  • Table 1

    2016 WHO classification of mature lymphoid, histiocytic, and dendritic neoplasms

    Mature B-cell neoplasms
     Chronic lymphocytic leukemia/small lymphocytic lymphoma
     Monoclonal B-cell lymphocytosis*
     B-cell prolymphocytic leukemia
     Splenic marginal zone lymphoma
     Hairy cell leukemia
    Splenic B-cell lymphoma/leukemia, unclassifiable
      Splenic diffuse red pulp small B-cell lymphoma
      Hairy cell leukemia-variant
     Lymphoplasmacytic lymphoma
      Waldenström macroglobulinemia
     Monoclonal gammopathy of undetermined significance (MGUS), IgM*
     μ heavy-chain disease
     γ heavy-chain disease
     α heavy-chain disease
     Monoclonal gammopathy of undetermined significance (MGUS), IgG/A*
     Plasma cell myeloma
     Solitary plasmacytoma of bone
     Extraosseous plasmacytoma
     Monoclonal immunoglobulin deposition diseases*
     Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
     Nodal marginal zone lymphoma
      Pediatric nodal marginal zone lymphoma
     Follicular lymphoma
      In situ follicular neoplasia*
      Duodenal-type follicular lymphoma*
     Pediatric-type follicular lymphoma*
    Large B-cell lymphoma with IRF4 rearrangement*
     Primary cutaneous follicle center lymphoma
     Mantle cell lymphoma
      In situ mantle cell neoplasia*
     Diffuse large B-cell lymphoma (DLBCL), NOS
      Germinal center B-cell type*
      Activated B-cell type*
     T-cell/histiocyte-rich large B-cell lymphoma
     Primary DLBCL of the central nervous system (CNS)
     Primary cutaneous DLBCL, leg type
     EBV+ DLBCL, NOS*
    EBV+ mucocutaneous ulcer*
     DLBCL associated with chronic inflammation
     Lymphomatoid granulomatosis
     Primary mediastinal (thymic) large B-cell lymphoma
     Intravascular large B-cell lymphoma
     ALK+ large B-cell lymphoma
     Plasmablastic lymphoma
     Primary effusion lymphoma
    HHV8+ DLBCL, NOS*
     Burkitt lymphoma
    Burkitt-like lymphoma with 11q aberration*
     High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements*
     High-grade B-cell lymphoma, NOS*
     B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
    Mature T and NK neoplasms
     T-cell prolymphocytic leukemia
     T-cell large granular lymphocytic leukemia
    Chronic lymphoproliferative disorder of NK cells
     Aggressive NK-cell leukemia
     Systemic EBV+ T-cell lymphoma of childhood*
     Hydroa vacciniforme–like lymphoproliferative disorder*
     Adult T-cell leukemia/lymphoma
     Extranodal NK-/T-cell lymphoma, nasal type
     Enteropathy-associated T-cell lymphoma
     Monomorphic epitheliotropic intestinal T-cell lymphoma*
    Indolent T-cell lymphoproliferative disorder of the GI tract*
     Hepatosplenic T-cell lymphoma
     Subcutaneous panniculitis-like T-cell lymphoma
     Mycosis fungoides
     Sézary syndrome
     Primary cutaneous CD30+ T-cell lymphoproliferative disorders
      Lymphomatoid papulosis
      Primary cutaneous anaplastic large cell lymphoma
     Primary cutaneous γδ T-cell lymphoma
    Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
    Primary cutaneous acral CD8+ T-cell lymphoma*
    Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder*
     Peripheral T-cell lymphoma, NOS
     Angioimmunoblastic T-cell lymphoma
    Follicular T-cell lymphoma*
    Nodal peripheral T-cell lymphoma with TFH phenotype*
     Anaplastic large-cell lymphoma, ALK+
     Anaplastic large-cell lymphoma, ALK*
    Breast implant–associated anaplastic large-cell lymphoma*
    Hodgkin lymphoma
     Nodular lymphocyte predominant Hodgkin lymphoma
     Classical Hodgkin lymphoma
      Nodular sclerosis classical Hodgkin lymphoma
      Lymphocyte-rich classical Hodgkin lymphoma
      Mixed cellularity classical Hodgkin lymphoma
      Lymphocyte-depleted classical Hodgkin lymphoma
    Posttransplant lymphoproliferative disorders (PTLD)
     Plasmacytic hyperplasia PTLD
     Infectious mononucleosis PTLD
     Florid follicular hyperplasia PTLD*
     Polymorphic PTLD
     Monomorphic PTLD (B- and T-/NK-cell types)
     Classical Hodgkin lymphoma PTLD
    Histiocytic and dendritic cell neoplasms
     Histiocytic sarcoma
     Langerhans cell histiocytosis
     Langerhans cell sarcoma
     Indeterminate dendritic cell tumor
     Interdigitating dendritic cell sarcoma
     Follicular dendritic cell sarcoma
     Fibroblastic reticular cell tumor
     Disseminated juvenile xanthogranuloma
     Erdheim-Chester disease*
    • Provisional entities are listed in italics.

    • * Changes from the 2008 classification.

  • Table 2

    Highlights of changes in 2016 WHO classification of lymphoid, histiocytic, and dendritic neoplasms

    Entity/categoryChange
    CLL/SLL• Cytopenias or disease-related symptoms are now insufficient to make a diagnosis of CLL with <5 × 109/L PB CLL cells.
    • Large/confluent and/or highly proliferative proliferation centers are adverse prognostic indicators.
    • Mutations of potential clinical relevance, such as TP53, NOTCH1, SF3B1, ATM, and BIRC3, have been recognized.
    Monoclonal B-cell lymphocytosis• Must distinguish low-count from high-count MBL.
    • A lymph node equivalent of MBL exists.
    Hairy cell leukemiaBRAF V600E mutations in vast majority of cases with MAP2K1 mutations in most cases that use IGHV4-34 and lack BRAF mutation.
    Lymphoplasmacytic lymphoma (LPL)MYD88 L265P mutation in vast majority of cases impacting diagnostic criteria even though finding is not specific for LPL.
    • IgM MGUS is more closely related to LPL and other B-cell lymphomas than to myeloma.
    Follicular lymphoma (FL)• Mutational landscape better understood but clinical impact remains to be determined.
    In situ follicular neoplasia• New name for in situ follicular lymphoma reflects low risk of progression to lymphoma.
    Pediatric-type FL• A localized clonal proliferation with excellent prognosis; conservative therapeutic approach may be sufficient.
    • Occurs in children and young adults, rarely in older individuals.
    Large B-cell lymphoma with IRF4 rearrangement• New provisional entity to distinguish from pediatric-type FL and other DLBCL.
    • Localized disease, often involves cervical lymph nodes or Waldeyer ring.
    Duodenal-type FL• Localized process with low risk for dissemination.
    Predominantly diffuse FL with 1p36 deletion• Accounts for some cases of diffuse FL, lacks BCL2 rearrangement; presents as localized mass, often inguinal.
    Mantle cell lymphoma (MCL)• Two MCL subtypes recognized with different clinicopathological manifestations and molecular pathogenetic pathways: one largely with unmutated/minimally mutated IGHV and mostly SOX11+ and the other largely with mutated IGHV and mostly SOX11 (indolent leukemic nonnodal MCL with PB, bone marrow (BM), ±splenic involvement, may become more aggressive).
    • Mutations of potential clinical importance, such as TP53, NOTCH 1/2, recognized in small proportion of cases.
    CCND2 rearrangements in approximately half of cyclin D1 MCL.
    In situ mantle cell neoplasia• New name for in situ MCL, reflecting low clinical risk.
    Diffuse large B-cell lymphoma, NOS• Distinction of GCB vs ABC/non-GC type required with use of immunohistochemical algorithm acceptable, may affect therapy.
    • Coexpression of MYC and BCL2 considered new prognostic marker (double-expressor lymphoma).
    • Mutational landscape better understood but clinical impact remains to be determined.
    EBV+ DLBCL, NOS• This term replaces EBV+ DLBCL of the elderly because it may occur in younger patients.
    • Does not include EBV+ B-cell lymphomas that can be given a more specific diagnosis.
    EBV+ mucocutaneous ulcer• Newly recognized entity associated with iatrogenic immunosuppression or age-related immunosenescence.
    Burkitt lymphomaTCF3 or ID3 mutations in up to ∼70% of cases.
    Burkitt-like lymphoma with 11q aberration• New provisional entity that closely resembles Burkitt lymphoma but lacks MYC rearrangement and has some other distinctive features.
    High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations• New category for all “double-/triple-hit” lymphomas other than FL or lymphoblastic lymphomas.
    High-grade B-cell lymphoma, NOS• Together with the new category for the “double-/triple-hit” lymphomas, replaces the 2008 category of B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU).
    • Includes blastoid-appearing large B-cell lymphomas and cases lacking MYC and BCL2 or BCL6 translocations that would formerly have been called BCLU.
    T-cell large granular lymphocyte leukemia• New subtypes recognized with clinicopathologic associations.
    STAT3 and STAT5B mutations in a subset, latter associated with more clinically aggressive disease.
    Systemic EBV+ T-cell lymphoma of childhood• Name changed from lymphoproliferative disorder to lymphoma due to its fulminant clinical course and desire to clearly distinguish it from chronic active EBV infection.
    Hydroa vacciniforme–like lymphoproliferative disorder• Name changed from lymphoma to lymphoproliferative disorder due to its relationship with chronic active EBV infection and a spectrum in terms of its clinical course.
    Enteropathy-associated T-cell lymphoma (EATL)• Diagnosis only to be used for cases formerly known as type I EATL, typically associated with celiac disease.
    Monomorphic epitheliotropic intestinal T-cell lymphoma• Formerly type II EATL; segregated from type I EATL and given a new name due to its distinctive nature and lack of association with celiac disease.
    Indolent T-cell lymphoproliferative disorder of the GI tract• New indolent provisional entity with superficial monoclonal intestinal T-cell infiltrate, some cases show progression.
    Lymphomatoid papulosis• New subtypes described with similar clinical behavior but atypical histologic/immunophenotypic features.
    Primary cutaneous γ δ T-cell lymphoma• Important to exclude other cutaneous T-cell lymphomas/lymphoproliferative disorders that may also be derived from γ δ T cells such as mycosis fungoides or lymphomatoid papulosis.
    Primary cutaneous acral CD8+ T-cell lymphoma• New indolent provisional entity, originally described as originating in the ear.
    Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder• No longer to be diagnosed as an overt lymphoma due to limited clinical risk, localized disease, and similarity to clonal drug reactions.
    • Remains a provisional entity.
    Peripheral T-cell lymphoma (PTCL), NOS• Subsets based on phenotype and molecular abnormalities being recognized that may have clinical implications but are mostly not a part of routine practice at this time.
    Nodal T-cell lymphomas with T-follicular helper (TFH) phenotype• An umbrella category created to highlight the spectrum of nodal lymphomas with a TFH phenotype including angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, and other nodal PTCL with a TFH phenotype (specific diagnoses to be used due to clinicopathologic differences).
    • Overlapping recurrent molecular/cytogenetic abnormalities recognized that potentially could impact therapy.
    ALK anaplastic large-cell lymphoma• Now a definite entity that includes cytogenetic subsets that appear to have prognostic implications (eg, 6p25 rearrangments at IRF4/DUSP22 locus).
    Breast implant–associated anaplastic large cell lymphoma• New provisional entity distinguished from other ALK ALCL; noninvasive disease associated with excellent outcome.
    Nodular lymphocyte–predominant Hodgkin lymphoma• Variant growth patterns, if present, should be noted in diagnostic report, due to their clinicopathologic associations.
    • Cases associated with synchronous or subsequent sites that are indistinguishable from T-cell histiocyte-rich large B-cell lymphoma (THRLBCL) without a nodular component should be designated THRLBCL-like transformation.
    Lymphocyte-rich classical Hodgkin lymphoma• Features recognized that are intermediate between NLPHL and other types of classical Hodgkin lymphoma.
    Erdheim-Chester disease• Should be distinguished from other members of the juvenile xanthogranuloma family; often associated with BRAF mutations.
    Other histiocytic/dendritic neoplasms• Clonal relationship to lymphoid neoplasms recognized in some cases.