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

Abstract

A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.

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 al and Swerdlow et al. 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 al 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.