- The 2016 revision to the WHO classification of lymphoid malignancies has elucidated many previously uncertain areas, introduced new distinct and provisional entities, and advanced our understanding about the molecular pathways that contribute to lymphomagenesis.
- The BCLU category has been eliminated, and all large B-cell lymphomas with MYC and BCL2 and/or BCL6 gene rearrangements are identified as a distinct entity. The terms double-hit DLBCL and triple-hit DLBCLs are abolished.
- Large B-cell lymphoma with IRF4 rearrangement is introduced as a new provisional entity in the 2016 classification.
- Pediatric-type follicular lymphoma is an independent entity in the 2016
The 2008 World Health Organization (WHO) classification established accepted nomenclature and provided diagnostic criteria for the various lymphoid malignancies. Advances in genomics have further characterized the mutational landscape, and clinical discoveries have shed light on the natural history of several entities. These advances have culminated in the initiation of new distinct entities, modification and renaming of some former entities, and creation of new provisional entities. These efforts are presented in the 2016 WHO revision of lymphoid neoplasms. In this review, we highlight these changes to emphasize the clinical implications.
Mature B-Cell Neoplasms
Chronic lymphocytic leukemia/small lymphocytic lymphoma and monoclonal B-cell lymphocytosis
Monoclonal B-cell lymphocytosis: distinct entity
The 2008 monograph defined monoclonal B-cell lymphocytosis (MBL) as the presence of a clonal B-cell population in the peripheral blood with less than 5 × 109/L B cells and no other signs of a lymphoproliferative disorder.1 In the 2016 revision, MBL is an independent entity, which is known to almost always precede all occurrences of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL). The new revision also emphasizes the differences between low- and high-count MBL as follows2:
- Low-count MBL: B-cell count less than 0.5 × 109/L, rare progression to CLL, and no need for regular follow-up visits.
- High-count MBL: B-cell count between 0.5 × 109/L and 5 × 109/L and similar molecular and immunophenotypic features as Rai stage 0 CLL. This subtype requires annual monitoring. Immunoglobulin heavy-chain variable region (IGHV)–mutated occurrences are observed more frequently in MBL than in CLL.
The new revision also introduces the concept of tissue-based MBL of CLL type with a significantly slow rate of progression. The findings of a retrospective study by Gibson et al.3 suggest that biopsies that contain CLL-type cells, which lack proliferation centers, in the presence of non-enlarged or slightly enlarged lymph nodes on imaging (< 1.5 cm) represent an indolent disease that may best be considered a tissue equivalent of MBL rather than overt SLL.2,3
In situ follicular neoplasia: subcategory of follicular lymphoma, renamed
Follicular lymphoma in situ has been renamed in situ follicular neoplasia (IFNP) to further accentuate the slow-growing nature of this entity. IFNP has a low rate of progression, is often associated with a prior or synchronous overt lymphoma, and has fewer chromosomal abnormalities than focal and overt follicular lymphomas (FLs).2
Duodenal follicular lymphoma: subcategory of follicular lymphoma
Gastrointestinal tract FL was considered a variant of FL in the 2008 WHO classification.1 The 2016 monograph highlights the unique features of duodenal FL. Duodenal FL features overlap between in situ follicular neoplasia (ISFN) and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. This subcategory of FL has an excellent prognosis, and the disease can be managed expectantly.2
Pediatric-type follicular lymphoma: distinct entity
Pediatric-type FL will become an independent entity in the 2016 classification. This new entity is a nodal disease characterized by highly proliferative follicles, often with blastoid follicular center cells, rather than classic centroblasts. Occurrences with diffuse areas should be excluded from this category. This entity is diagnosed only in the absence of BCL2 gene rearrangement. Nearly all cases are localized and may not require treatment other than excision.2
Large B-cell lymphoma with IRF4 rearrangement: provisional entity
Large B-cell lymphoma (LBCL) with IRF4 rearrangement is introduced as a new provisional entity in the 2016 classification.2 LBCL with IRF4 rearrangement is more common in children and tends to occur in the Waldeyer ring and in cervical lymph nodes. This disease can have a follicular, combined follicular and diffuse, or diffuse growth pattern similar to that of FL grade 3B or diffuse large B-cell lymphoma (DLBCL). Most of these occurrences have IG/IRF4 gene rearrangement but almost always lack BCL2 gene rearrangement. By immunohistochemical staining, these occurrences have strong IRF4/MUM1 expression that usually co-express BCL6, BCL2, CD10, and in a small number of cases, CD5. This lymphoma tends to be more aggressive than pediatric-type FL but has excellent outcomes with treatment.2
Mantle cell lymphoma
Two distinct types of mantle cell lymphoma (MCL) have been described1:
Classic MCL, composed of IGHV-unmutated or minimally mutated B cells that usually express SOX11 and involves lymph nodes and other extranodal sites; and
Leukemic nonnodal MCL, composed of IGHV-mutated B cells without SOX11 expression with involvement of peripheral blood, bone marrow, and the spleen.
In situ mantle cell neoplasia: subcategory of mantle cell lymphoma, renamed
In situ MCL is now renamed in situ mantle cell neoplasia (ISMCN). ISMCN is mostly an incidental diagnosis characterized by the presence of cyclin D1–positive cells in the inner mantle zones of follicles. ISMCN is far less common than ISFN, but the two share a slow rate of progression.2
In the new revision, heavy-chain disease has been divided into two distinct categories of monoclonal gammopathy of undetermined significance (MGUS): MGUS, IgM and MGUS, IgG/A.
MGUS, IgM: distinct entity
The MYD88 L265P mutation, which now is known to be a disease-defining mutation in lymphoplasmacytic lymphoma (LPL) and Waldenstrom macroglobulinemia, is found in a substantial number of IgM, but not IgG or IgA, MGUS occurrences. In addition, CXCR4 mutations have been reported in 30% of LPL diagnoses and in 20% of MGUS, IgM diagnoses. These findings suggest that MGUS, IgM can be considered more closely related to LPL or other B-cell lymphomas than MGUS, IgG/A.2
MGUS, IgG/A: distinct entity
The lack of MYD88 L265P and CXCR4 mutations in MGUS, IgG/A, which is unlike MGUS, IgM, makes this entity more closely related to plasma cell myeloma.2
Diffuse large B-Cell lymphoma
The 2008 classification, on the basis of gene expression profiling, acknowledged the presence of two subgroups of DLBCL that are distinguished by cell of origin—germinal center B-cell–like and activated B-cell–like groups. Given the lack of availability of gene expression profiling for most clinicians, the Hans algorithm that is based on CD10, BCL6, and IRF4/MUM1 immunohistochemical staining is commonly used in clinical settings.1 Since 2008, our knowledge about these two subgroups has grown. It is now well established that these two subgroups are distinct in their mutational landscape, signaling pathways, and clinical outcomes. The 2016 classification recommends identification of these two subgroups in all new DLBCL diagnoses.2
The other advancement of clinical importance is the identification of double-expressor lymphomas. Dual expression of MYC and BCL2 by immunohistochemistry (without dual gene rearrangement by fluorescent in situ hybridization [FISH]) has been described in 20% to 35% of DLBCL diagnoses. Currently, MYC positivity of 40% or greater and BCL2 positivity of 50% or greater are generally used to make the diagnosis. The majority (60% to 70%) of double-expressor DLBCLs are of activated B-cell origin. Several studies have shown that double-expressor lymphomas have inferior outcomes compared with typical DLBCL, whereas double-expressor outcomes are better than high-grade B-cell lymphomas with rearrangements of MYC and BCL2 and/or BCL6 genes (previously labeled double- and triple-hit lymphomas; see below).2
Epstein-Barr virus–positive DLBCL, not otherwise specified: distinct entity, renamed
The 2008 monograph recognized Epstein-Barr virus (EBV)–positive DLBCL in elderly patients as a provisional entity.1 Since 2008, it has become clear that these tumors also are seen in patients younger than age 50. The substitution of the elderly specification with not otherwise specified encompasses the broader spectrum of EBV-associated DLBCLs.2
EBV-positive mucocutaneous ulcer: provisional entity
In the new revision, EBV-positive mucocutaneous ulcer is separate from EBV-positive DLBCL because of its self-limited, indolent course that responds mostly to conservative management. This provisional entity has been associated with various types of immune suppression.2
High-grade B-cell lymphomas, with and without MYC and BCL2 and/or BCL6 translocations
Previously, so called double-hit or triple-hit DLBCL diagnoses were identified as diseases with typical DLBCL morphology but with rearrangements of the MYC gene plus either BCL2 or BCL6 rearrangement detected by FISH.1 In addition, some occurrences with double-hit or triple-hit genetic findings did not have morphology consistent with DLBCL, and, thus, the 2008 classification introduced a new category called B-cell lymphoma, unclassifiable (BCLU) with features intermediate between DLBCL and Burkitt lymphoma (BL), to bring attention to a subset of aggressive lymphomas that were difficult to categorize as purely DLBCL or BL.1 In the 2016 revision, the category of BCLU has been eliminated, and all large B-cell lymphomas with MYC and BCL2 and/or BCL6 gene rearrangements are identified as a distinct entity: high-grade B-cell lymphoma (HGBL) with rearrangement of MYC and BCL2 and/or BCL6. Hence, the term double-hit (and triple-hit) DLBCL is abolished. Controversy remains about whether all DLBCL diagnoses should be tested for MYC, BCL2, and BCL6 gene rearrangements. It is established that more than 90% of double-hit DLBCL occurrences are of germinal center B-cell origin. Some have suggested that DLBCL occurrences with high-grade morphology, germinal center B-cell phenotype, aggressive clinical presentation (such as central nervous system involvement), and MYC expression of 40% or more should be tested for gene rearrangements. Further studies are required to clarify this area and establish guidelines for clinical practice. Occurrences with morphologic appearance between DLBCL and BL but without MYC, BCL2, and BCL6 rearrangements are classified as another distinct entity: HGBL, not otherwise specified.2
Burkitt-like lymphoma with 11q aberration: provisional entity
One area of controversy about Burkitt lymphoma is the subset of diagnoses that lack MYC rearrangement despite its morphologic features, immunophenotype, and clinical course shared with Burkitt lymphoma. This subset of lymphomas has a chromosome 11q alteration. Although more studies are needed to further characterize this subset of lymphomas, the new classification has listed a new provisional entity for these lymphomas: Burkitt-like lymphoma with 11q aberration.2
Mature T-Cell and Natural Killer Cell Neoplasms
Genomic studies to unravel the mutational landscape of nodal and extranodal T-cell and natural killer cell neoplasms have led to significant changes in the classifications, including introduction of new provisional entities and refinement of the old entities.
EBV-associated T-Cell and natural killer cell lymphomas
In the 2008 monograph, systemic EBV-positive T-cell lymphoproliferative disorder of childhood was listed and was thought to be associated with chronic active EBV infection.1 In the new revision, this category is replaced by two distinct entities: systemic EBV-positive T-cell lymphoma of childhood and hydroa vacciniforme–like lymphoproliferative disorder.2 These two entities are both more common among Asian, Central American, and South American populations.
Systemic EBV-positive T-cell lymphoma of childhood: distinct entity, renamed
The previous term, lymphoproliferative disorder, in the diagnosis of systemic EBV-positive T-cell lymphoproliferative disorder of childhood has been replaced by lymphoma to highlight the fulminant course of the disease.
Hydroa vacciniforme–like lymphoproliferative disorder: distinct entity, renamed
This entity is more associated with chronic EBV infection. It has a broad range of clinical presentations, from indolent and localized to severe systemic involvement that includes hepatosplenomegaly and lymphadenopathy with or without skin manifestations.
Intestinal T-cell lymphomas
In the 2008 classification, enteropathy-associated T-cell lymphoma (EATL) was listed with two identified subgroups: I and II.1 These two subgroups have become two distinct entities in the new revision: EATL and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).2
Enteropathy-associated T-cell lymphoma: distinct entity
This entity is closely related to celiac disease and is mainly seen in people of Northern European descent. These occurrences have a polymorphic composition and are derived mostly from ab T cells.
Monomorphic epitheliotropic intestinal T-cell lymphoma: distinct entity
Previously known as EATL type II, MEITL is now a distinct entity that is not associated with celiac disease and is seen mostly in Asian and Hispanic populations. Unlike EATL, MEITL is monomorphic and usually positive for CD8, CD56, and MATK. Gains in chromosome 8q24 that involve MYC mutation are seen in a high proportion of the occurrences. Most occurrences are derived from gd T cells.
The other update related to intestinal T-cell lymphomas is the addition of a new provisional entity called indolent T-cell proliferative disorder of the gastrointestinal tract. This entity is composed mostly of CD8+ T cells, can be detected in any part of the gastrointestinal tract, and has an indolent course. The ideal disease management is yet to be established.2
Cutaneous T-cell lymphomas
The two major changes in cutaneous T-cell lymphomas are provisional entities.2
Primary cutaneous acral CD8+ T-cell lymphoma: provisional entity
This is a clonal disorder, usually composed of CD8+ T cells, and was first described as affecting the ear. It is almost always localized to one site, and the disease is safely managed conservatively.
Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder: provisional entity, renamed
Primary cutaneous CD4+ small/medium T-cell lymphoma was introduced as a new provisional entity in the 2008 monograph.1 Our current knowledge indicates that these lymphomas have a T–follicular helper (TFH) phenotype. They present as localized disease with an indolent clinical course. In many cases, conservative management suffices. For the aforementioned reasons, the term lymphoma in the 2008 classification has been replaced by lymphoproliferative disorder in the new revision.2
Nodal T-cell lymphomas
Two new provisional entities have been added and unified under the heading of angioimmunoblastic T-cell lymphoma (AITL): follicular T-cell lymphoma (FTCL) and nodal peripheral T-cell lymphoma with TFH phenotype.2 These diseases manifest a TFH phenotype, as evidenced by the presence of at least three TFH-related antigens, including PD1, CD10, BCL6, CXCL13, ICOS, SAP, and CCR5. FTCL differs from AITL in that it lacks hyperplasia of follicular dendritic cells and high endothelial venules; FTCL also differs from AITL because it has a more localized clinical presentation with mild systemic symptoms.2
Anaplastic large cell lymphomas
The 2008 WHO classification recognized both ALK-positive and ALK-negative anaplastic large cell lymphomas (ALCLs).1ALK-negative ALCL was listed as a provisional entity in the 2008 monograph.1 In the new revision, improved criteria to distinguish ALK-negative ALCL and CD30+ peripheral T-cell lymphomas (PTCLs) have made ALK-negative ALCL a distinct entity. Genomic studies have shown that ALK-negative ALCLs have chromosomal rearrangements of DUSP22 or TP63 in 30% and 8% of occurrences, respectively. DUSP22-rearranged occurrences have favorable outcomes similar to ALK-positive ALCLs, whereas other genetic subtypes have dismal outcomes.2
In the recent years, a new ALK-negative ALCL associated with breast implants has been described and introduced as a new provisional entity in the new revision.2 Breast implant–associated anaplastic large cell lymphoma presents as an accumulation of seroma between the implant and the surrounding fibrous capsule. It has been reported with the use of both saline- and silicone-filled implants. Occurrences that are restricted to the seroma fluid are treated by removal of the implant and capsule, whereas chemotherapy and/or radiation may be required in occurrences with capsule invasion.2
In the new revision, the classification of Hodgkin lymphomas has stayed the same as the 2008 classification but has new updates about nodular lymphocyte-predominant Hodgkin lymphomas (NLPHL). NLPHL has variable growth patterns, including areas of diffuse large cells that are rich in T cells. NLPHL may transform to a T-cell histiocyte-rich large B-cell lymphoma (THRLBCL). The new revision recommends that this transformation be labeled THRLBCL-like transformation of NLPHL. The word “like” is used to highlight the unresolved ambiguities about this evolution. NLPHL, once transformed, has a more aggressive behavior and warrants a more intense treatment.2
Histiocytic and Dendritic Cell Neoplasms
The major change in this category is the addition of Erdheim-Chester disease as a distinct entity. Recent studies have suggested differentiation of features among this disease and other members of the juvenile granulomatous family.2
The 2016 revision of the lymphoid malignancies has elucidated many of the previously uncertain areas, introduced new distinct and provisional entities, and advanced our understanding about the molecular pathways that contribute to lymphomagenesis. The new revision should be used as a foundation for a more sophisticated morphologic, biologic, and molecular classification. As new knowledge emerges, more changes are sure to come and should be welcomed as a testament to advances in the field.
About the Authors: Dr. Fakhri is with the Washington University School of Medicine, St. Louis. Dr. Kahl is with the Washington University School of Medicine, St. Louis.