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.

Introduction

The 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid tumors and the associated monograph represent the established guidelines for the diagnosis of malignant lymphomas; however, subsequently there have been major advances with significant clinical and biologic implications.1  A major revision is therefore being published that will be an update of the current fourth edition and not a truly new fifth edition as there are still other volumes pending in the fourth edition of the WHO tumor monograph series. Because it is considered a part of the fourth edition, while some provisional entities will be promoted to definite entities and a small number of new provisional entities added, there will be no new definite entities.

As with the 2001 and 2008 classifications, an all-important Clinical Advisory Committee meeting was held in 2014 to obtain the advice and consent of clinical hematologists/oncologists and other physicians critical to the revision (supplemental Appendix, available on the Blood Web site). Additional editorial meetings and consultations followed leading to the updated classification (Table 1).22 Although there are only limited alterations in the classification compared with 2008, the revised monograph will incorporate a large body of information published over the last 8 years relating to existing entities with some important diagnostic, prognostic, and therapeutic implications. The classification maintains the goals of helping to identify homogeneous groups of well-defined entities and facilitating the recognition of uncommon diseases that require further clarification.3  This manuscript will review the major areas in lymphoid, histiocytic, and dendritic neoplasms where changes from the prior edition are foreseen as well as emphasize conceptual themes (Table 2).

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* 
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/category Change 
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 leukemia BRAF 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 lymphoma TCF3 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. 
Entity/category Change 
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 leukemia BRAF 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 lymphoma TCF3 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. 

Mature B-cell lymphoid neoplasms

An important element that pervades many parts of the new monograph derives from an explosion of new clinical, pathological, and genetic/molecular data concerning the “small B-cell” lymphomas. The concept that there are lymphoid proliferations that we used to diagnose as overt lymphoid neoplasms but which are not considered as such in 2016 will be further emphasized. Among the aggressive B-cell lymphomas, there are major changes that impact how these cases should be evaluated and diagnosed that have important therapeutic implications as well as being of biologic interest.

Chronic lymphocytic leukemia/small lymphocytic lymphoma and monoclonal B-cell lymphocytosis

The 2008 monograph recognized monoclonal B-cell lymphocytosis (MBL) as the presence of monoclonal B-cell populations in the peripheral blood (PB) of up to 5 × 109/L either with the phenotype of chronic lymphocytic leukemia (CLL), atypical CLL, or non-CLL (CD5) B cells in the absence of other lymphomatous features. Found in up to 12% of healthy individuals, in some it may be an extremely small population, but in others associated with a lymphocytosis.4  Whereas in 2008 it was unknown whether MBL was a precursor of CLL, we now know that MBL precedes virtually all cases of CLL/small lymphocytic lymphoma (SLL).5  The updated WHO will retain the current criteria for MBL, but will emphasize that “low-count” MBL, defined as a PB CLL count of <0.5 × 109/L, must be distinguished from “high-count” MBL because low count MBL has significant differences from CLL, an extremely limited, if any, chance of progression, and, until new evidence is provided, does not require routine follow-up outside of standard medical care.6,7  In contrast, high-count MBL requires routine/yearly follow-up, and has very similar phenotypic and genetic/molecular features as Rai stage 0 CLL, although immunoglobulin heavy chain variable region (IGHV)-mutated cases are more frequent in MBL.8  Also impacting our diagnostic criteria, the revision will eliminate the option to diagnose CLL with <5 × 109/L PB CLL cells in the absence of extramedullary disease even if there are cytopenias or disease-related symptoms. Non-CLL type MBL, at least some of which may be closely related to splenic marginal zone lymphoma, is also recognized.9,10 

In addition, although other confirmatory studies are necessary, the concept of tissue-based MBL of CLL type will be discussed as there are a subset of cases with lymph node involvement by “SLL” that also do not seem to have a significant rate of progression. In 1 retrospective study, lymph nodes with CLL/SLL in which proliferation centers were not observed and patients in whom adenopathy was <1.5 cm based on computed tomography scans were the best candidates for tissue-based MBL.11 

Also related to CLL/SLL, there is increasing interest in proliferation centers (PCs) in overt CLL/SLL. We have learned that: PCs can have cyclin D1 expression in up to about 30% of CLL/SLL, they express MYC protein, and, based on 3 of 4 studies, PCs which are large/confluent and/or have a high proliferative fraction are a significant and independent adverse prognostic indicator.12-16 

Follicular lymphoma, in situ follicular neoplasia, pediatric-type follicular lymphoma, and other related lymphomas

Consistent with the growing conservatism in lymphoma diagnosis, in situ follicular lymphoma (FL) will be renamed in situ follicular neoplasia (ISFN) with the criteria remaining those described previously. Much has been learned about these neoplasms, which have a low rate of progression, but are more often associated with prior or synchronous overt lymphomas, thus requiring additional clinical assessment.17,18  They must be distinguished from partial involvement by FL that is more likely to progress.17  Unfortunately, the extent of the in situ lesions, such as the number or proportion of abnormal follicles or the degree of involvement within the abnormal follicles, cannot be used to predict which patients have isolated ISFN or who are least likely to progress to an overt lymphoma.17,18  ISFN does have fewer chromosomal copy-number abnormalities than focal and especially overt FL, although secondary genetic abnormalities are present even in the earliest lesions in addition to BCL2 rearrangements.19,20  At the very lowest end of this spectrum, cells similar to those with t(14;18)(q32;q21) IGH/BCL2 translocation that circulate in many healthy individuals may reside in the germinal centers as nonproliferative centrocytes even in the absence of recognizable ISFN.21  However, higher levels of circulating t(14;18)+ lymphocytes (>10−4 of total cells) indicate a higher risk for FL.22  It is also important to recognize that flow cytometric studies demonstrate populations of B cells with a FL-type phenotype in about half of all lymph nodes with ISFN.18  This is of particular importance in the evaluation of fine-needle aspirations in which architectural features cannot be evaluated.

Pediatric FL will become a definite entity in the 2016 classification but are now known as pediatric-type FL because similar lymphomas may occur in adults.23,24  It is a nodal disease characterized by large expansile highly proliferative follicles that often have prominent blastoid follicular center cells rather than classic centroblasts (or centrocytes).23  Some have reported a moderate number of cases as grade 1-2 of 3. BCL2 rearrangements must not be present, but there may be some BCL2 protein expression. They also lack BCL6 and MYC rearrangements with ongoing investigations of their genetic/molecular landscape.25  Nearly all cases are localized and may not require treatment other than excision. The criteria for pediatric-type FL, however, must be strictly applied to avoid underdiagnosing conventional grade 3 FL, with particular caution required before making this diagnosis in an adult. This category also excludes cases with diffuse areas (ie, foci of diffuse large B-cell lymphoma [DLBCL]). Some studies have raised the possibility that pediatric-type FL might be a “benign clonal proliferation with low malignant potential.”23,24 

Large B-cell lymphoma (LBCL) with IRF4 rearrangement, which also occurs most commonly in children and young adults, will be considered a distinct new provisional entity (Figure 1A-D).23,26  These lymphomas most typically occur in Waldeyer ring and/or cervical lymph nodes and are low stage. They may have a follicular, follicular and diffuse, or pure diffuse growth pattern resembling FL grade 3B or a DLBCL. Strong IRF4/MUM1 expression is seen usually with BCL6 and a high proliferative fraction. BCL2 and CD10 are also expressed in more than half of the cases with a minority CD5+. They are most often of germinal center type, particularly based on gene expression profiling (GEP) studies.26  Most cases have IG/IRF4 rearrangements sometimes together with BCL6 rearrangements but they uniformly lack BCL2 rearrangements. Some cases that also seem to belong in this category lack a demonstrable IRF4 rearrangement but have strong IRF4/MUM1 expression.23  This lymphoma is considered to be more aggressive than other pediatric-type FL but patients, at least when treated, have done very well.26  These cases must be distinguished from the CD10, IRF4/MUM1+ FL which are often associated with DLBCL and occur in older individuals.27 

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 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.

The current monograph recognizes gastrointestinal (GI) tract FL as a variant. The revision will emphasize the distinctive nature specifically of duodenal-type FL, which although having features of a localized overt low-grade FL, is distinct from other GI tract FL, and has many features that overlap with ISFN as well as some features resembling an extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue.19,28,29  These patients appear to have an excellent outcome, including some cases managed with a watch-and-wait strategy.28 

The new monograph will also recognize that although some diffuse-appearing FL may simply reflect a sampling issue, there is a group of distinctive largely diffuse low-grade FL that typically present as large localized inguinal masses, lack BCL2 rearrangements, and have 1p36 deletions.30  It should be noted that the latter is not a specific finding and can be seen in other lymphomas including conventional FL.

Mantle cell lymphoma, leukemic nonnodal mantle cell lymphoma, and in situ mantle cell neoplasia

Mantle cell lymphoma (MCL) classically has been recognized as an aggressive but incurable small B-cell lymphoma that developed in a linear fashion from naïve B cells. Two types of clinically indolent variants are now recognized and reflect, in part, that MCL develops along 2 very different pathways (Figure 2).31  Classical MCL is usually composed of IGHV-unmutated or minimally mutated B cells that usually express SOX11 and typically involves lymph nodes and other extranodal sites. Acquisition of additional molecular/cytogenetic abnormalities can lead to even more aggressive blastoid or pleomorphic MCL. Other MCL develop from IGHV-mutated SOX11 B cells which leads to leukemic nonnodal MCL, usually involving the PB, bone marrow, and often spleen. These cases are frequently clinically indolent; however, secondary abnormalities, often involving TP53, may occur and lead to very aggressive disease. In situ MCL is now to be called in situ mantle cell neoplasia (ISMCN), again emphasizing a more conservative approach for lymphoid neoplasms with a low rate of progression. It is characterized by the presence of cyclin D1+ cells, most typically in the inner mantle zones of follicles, in lymphoid tissues that do not otherwise suggest the diagnosis of a MCL, and is often found incidentally, sometimes in association with other lymphomas.32  They are much less common than ISFN and although they may be disseminated, appear to have a low rate of progression.32  ISMCN should be distinguished from overt MCL with a mantle zone growth pattern. Nevertheless, these latter cases as well as other classical MCL with a low proliferative fraction may also be relatively indolent.

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 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.

Impact of newer molecular/cytogenetic studies related to the small B-cell lymphoid neoplasms

Next-generation sequencing (NGS) studies have led not only to major advances in better understanding the small B-cell lymphoid neoplasms, but also to discoveries of diagnostic importance. Whereas the 2008 monograph reported that “No cytogenetic abnormality is specific for [hairy cell leukemia]”, we now know that BRAF V600E mutations are found in almost all cases of hairy cell leukemia (HCL) but not in HCL-variant (HCL-v) or other small B-cell lymphoid neoplasms.33  More recently, mutations in MAP2K1 which encodes MEK1 (which is downstream of BRAF) have been reported in almost half of HCL-v and in the majority of HCL that use IGHV4-34 and which, like HCL-v, lack BRAF V600E mutations.34 

Similarly, the 2008 monograph noted that “no specific chromosomal or oncogene abnormalities are recognized” in lymphoplasmacytic lymphoma (LPL); however, we now know that about 90% of LPL or Waldenström macroglobulinemia (LPL plus an immunoglobulin M [IgM] paraprotein) have MYD88 L265P mutations.35  This mutation also is found in a significant proportion of IgM but not IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) cases, a small proportion of other small B-cell lymphomas even after careful review, in ∼30% of non–germinal center-type DLBCL, more than half of primary cutaneous DLBCL, leg type, and many DLBCL at immune-privileged sites but not in plasma cell myeloma, even of IgM type.36  Review of cases with and without the mutation have led to revised criteria for LPL, emphasizing the monotony of the lymphoplasmacytic proliferation in cases other than those undergoing transformation, total architectural effacement in some cases, and allowing for significant follicular colonization.37  Although seeming to be more inclusive, these studies also suggest that cases previously described as polymorphic LPL and some LPL-like cases of γ heavy chain disease be excluded from the LPL category.37,38  These studies also have led to IgM MGUS being thought of as more closely related to LPL or other B-cell lymphomas and segregated from the uniformly wild-type MYD88 IgG and IgA MGUS cases that are more closely related to plasma cell myeloma. Consistent with this approach, CXCR4 mutations are found in about 30% of LPL and 20% of IgM MGUS but are not found in IgG or IgA MGUS cases.39-41 

The situation with CLL/SLL is quite different and more complex because although there are no recognized disease-defining mutations, there are a large number of mutations that occur with a relatively low frequency.42-51  In addition to their biological implications, at least some, such as TP53, NOTCH1, SF3B1, and BIRC3, are of clinical interest because of their adverse prognostic implications and with some being potential direct or indirect therapeutic targets (Figure 3). It has been suggested that some of these could be integrated into an updated cytogenetic risk profile that also includes the well-known recurrent chromosomal abnormalities typically identified with fluorescence in situ hybridization studies50,52 ; however, although interest remains in this concept, the literature is inconsistent regarding the clinical implications of some of the mutations and combined risk profile, and it will not be recommended in the revised monograph.49,51 

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 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.

In addition to having many nonrandom secondary chromosomal gains and losses as well as recurrent copy-neutral loss of heterozygosity that often involves the same regions where the losses occur such as TP53, MCL also are characterized by having mutations affecting many different genes with ATM (40%-75%) and CCND1 (35%) the most frequent.53  Other mutations are present in <15% of cases, including some such as NOTCH1 and NOTCH2 that are of prognostic and potential therapeutic importance.53,54  It has also been learned that about half of MCL that lack cyclin D1 expression/CCND1 rearrangements have CCND2 translocations, often with IGK or IGL as a partner locus, a finding that can be of diagnostic utility.55 

Much has also been learned about the mutational landscape in terms of the development and progression in FL. Mutations in chromatin regulator/modifier genes, such as CREBBP and KMT2D (MLL2), are extremely common early events and may be potential therapeutic targets.56-59 EZH2 mutations, present in about 20% to 25% of FL, are another early event and potential therapeutic target.57,58,60  Mutations are present in a large number of other genes, including some seen predominantly with transformation, but in significantly lower proportions of patients. A new prognostic model integrating gene mutations with clinical parameters has been proposed, but, although conceptually interesting, requires validation.58  Whether mutational analysis should be performed routinely for diagnostic, prognostic, or therapeutic purposes and whether it should be integrated with other pathological and clinical prognostic factors remains to be determined.

Diffuse large B-cell lymphoma

Cell-of-origin classification

The 2008 classification recognized germinal center B-cell-like (GCB) and activated B-cell-like (ABC) molecular “subgroups” of DLBCL based on GEP as well as a group of cases that could not be put into either category (unclassifiable). The GCB and ABC subgroups differed in their chromosomal alterations, activation of signaling pathways, and clinical outcome.61  It separately recognized GCB and non-GCB immunohistochemical subgroups based on the Hans algorithm which used antibodies to CD10, BCL6, and IRF4/MUM1 but noted that these groups did not “exactly correlate” with the molecular categories and that these subgroups did not determine therapy. However, because GEP was not available as a routine clinical test, and because there were issues of reproducibility and reliability of immunohistochemical algorithms, subclassification of DLBCL, not otherwise specified (NOS) was considered optional in the 2008 classification. The better understanding of the molecular pathogenesis of these 2 subgroups since 2008, however, has led to the investigation of more specific therapeutic strategies to mitigate the worse outcome among those with ABC/non-GCB type DLBCL reported in most studies; prospective trials are ongoing to determine whether these therapies should be incorporated into clinical practice.62  For this reason, the revised classification will require the identification of these 2 subtypes. With GEP still not a routine clinical test, the use of immunohistochemistry (IHC) algorithms will be considered acceptable. Although the Hans algorithm remains the most popular and has a reasonable correlation with the GEP, other algorithms also may be used. It is acknowledged that the IHC algorithms do not recognize the 10% to 15% of tumors unclassified by GEP, have reproducibility issues, and are not uniformly reported to have prognostic utility. Newer methods based on quantification of RNA transcripts extracted from formalin-fixed paraffin-embedded tissues provide concordant results with conventional microarray GEP, are reproducible between laboratories, and capture the prognostic impact of the cell-of-origin classification.63-66  These methods are still not accessible to most laboratories but may represent a promising alternative to the current IHC-based algorithms.

Other phenotypic and molecular/cytogenetic features of clinical importance

A significant advance in recent years has been the better understanding of MYC alterations in LBCLs.67 MYC is rearranged in 5% to 15% of DLBCL, NOS, and is frequently associated with BCL2 or, to a lesser extent, BCL6 translocation, in the so-called “double-hit” or “triple-hit” lymphomas that are included in the updated WHO classification in the new category of high-grade B-cell lymphoma (HGBL), with rearrangements of MYC and BCL2 and/or BCL6 (see detailed discussion under “High-grade B-cell lymphomas, with and without MYC and BCL2 or BCL6 translocations”).68 

MYC protein expression is detected in a much higher proportion of DLBCL (30%-50%) and is associated with concomitant expression of BCL2 in 20% to 35% of cases.67  Most of these tumors do not carry MYC/BCL2 chromosomal alterations and have been named “double-expressor lymphoma.” Most studies use a cutoff of 40% MYC-expressing cells to define these cases; the cutoff for BCL2 expression has varied considerably in the literature, but a figure of >50% is recommended. In several but not all studies, the double-expressor lymphomas have a worse outcome than other DLBCL, NOS but they are not as aggressive as the HGBL, with rearrangements of MYC and BCL2 and/or BCL6.69,70  These observations have suggested that double expression of MYC and BCL2 proteins without gene aberrations should be considered a prognostic indicator in DLBCL, NOS but not a separate category. CD30 expression in DLBCL, NOS is also of potential interest as it may be a potential target for new antibody-based therapies.

Recent NGS studies have identified common somatic mutations in all subgroups of DLBCL but also a profile of alterations differentially represented in both GCB and ABC subtypes.71  Somatic mutations common in both DLBCL subtypes are inactivating mutations of TP53 and genes involved in immunosurveillance (B2M, CD58), alterations in epigenetic regulators (CREBBP/EP300, KMT2D/C [MLL2/3], MEF2B), and oncogenic activation of BCL6. GCB-DLBCL carry frequent alteration in the histone methyl transferase EZH2, BCL2 translocations, and mutations in the cell motility regulator GNA13, whereas ABC-DLBCL have mutations in genes (MYD88, CD79A, CARD11, TNFAIP3) activating the B-cell receptor/Toll-like receptor and NF-κB pathways. Although the clinical implications of these mutations are not fully understood, there are increasing expectations that they will become important in guiding future targeted therapies.62,72 

EBV+ large B-cell lymphomas and EBV+ mucocutaneous ulcer

The 2008 monograph included “EBV-positive DLBCL of the elderly” as a provisional entity. These tumors occur in apparently immunocompetent patients usually >50 years old and have a worse prognosis than Epstein-Barr virus–negative (EBV) tumors. Epstein-Barr virus–positive (EBV+) DLBCL, however, have been increasingly recognized in younger patients, with a broader morphological spectrum and better survival than initially thought.73-75  This new information has led to substitution of the modifier “elderly” with “not otherwise specified” (EBV+ DLBCL, NOS) in the updated classification. The NOS is to highlight that there are other more specific entities with neoplastic EBV+ large B cells, such as lymphomatoid granulomatosis. In addition, the new category EBV+ mucocutaneous ulcer has been segregated from EBV+ DLBCL as a provisional entity due to its self-limited growth potential and response to conservative management. These lesions may present in advanced age or with iatrogenic immunosuppression.76,77 

Burkitt lymphoma

Recent NGS studies of Burkitt lymphoma (BL) have improved our understanding of the pathogenesis of these tumors. Mutations in the transcription factor TCF3 or its negative regulator ID3 occur in about 70% of sporadic and immunodeficiency-related BL and 40% of endemic cases. TCF3 promotes survival and proliferation in lymphoid cells by activating the B-cell receptor/phosphatidylinositol 3-kinase signaling pathways and modulating the expression of cyclin D3, which is also mutated in 30% of BL.78-81 

One controversial issue not fully resolved is whether true BL without MYC translocations really exist. Some recent studies have identified a subset of lymphomas that resemble BL morphologically, to a large extent phenotypically and by GEP, but which lack MYC rearrangements. Instead, they have a chromosome 11q alteration characterized by proximal gains and telomeric losses.82,83  Compared with BL, these lymphomas have more complex karyotypes, lower levels of MYC expression, a certain degree of cytological pleomorphism, occasionally a follicular pattern, and frequently a nodal presentation. The clinical course seems to be similar to BL, but the number of cases reported is still limited. Although more studies are needed, the consensus for the revised WHO classification was to consider these a new provisional entity designated Burkitt-like lymphoma with 11q aberration (Figure 1E-H).

High-grade B-cell lymphomas, with and without MYC and BCL2 or BCL6 translocations

The 2008 WHO classification introduced the category of “B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL” (BCLU) to recognize a subset of very aggressive tumors in which the distinction between DLBCL and BL was very difficult. Lymphomas with a GEP intermediate between that of molecular BL and molecular non-BL (mostly DLBCL), also lends support to the existence of these intermediate-type cases, which were not, however, considered a specific entity.84,85  Segregation of these cases was also necessary to better define these clinically problematic tumors.3  Additional studies followed that demonstrated that BCLU and other LBCL, with rearrangements of MYC and BCL2 and/or BCL6, had mutational features intermediate between DLBCL and BL. They also better characterized the double-/triple-hit lymphomas, including identifying features that might mitigate the adverse clinical impact of MYC translocations.68,86-88  The criteria for BCLU, however, are vague and the diagnosis has not been used uniformly, limiting its utility as a diagnostic category.68,86,87 

All LBCL with MYC and BCL2 and/or BCL6 rearrangements will be included in a single category to be designated HGBL, with MYC and BCL2 and/or BCL6 rearrangements, except for cases that fulfill the criteria for a follicular or lymphoblastic lymphoma (Figures 4 and 5).89  The morphologic appearance should be noted in a comment. The category of BCLU will be eliminated. Cases that appear blastoid or cases intermediate between DLBCL and BL, but which lack a MYC and BCL2 and/or BCL6 rearrangement, will be placed in the category of HGBL, NOS. A consensus has not yet been reached to provide specific guidelines as to which LBCL should have fluorescence in situ hybridization studies. Some believe that all DLBCL should have genetic studies for the detection of MYC, BCL2, and BCL6 rearrangements, whereas others would limit them, for example, to cases with a GCB phenotype and/or high-grade morphology or to cases with >40% MYC+ cells.

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 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 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.

Mature T- and NK-cell neoplasms

Nodal T-cell lymphomas: angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, and peripheral T-cell lymphoma, not otherwise specified

Significant advances have occurred in the classification of both nodal and extranodal T-cell and natural killer (NK)-cell neoplasms, which have led to revisions in the classification and introduction of new provisional entities. Many of these changes are the result of genomic studies using approaches to examine GEP and the genetic landscape of T-cell and NK-cell neoplasms.

There have been new insights into the complexity of nodal peripheral T-cell lymphoma (PTCL). Genetic studies have shown recurrent mutations that affect a significant proportion of cases of angioimmunoblastic T-cell lymphoma (AITL). Importantly, many of the same genetic changes are observed in cases of PTCL, NOS that manifest a T follicular helper (TFH) phenotype.90-92  For this designation, the neoplastic cells should express at least 2 or 3 TFH-related antigens, including CD279/PD1, CD10, BCL6, CXCL13, ICOS, SAP, and CCR5. This common phenotype has led to follicular T-cell lymphoma (FTCL) and AITL being unified under a common heading. Cases of nodal PTCL with TFH phenotype will be included here as well. Recurrent genetic abnormalities include TET2, IDH2, DNMT3A, RHOA, and CD28 mutations, as well as gene fusions such as ITK-SYK or CTLA4-CD28. All these lesions can take part in the process of lymphomagenesis and may represent the target of tailored therapies (eg, epigenetic modifiers). These cases also share many features by GEP.

Both AITL and FTCL may contain B-cell blasts, often EBV+, in addition to the neoplastic TFH cells. In some cases, the atypical B-cell blasts simulate Hodgkin–Reed-Sternberg cells, leading to a mistaken diagnosis of classical Hodgkin lymphoma (CHL).93,94  Progression to EBV+, and more rarely EBV, B-cell neoplasms may occur in a subset of cases.95  Nevertheless, although the neoplastic cells share a TFH phenotype and share many genetic changes, clinical and pathological differences remain, so that both diagnoses are retained in the classification. FTCL more often presents with localized disease, with fewer systemic symptoms.

The cases remaining in the PTCL, NOS category still show extreme cytological and phenotypic heterogeneity. GEP studies display a global signature close to the one of activated T-lymphocytes. GEP analysis of 372 cryopreserved PTCLs identified at least 3 subtypes characterized by overexpression of GATA3, TBX21, and cytotoxic genes, as well as expression of the corresponding molecules using IHC.96  These subtypes are associated with a different clinical behavior and response to therapy. The GATA3 subtype has an inferior prognosis, shows high levels of Th2 cytokines, and can be identified by IHC.97  Studies using NGS are at an early stage in PTCL, NOS, but have provided new insights, which may lead to further refinement in the classification or new targets for therapy. These studies have identified mutations of epigenetic mediators (KMT2D [MLL2], TET2, KDM6A, ARID1B, DNMT3A, CREBBP, MLL, and ARID2), genes involved in signaling pathways (TNFAIP3, APC, CHD8, ZAP70, NF1, TNFRSF14, TRAF3), and tumor suppressors (TP53, FOXO1, BCORL1, ATM).98 

Anaplastic large-cell lymphomas: ALK+, ALK, and breast implant–associated

GEP studies also have provided insights into the distinction of CD30-expressing T-cell lymphomas (TCLs), and have facilitated the distinction of PTCL with high CD30 expression from ALK anaplastic large-cell lymphoma (ALCL), the latter having a superior prognosis.99,100 ALK+ and ALK ALCL were both recognized in the 2008 classification, although ALK ALCL was considered a provisional entity, as criteria for distinguishing ALK ALCL from CD30+ PTCL were imperfect. Improved criteria now exist for the recognition of ALK ALCL in daily practice, and it is no longer considered provisional.101 

GEP studies have shown that ALK ALCL has a signature quite close to that of ALK+ ALCL and distinct from other NK/TCLs. More recent studies illuminating the genetic landscape of ALK ALCL have shown convergent mutations and kinase fusions that lead to constitutive activation of the JAK/STAT3 pathway.102  These studies provide a genetic rationale for the morphologic and phenotypic similarities between ALK+ and ALK ALCL. However, not all cases of ALK ALCLs are created equal. A subset with rearrangements at the locus containing DUSP22 and IRF4 in chromosome 6p25 tends to be relatively monomorphic, usually lack cytotoxic granules, and have been reported to have a superior prognosis, whereas a small subset with TP63 rearrangements are very aggressive (Figure 6A).103-105  Interestingly, the same locus in 6p25 has also been implicated in lymphomatoid papulosis (LYP) and primary cutaneous ALCL.106,107  LYP is a clinically diverse disorder, and in recent years a number of new pathological and clinical variants have been described. The WHO classification recognizes the original variants, types A, B, and C; as well as the more recently described types D (mimics primary cutaneous aggressive epidermotropic CD8+ cytotoxic TCL),108  E (angioinvasive),109  and LyP with chromosome 6p25 rearrangement,107  as well as some even more rare variants. Appreciation of these variants is important, as histologically they can mimic very aggressive TCLs, but they are clinically similar to other forms of LYP.

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.

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.

A number of studies in recent years have identified a unique form of ALK ALCL arising in association with breast implants designated as breast implant–associated ALCL (Figure 6B).110  First described in 1997, it usually presents as an accumulation of seroma fluid between the implant itself and the surrounding fibrous capsule.111  Both saline- and silicone-filled implants have been implicated, with a median interval from the time of the implant to the lymphoma of about 10 years.112  In most cases, the neoplastic cells are confined to the seroma fluid, without invasion of the capsule. In such cases, conservative management is recommended, with removal of the implant and capsule.113  If there is invasion through the capsule, there is risk of lymph node involvement and systemic spread, warranting systemic chemotherapy.114  The factors leading to progression have not been delineated.

Cytotoxic T-cell lymphomas and leukemias

Mature T-cell and NK-cell lymphomas and leukemias expressing cytotoxic molecules constitute a heterogeneous group of diseases with variations in clinical behavior and prognosis.115  Other than ALCL, most of these neoplasms present with extranodal disease, or are systemic with involvement of liver, spleen, and bone marrow. Since the publication of the 2008 monograph, several entities have received greater recognition, and the revised classification reflects the new data. Besides breast implant–associated ALCL, we have the addition of indolent T-cell lymphoproliferative disorder (LPD) of the GI tract and primary cutaneous acral CD8+ TCL as provisional entities.116,117  Both are clonal disorders, usually composed of CD8+ T cells, with an indolent clinical course. The cutaneous acral lesions, first recognized affecting the ear, are nearly always localized to a single site and can be managed conservatively (Figure 6C-D). Indolent T-cell LPD of the GI tract can be derived from either CD8 or less often CD4+ T cells, affects many sites in the GI tract, but has an indolent clinical course. Their optimal management is not yet determined.

The desire to categorize lymphomas according to the precise cellular origin is attractive, but among the mature TCLs, promiscuity is observed. Some years ago, it was recognized that although hepatosplenic TCL is usually of γδ T-cell derivation, some cases have an αβ phenotype,118  yet are otherwise clinically and genetically similar. Furthermore, among cutaneous TCLs, although γδ TCL are generally aggressive,119,120  γδ variants of mycosis fungoides or other TCLs with an indolent clinical course have been described.121,122 

Recent studies have identified recurrent mutations affecting the JAK/STAT pathway in many T-cell and NK-cell malignancies, further emphasizing the overlapping biology in many of these malignancies.123-126 STAT3 mutations are common in large granular lymphocyte leukemias of both T-cell and NK-cell types.123,124 STAT5B mutations are more uncommon and are associated with more clinically aggressive disease.127  Recurrent mutations of STAT5B and less often STAT3 are seen in hepatosplenic TCL of γδ origin128  and a similar pattern was observed in primary cutaneous TCL.129  Additionally, STAT5B mutations were reported in 36% of cases of what has been known as enteropathy-associated TCL (EATL), type II, all of which were of γδ T-cell origin.129 

These data and others have led to changes in the categorization of intestinal TCLs. It has become apparent that the 2 subtypes of EATL are distinct, and will be more clearly distinguished in the revised WHO classification.130  EATL, type I, now simply designated as enteropathy-associated TCL, is closely linked to celiac disease, and is primarily a disease of individuals of northern European origin. EATL, type II, now formally designated as monomorphic epitheliotropic intestinal TCL (MEITL), shows no association with celiac disease, and appears increased in incidence in Asians, and Hispanic populations (Figure 6E-F). Although EATL generally has a polymorphic cellular composition and wide range in cytology, MEITL is monomorphic, and usually positive for CD8, CD56, and MATK.131  Gains in chromosome 8q24 involving MYC are seen in a high proportion of cases.132  Many cases of MEITL are derived from γδ T cells, but exceptions exist; some cases are T-cell receptor (TCR) silent and some cases express TCR αβ.133  Likewise, most cases of EATL express TCR αβ, but γδ variants exist. As noted in the previous paragraph, mutations in STAT5B were only associated with γδ MEITL, but investigation of classical EATL or αβ cases was limited.

Cutaneous T-cell lymphomas

Primary cutaneous acral CD8+ TCL and primary cutaneous γδ TCL are discussed in the previous section. Primary cutaneous CD4+ small/medium TCL was included as a provisional entity in the 2008 classification (Figure 6G-H). Since then, several clinical series have been reported, further elucidating its cellular origin and clinical behavior. The cells have a TFH phenotype,134  but recurrent mutations as seen in nodal TFH lymphoma have not been reported. The clinical behavior is almost always indolent, with most patients presenting with localized disease. Systemic disease is rare, and conservative local management is sufficient in most patients.135-137  It has been suggested that this may represent a limited clonal response to an unknown stimulus, not fulfilling criteria for malignancy. The terminology in the revised classification has been modified to reflect this uncertain malignant potential, designating these cases as primary cutaneous CD4+ small/medium T-cell LPD.

EBV+ T-cell and NK-cell lymphomas

The most common EBV+ NK-cell lymphoma or TCL is extranodal NK/T-cell lymphoma, nasal type, which usually presents in the upper aerodigestive tract. However, there are less common EBV+ TCLs and leukemias with different clinical presentations and biology. These are delineated in the upcoming revision of the WHO classification, and somewhat modified from the 2008 monograph. EBV-associated T- and NK-cell lymphoproliferative disorders in the pediatric age group include 2 major groups: chronic active EBV infection and systemic EBV+ TCL of childhood.138,139  Both occur with increased frequency in Asians, and in indigenous populations from Central and South America and Mexico. Chronic active EBV infection of T/NK type shows a broad range of clinical manifestations from indolent, localized forms like hydroa vacciniforme–like LPD and severe mosquito bite allergy to a more systemic form characterized by fever, hepatosplenomegaly, and lymphadenopathy with or without cutaneous manifestations.140,141  Systemic EBV+ TCL of childhood, no longer referred to as a “lymphoproliferative disorder,” has a fulminant clinical course usually associated with a hemophagocytic syndrome. The differential diagnosis includes acute EBV-associated hemophagocytic lymphohistiocytosis (HLH), which can present acutely, but in some patients responds well to the HLH 94 protocol, and is not considered neoplastic. Node-based EBV+ PTCL, defined as demonstrating EBV in the majority of the neoplastic cells, are uncommon and included under the broad heading of PTCL, NOS. They are generally monomorphic and lack the angioinvasion and necrosis of extranodal NK/T-cell lymphoma. They most often present in older adults, and also can be seen in the posttransplant setting and other immunodeficiency states.101,142,143 

Hodgkin lymphomas

Although the classification of Hodgkin lymphomas (HLs) has not changed, the revision will include updates concerning nodular lymphocyte–predominant HL (NLPHL). It has long been recognized that NLPHL can have varied growth patterns, including some with diffuse areas and/or numerous T cells.144  Additionally, cases manifesting one of the variant patterns have been reported to be associated with advanced disease and a higher relapse rate, although they still have good survival.144-146  Thus, it is useful to note these features in the diagnostic report.

NLPHL may evolve to a completely diffuse T-cell–rich proliferation lacking any follicular dendritic cells which would be consistent with a T-cell histiocyte-rich LBCL (THRLBCL) or can be associated with such a proliferation at a separate site. Whereas the 2008 monograph said, “It is probably good practice to label cases of NLPHL that progress to a diffuse T-cell–rich pattern as NLPHL, THRLBCL-like…,” the revision will recommend the designation of THRLBCL-like transformation of NLPHL, with inclusion of the word “like” due to some remaining uncertainties. This consensus was based on the conclusion from the Clinical Advisory Committee that transformation of NLPHL to DLBCL should be based on WHO criteria (with THRLBCL being a type of LBCL). Recent data indicate that progression to a process with features of THRLBCL is associated with a more aggressive clinical course, and requires different management, such that the term NLPHL in this setting may not be sufficient.147,148  However, cases with only focal diffuse areas are not considered transformation. It is also of interest that aside from their immunomorphologic appearance, GEP and array comparative genomic hybridization studies have shown similarities between NLPHL and THRLBCL, suggesting a relationship to each other, in spite of other major differences.147,149  The revision will also acknowledge that lymphocyte-rich CHL has some features that are intermediate between other CHL and NLPHL.150 

Histiocytic and dendritic cell neoplasms

The classification of the histiocytic and dendritic cell neoplasm is similar to that from 2008 except that the order of the entities is minimally altered and Erdheim-Chester disease has been added, as it should be distinguished from other members of the juvenile xanthogranuloma family.1,151  Histiocytic and dendritic cell neoplasms are grouped together based on the functional properties of their normal counterpart (ie, phagocytosis and/or processing and presentation of antigens) rather than their cell of origin. Although most arise from a common myeloid precursor, a few are of mesenchymal origin (ie, follicular dendritic cell sarcoma and fibroblastic reticular cell tumor).

During the last few years, several publications highlighted that, irrespective of their myeloid or mesenchymal origin, some of these neoplasms are associated with or preceded by FL, CLL, B- or T-lymphoblastic neoplasms, or PTCL.152-157  These cases carry the same TCR or IGHV rearrangements and chromosomal aberrations as the associated lymphoid neoplasms, suggesting a process of transdifferentiation.152-157  Moreover, the BRAF V600E mutation has been reported in the setting of Langerhans cell histiocytosis, histiocytic sarcoma, disseminated juvenile xanthogranuloma, Erdheim-Chester disease, and even follicular dendritic cell sarcoma.158 

Summary

There have been major advances in our knowledge of the lymphoid neoplasms and how they should best be treated over the last 8 years. We have seen new insights into the biology and management of both clonal proliferations with limited malignant potential, as well as the aggressive lymphoid neoplasms where more targeted and effective therapies are being investigated. The 2016 WHO classification and associated monograph aim to provide updated diagnostic categories and criteria, together with biological and clinical correlates, and facilitate state-of-the-art patient care, future therapeutic advances, and basic research in this field.

The online version of this article contains a data supplement.

Acknowledgments

The Clinical Advisory Committee meeting would not have been possible without the major support from James W. Vardiman, lead organizer, and the staff at the University of Chicago.

S.A.P. was supported in part through the Italian Association for Cancer Research (AIRC, Milan) grant 5x1000 number 10007. A.D.Z. was supported in part through the National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support Grant P30 CA008748. The authors acknowledge the unrestricted financial support of the Clinical Advisory Committee meeting held in Chicago, IL, March 31-April 1, 2014 from the following organizations: American Society of Hematology, Josep Carreras Foundation, Fondazione Italiana Linfomi (FIL), Leukemia Clinical Research Foundation, University of Chicago Comprehensive Cancer Center, Beckman Coulter Corporation, Celgene Corporation, Dako, Genentech Corporation, Incyte Corporation, Leica Corporation, Millennium Pharmaceuticals, Pharmacyclics, Seattle Genetics Corporation, Sysmex Corporation, and Ventana Medical Systems, Inc, a member of the Roche Group.

Authorship

Contribution: All authors contributed to the contents of this manuscript which was written by S.H.S., E.C., S.A.P., and E.S.J. and reviewed and edited by all authors.

Conflict-of-interest disclosure: S.A.P. is member of the Scientific Advisory Board of Takeda/Millennium. M.G. has received honoraria from Roche, Celgene, Janssen, Gilead, Millenium, and Mundipharma. The remaining authors declare no competing financial interests.

The current affiliation for R.S. is Institute of Human Genetics, Ulm University, Ulm, Germany.

Correspondence: Steven H. Swerdlow, Division of Hematopathology, Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop St, Pittsburgh, PA 15213; e-mail: swerdlowsh@upmc.edu; Elias Campo, Department of Pathology, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain; e-mail: ecampo@clinic.cat; and Elaine S. Jaffe, Hematopathology Section, Laboratory of Pathology, CCR, NCI, Building 10, Room 3s235, Bethesda, MD 20892-1500; e-mail: elainejaffe@nih.gov.

References

References
1
Swerdlow
SH
Campo
E
Harris
NL
, et al. 
 
WHO classification of tumours of haematopoietic and lymphoid tissues. In: Bosman FT, Jaffe ES, Lakhani SR, Ohgaki H, eds. World Health Organization Classification of Tumours. Lyon, France: IARC; 2008
2
Swerdlow
SH
, et al. 
WHO classification of tumours of haematopoietic and lymphoid tissues.
 
In: World Health Organization Classification of Tumours. Lyon, France: IARC. In press
3
Campo
E
Swerdlow
SH
Harris
NL
Pileri
S
Stein
H
Jaffe
ES
The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
Blood
2011
, vol. 
117
 
19
(pg. 
5019
-
5032
)
4
Nieto
WG
Almeida
J
Romero
A
, et al. 
Primary Health Care Group of Salamanca for the Study of MBL
Increased frequency (12%) of circulating chronic lymphocytic leukemia-like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach.
Blood
2009
, vol. 
114
 
1
(pg. 
33
-
37
)
5
Landgren
O
Albitar
M
Ma
W
, et al. 
B-cell clones as early markers for chronic lymphocytic leukemia.
N Engl J Med
2009
, vol. 
360
 
7
(pg. 
659
-
667
)
6
Rawstron
AC
Shanafelt
T
Lanasa
MC
, et al. 
Different biology and clinical outcome according to the absolute numbers of clonal B-cells in monoclonal B-cell lymphocytosis (MBL).
Cytometry B Clin Cytom
2010
, vol. 
78
 
suppl 1
(pg. 
S19
-
S23
)
7
Vardi
A
Dagklis
A
Scarfò
L
, et al. 
Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL.
Blood
2013
, vol. 
121
 
22
(pg. 
4521
-
4528
)
8
Morabito
F
Mosca
L
Cutrona
G
, et al. 
Clinical monoclonal B lymphocytosis versus Rai 0 chronic lymphocytic leukemia: a comparison of cellular, cytogenetic, molecular, and clinical features.
Clin Cancer Res
2013
, vol. 
19
 
21
(pg. 
5890
-
5900
)
9
Xochelli
A
Kalpadakis
C
Gardiner
A
, et al. 
Clonal B-cell lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin: is this a distinct entity?
Blood
2014
, vol. 
123
 
8
(pg. 
1199
-
1206
)
10
Bruscaggin
A
Monti
S
Arcaini
L
, et al. 
Molecular lesions of signalling pathway genes in clonal B-cell lymphocytosis with marginal zone features.
Br J Haematol
2014
, vol. 
167
 
5
(pg. 
718
-
720
)
11
Gibson
SE
Swerdlow
SH
Ferry
JA
, et al. 
Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis.
Haematologica
2011
, vol. 
96
 
8
(pg. 
1144
-
1152
)
12
Gradowski
JF
Sargent
RL
Craig
FE
, et al. 
Chronic lymphocytic leukemia/small lymphocytic lymphoma with cyclin D1 positive proliferation centers do not have CCND1 translocations or gains and lack SOX11 expression.
Am J Clin Pathol
2012
, vol. 
138
 
1
(pg. 
132
-
139
)
13
Gibson
SE
Leeman-Neill
RJ
Jain
S
Piao
W
Cieply
KM
Swerdlow
SH
Proliferation centres of chronic lymphocytic leukaemia/small lymphocytic lymphoma have enhanced expression of MYC protein, which does not result from rearrangement or gain of the MYC gene [published online ahead of print November 16, 2015].
Br J Haematol
14
Giné
E
Martinez
A
Villamor
N
, et al. 
Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior.
Haematologica
2010
, vol. 
95
 
9
(pg. 
1526
-
1533
)
15
Ciccone
M
Agostinelli
C
Rigolin
GM
, et al. 
Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays.
Leukemia
2012
, vol. 
26
 
3
(pg. 
499
-
508
)
16
Falchi
L
Keating
MJ
Marom
EM
, et al. 
Correlation between FDG/PET, histology, clinical characteristics, and survival in 332 patients with chronic lymphocytic leukemia.
Blood
2014
, vol. 
123
 
18
(pg. 
2783
-
2790
)
17
Jegalian
AG
Eberle
FC
Pack
SD
, et al. 
Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma.
Blood
2011
, vol. 
118
 
11
(pg. 
2976
-
2984
)
18
Pillai
RK
Surti
U
Swerdlow
SH
Follicular lymphoma-like B cells of uncertain significance (in situ follicular lymphoma) may infrequently progress, but precedes follicular lymphoma, is associated with other overt lymphomas and mimics follicular lymphoma in flow cytometric studies.
Haematologica
2013
, vol. 
98
 
10
(pg. 
1571
-
1580
)
19
Mamessier
E
Song
JY
Eberle
FC
, et al. 
Early lesions of follicular lymphoma: a genetic perspective.
Haematologica
2014
, vol. 
99
 
3
(pg. 
481
-
488
)
20
Schmidt
J
Salaverria
I
Haake
A
, et al. 
Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma.
Leukemia
2014
, vol. 
28
 
5
(pg. 
1103
-
1112
)
21
Tellier
J
Menard
C
Roulland
S
, et al. 
Human t(14;18)positive germinal center B cells: a new step in follicular lymphoma pathogenesis?
Blood
2014
, vol. 
123
 
22
(pg. 
3462
-
3465
)
22
Roulland
S
Kelly
RS
Morgado
E
, et al. 
t(14;18) translocation: a predictive blood biomarker for follicular lymphoma.
J Clin Oncol
2014
, vol. 
32
 
13
(pg. 
1347
-
1355
)
23
Liu
Q
Salaverria
I
Pittaluga
S
, et al. 
Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma.
Am J Surg Pathol
2013
, vol. 
37
 
3
(pg. 
333
-
343
)
24
Louissaint
A
Jr
Ackerman
AM
Dias-Santagata
D
, et al. 
Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement.
Blood
2012
, vol. 
120
 
12
(pg. 
2395
-
2404
)
25
Martin-Guerrero
I
Salaverria
I
Burkhardt
B
, et al. 
Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas.
Haematologica
2013
, vol. 
98
 
8
(pg. 
1237
-
1241
)
26
Salaverria
I
Philipp
C
Oschlies
I
, et al. 
Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe; German High-Grade Lymphoma Study Group; Berlin-Frankfurt-Münster-NHL Trial Group
Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults.
Blood
2011
, vol. 
118
 
1
(pg. 
139
-
147
)
27
Karube
K
Guo
Y
Suzumiya
J
, et al. 
CD10-MUM1+ follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features.
Blood
2007
, vol. 
109
 
7
(pg. 
3076
-
3079
)
28
Schmatz
AI
Streubel
B
Kretschmer-Chott
E
, et al. 
Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases.
J Clin Oncol
2011
, vol. 
29
 
11
(pg. 
1445
-
1451
)
29
Takata
K
Sato
Y
Nakamura
N
, et al. 
Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics [published correction appears in Mod Pathol. 2013;26(8):1152].
Mod Pathol
2013
, vol. 
26
 
1
(pg. 
22
-
31
)
30
Katzenberger
T
Kalla
J
Leich
E
, et al. 
A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36.
Blood
2009
, vol. 
113
 
5
(pg. 
1053
-
1061
)
31
Jares
P
Colomer
D
Campo
E
Molecular pathogenesis of mantle cell lymphoma.
J Clin Invest
2012
, vol. 
122
 
10
(pg. 
3416
-
3423
)
32
Carvajal-Cuenca
A
Sua
LF
Silva
NM
, et al. 
In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior.
Haematologica
2012
, vol. 
97
 
2
(pg. 
270
-
278
)
33
Tiacci
E
Trifonov
V
Schiavoni
G
, et al. 
BRAF mutations in hairy-cell leukemia.
N Engl J Med
2011
, vol. 
364
 
24
(pg. 
2305
-
2315
)
34
Waterfall
JJ
Arons
E
Walker
RL
, et al. 
High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias.
Nat Genet
2014
, vol. 
46
 
1
(pg. 
8
-
10
)
35
Treon
SP
Xu
L
Yang
G
, et al. 
MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia.
N Engl J Med
2012
, vol. 
367
 
9
(pg. 
826
-
833
)
36
Swerdlow
SH
Kuzu
I
Dogan
A
, et al. 
The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing.
Virchows Arch
 
2016;468(3):259-275
37
Hamadeh
F
MacNamara
SP
Aguilera
NS
Swerdlow
SH
Cook
JR
MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma.
Mod Pathol
2015
, vol. 
28
 
4
(pg. 
564
-
574
)
38
Hamadeh
F
MacNamara
S
Bacon
CM
Sohani
AR
Swerdlow
SH
Cook
JR
Gamma heavy chain disease lacks the MYD88 L265p mutation associated with lymphoplasmacytic lymphoma.
Haematologica
2014
, vol. 
99
 
9
(pg. 
e154
-
e155
)
39
Treon
SP
Cao
Y
Xu
L
Yang
G
Liu
X
Hunter
ZR
Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia.
Blood
2014
, vol. 
123
 
18
(pg. 
2791
-
2796
)
40
Roccaro
AM
Sacco
A
Jimenez
C
, et al. 
C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma.
Blood
2014
, vol. 
123
 
26
(pg. 
4120
-
4131
)
41
Schmidt
J
Federmann
B
Schindler
N
, et al. 
MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity.
Br J Haematol
2015
, vol. 
169
 
6
(pg. 
795
-
803
)
42
Wang
L
Lawrence
MS
Wan
Y
, et al. 
SF3B1 and other novel cancer genes in chronic lymphocytic leukemia.
N Engl J Med
2011
, vol. 
365
 
26
(pg. 
2497
-
2506
)
43
Puente
XS
Pinyol
M
Quesada
V
, et al. 
Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.
Nature
2011
, vol. 
475
 
7354
(pg. 
101
-
105
)
44
Quesada
V
Conde
L
Villamor
N
, et al. 
Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.
Nat Genet
2011
, vol. 
44
 
1
(pg. 
47
-
52
)
45
Villamor
N
Conde
L
Martinez-Trillos
A
, et al. 
NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome.
Leukemia
2013
, vol. 
27
 
5
(pg. 
1100
-
1106
)
46
Puente
XS
Beà
S
Valdés-Mas
R
, et al. 
Non-coding recurrent mutations in chronic lymphocytic leukaemia.
Nature
2015
, vol. 
526
 
7574
(pg. 
519
-
524
)
47
Queirós
AC
Villamor
N
Clot
G
, et al. 
A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact.
Leukemia
2015
, vol. 
29
 
3
(pg. 
598
-
605
)
48
Fabbri
G
Rasi
S
Rossi
D
, et al. 
Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation.
J Exp Med
2011
, vol. 
208
 
7
(pg. 
1389
-
1401
)
49
Jeromin
S
Weissmann
S
Haferlach
C
, et al. 
SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients.
Leukemia
2014
, vol. 
28
 
1
(pg. 
108
-
117
)
50
Rossi
D
Rasi
S
Spina
V
, et al. 
Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia.
Blood
2013
, vol. 
121
 
8
(pg. 
1403
-
1412
)
51
Baliakas
P
Hadzidimitriou
A
Sutton
LA
, et al. 
European Research Initiative on CLL (ERIC)
Recurrent mutations refine prognosis in chronic lymphocytic leukemia.
Leukemia
2015
, vol. 
29
 
2
(pg. 
329
-
336
)
52
Foà
R
Guarini
A
A mechanism-driven treatment for chronic lymphocytic leukemia?
N Engl J Med
2013
, vol. 
369
 
1
(pg. 
85
-
87
)
53
Beà
S
Valdés-Mas
R
Navarro
A
, et al. 
Landscape of somatic mutations and clonal evolution in mantle cell lymphoma.
Proc Natl Acad Sci USA
2013
, vol. 
110
 
45
(pg. 
18250
-
18255
)
54
Kridel
R
Meissner
B
Rogic
S
, et al. 
Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma.
Blood
2012
, vol. 
119
 
9
(pg. 
1963
-
1971
)
55
Salaverria
I
Royo
C
Carvajal-Cuenca
A
, et al. 
CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma.
Blood
2013
, vol. 
121
 
8
(pg. 
1394
-
1402
)
56
Green
MR
Kihira
S
Liu
CL
, et al. 
Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation.
Proc Natl Acad Sci USA
2015
, vol. 
112
 
10
(pg. 
E1116
-
E1125
)
57
Okosun
J
Bödör
C
Wang
J
, et al. 
Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.
Nat Genet
2014
, vol. 
46
 
2
(pg. 
176
-
181
)
58
Pastore
A
Jurinovic
V
Kridel
R
, et al. 
Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry.
Lancet Oncol
2015
, vol. 
16
 
9
(pg. 
1111
-
1122
)
59
Loeffler
M
Kreuz
M
Haake
A
, et al. 
HaematoSys-Project
Genomic and epigenomic co-evolution in follicular lymphomas.
Leukemia
2015
, vol. 
29
 
2
(pg. 
456
-
463
)
60
Bödör
C
Grossmann
V
Popov
N
, et al. 
EZH2 mutations are frequent and represent an early event in follicular lymphoma.
Blood
2013
, vol. 
122
 
18
(pg. 
3165
-
3168
)
61
Young
RM
Shaffer
AL
3rd
Phelan
JD
Staudt
LM
B-cell receptor signaling in diffuse large B-cell lymphoma.
Semin Hematol
2015
, vol. 
52
 
2
(pg. 
77
-
85
)
62
Roschewski
M
Staudt
LM
Wilson
WH
Diffuse large B-cell lymphoma-treatment approaches in the molecular era.
Nat Rev Clin Oncol
2014
, vol. 
11
 
1
(pg. 
12
-
23
)
63
Scott
DW
Wright
GW
Williams
PM
, et al. 
Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue.
Blood
2014
, vol. 
123
 
8
(pg. 
1214
-
1217
)
64
Scott
DW
Mottok
A
Ennishi
D
, et al. 
Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies.
J Clin Oncol
2015
, vol. 
33
 
26
(pg. 
2848
-
2856
)
65
Masqué-Soler
N
Szczepanowski
M
Kohler
CW
Spang
R
Klapper
W
Molecular classification of mature aggressive B-cell lymphoma using digital multiplexed gene expression on formalin-fixed paraffin-embedded biopsy specimens.
Blood
2013
, vol. 
122
 
11
(pg. 
1985
-
1986
)
66
Mareschal
S
Ruminy
P
Bagacean
C
, et al. 
Accurate classification of germinal center B-cell-like/activated B-cell-like diffuse large B-cell lymphoma using a simple and rapid reverse transcriptase-multiplex ligation-dependent probe amplification assay: a CALYM Study.
J Mol Diagn
 
2015;17(3):273-283
67
Karube
K
Campo
E
MYC alterations in diffuse large B-cell lymphomas.
Semin Hematol
2015
, vol. 
52
 
2
(pg. 
97
-
106
)
68
Swerdlow
SH
Diagnosis of ‘double hit’ diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC.
Hematology Am Soc Hematol Educ Program
2014
, vol. 
2014
 
1
(pg. 
90
-
99
)
69
Johnson
NA
Slack
GW
Savage
KJ
, et al. 
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
J Clin Oncol
2012
, vol. 
30
 
28
(pg. 
3452
-
3459
)
70
Molina
TJ
Canioni
D
Copie-Bergman
C
, et al. 
Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d’Etudes des Lymphomes de l’Adulte/Lymphoma Study Association phase III trial LNH 03-2B.
J Clin Oncol
2014
, vol. 
32
 
35
(pg. 
3996
-
4003
)
71
Pasqualucci
L
Dalla-Favera
R
The genetic landscape of diffuse large B-cell lymphoma.
Semin Hematol
2015
, vol. 
52
 
2
(pg. 
67
-
76
)
72
Intlekofer
AM
Younes
A
Precision therapy for lymphoma--current state and future directions.
Nat Rev Clin Oncol
2014
, vol. 
11
 
10
(pg. 
585
-
596
)
73
Dojcinov
SD
Venkataraman
G
Pittaluga
S
, et al. 
Age-related EBV-associated lymphoproliferative disorders in the Western population: a spectrum of reactive lymphoid hyperplasia and lymphoma.
Blood
2011
, vol. 
117
 
18
(pg. 
4726
-
4735
)
74
Nicolae
A
Pittaluga
S
Abdullah
S
, et al. 
EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment.
Blood
2015
, vol. 
126
 
7
(pg. 
863
-
872
)
75
Said
J
The expanding spectrum of EBV+ lymphomas.
Blood
2015
, vol. 
126
 
7
(pg. 
827
-
828
)
76
Dojcinov
SD
Venkataraman
G
Raffeld
M
Pittaluga
S
Jaffe
ES
EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression.
Am J Surg Pathol
2010
, vol. 
34
 
3
(pg. 
405
-
417
)
77
Hart
M
Thakral
B
Yohe
S
, et al. 
EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder.
Am J Surg Pathol
2014
, vol. 
38
 
11
(pg. 
1522
-
1529
)
78
Love
C
Sun
Z
Jima
D
, et al. 
The genetic landscape of mutations in Burkitt lymphoma.
Nat Genet
2012
, vol. 
44
 
12
(pg. 
1321
-
1325
)
79
Richter
J
Schlesner
M
Hoffmann
S
, et al. 
ICGC MMML-Seq Project
Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing.
Nat Genet
2012
, vol. 
44
 
12
(pg. 
1316
-
1320
)
80
Schmitz
R
Young
RM
Ceribelli
M
, et al. 
Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics.
Nature
2012
, vol. 
490
 
7418
(pg. 
116
-
120
)
81
Sander
S
Calado
DP
Srinivasan
L
, et al. 
Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis.
Cancer Cell
2012
, vol. 
22
 
2
(pg. 
167
-
179
)
82
Salaverria
I
Martin-Guerrero
I
Wagener
R
, et al. 
Molecular Mechanisms in Malignant Lymphoma Network Project; Berlin-Frankfurt-Münster Non-Hodgkin Lymphoma Group
A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.
Blood
2014
, vol. 
123
 
8
(pg. 
1187
-
1198
)
83
Ferreiro
JF
Morscio
J
Dierickx
D
, et al. 
Post-transplant molecularly defined Burkitt lymphomas are frequently MYC-negative and characterized by the 11q-gain/loss pattern.
Haematologica
2015
, vol. 
100
 
7
(pg. 
e275
-
e279
)
84
Dave
SS
Fu
K
Wright
GW
, et al. 
Lymphoma/Leukemia Molecular Profiling Project
Molecular diagnosis of Burkitt’s lymphoma.
N Engl J Med
2006
, vol. 
354
 
23
(pg. 
2431
-
2442
)
85
Hummel
M
Bentink
S
Berger
H
, et al. 
Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe
A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling.
N Engl J Med
2006
, vol. 
354
 
23
(pg. 
2419
-
2430
)
86
Campo
E
MYC in DLBCL: partners matter.
Blood
2015
, vol. 
126
 
22
(pg. 
2439
-
2440
)
87
Momose
S
Weißbach
S
Pischimarov
J
, et al. 
The diagnostic gray zone between Burkitt lymphoma and diffuse large B-cell lymphoma is also a gray zone of the mutational spectrum.
Leukemia
2015
, vol. 
29
 
8
(pg. 
1789
-
1791
)
88
Gebauer
N
Bernard
V
Feller
AC
Merz
H
ID3 mutations are recurrent events in double-hit B-cell lymphomas.
Anticancer Res
2013
, vol. 
33
 
11
(pg. 
4771
-
4778
)
89
Kluin
P
, et al. 
High grade B-cell lymphoma.
 
In: Swerdlow SH, et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumours. Lyon, France: IARC. In press
90
Lemonnier
F
Couronné
L
Parrens
M
, et al. 
Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters.
Blood
2012
, vol. 
120
 
7
(pg. 
1466
-
1469
)
91
Sakata-Yanagimoto
M
Enami
T
Yoshida
K
, et al. 
Somatic RHOA mutation in angioimmunoblastic T cell lymphoma.
Nat Genet
2014
, vol. 
46
 
2
(pg. 
171
-
175
)
92
Cairns
RA
Iqbal
J
Lemonnier
F
, et al. 
IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma.
Blood
2012
, vol. 
119
 
8
(pg. 
1901
-
1903
)
93
Nicolae
A
Pittaluga
S
Venkataraman
G
, et al. 
Peripheral T-cell lymphomas of follicular T-helper cell derivation with Hodgkin/Reed-Sternberg cells of B-cell lineage: both EBV-positive and EBV-negative variants exist.
Am J Surg Pathol
2013
, vol. 
37
 
6
(pg. 
816
-
826
)
94
Moroch
J
Copie-Bergman
C
de Leval
L
, et al. 
Follicular peripheral T-cell lymphoma expands the spectrum of classical Hodgkin lymphoma mimics.
Am J Surg Pathol
2012
, vol. 
36
 
11
(pg. 
1636
-
1646
)
95
Balagué
O
Martínez
A
Colomo
L
, et al. 
Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: a phenomenon with distinctive clinicopathologic features.
Am J Surg Pathol
2007
, vol. 
31
 
9
(pg. 
1310
-
1322
)
96
Iqbal
J
Wright
G
Wang
C
, et al. 
Lymphoma Leukemia Molecular Profiling Project and the International Peripheral T-cell Lymphoma Project
Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma.
Blood
2014
, vol. 
123
 
19
(pg. 
2915
-
2923
)
97
Wang
T
Feldman
AL
Wada
DA
, et al. 
GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features.
Blood
2014
, vol. 
123
 
19
(pg. 
3007
-
3015
)
98
Palomero
T
Couronné
L
Khiabanian
H
, et al. 
Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas.
Nat Genet
2014
, vol. 
46
 
2
(pg. 
166
-
170
)
99
Agnelli
L
Mereu
E
Pellegrino
E
, et al. 
European T-Cell Lymphoma Study Group
Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma.
Blood
2012
, vol. 
120
 
6
(pg. 
1274
-
1281
)
100
Piccaluga
PP
Fuligni
F
De Leo
A
, et al. 
Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study.
J Clin Oncol
2013
, vol. 
31
 
24
(pg. 
3019
-
3025
)
101
Attygalle
AD
Cabeçadas
J
Gaulard
P
, et al. 
Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the Lymphoma Workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology.
Histopathology
2014
, vol. 
64
 
2
(pg. 
171
-
199
)
102
Crescenzo
R
Abate
F
Lasorsa
E
, et al. 
European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium “Genetics-Driven Targeted Management of Lymphoid Malignancies”
Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma [published correction appears in Cancer Cell. 2015;27(5):744].
Cancer Cell
2015
, vol. 
27
 
4
(pg. 
516
-
532
)
103
Parilla Castellar
ER
Jaffe
ES
Said
JW
, et al. 
ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes.
Blood
2014
, vol. 
124
 
9
(pg. 
1473
-
1480
)
104
King
RL
Dao
LN
McPhail
ED
, et al. 
Morphologic features of ALK-negative anaplastic large cell lymphomas with DUSP22 rearrangements.
Am J Surg Pathol
2016
, vol. 
40
 
1
(pg. 
36
-
43
)
105
Parrilla Castellar
ER
Jaffe
ES
Said
JW
, et al. 
ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes.
Blood
2014
, vol. 
124
 
9
(pg. 
1473
-
1480
)
106
Feldman
AL
Dogan
A
Smith
DI
, et al. 
Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing.
Blood
2011
, vol. 
117
 
3
(pg. 
915
-
919
)
107
Karai
LJ
Kadin
ME
Hsi
ED
, et al. 
Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis.
Am J Surg Pathol
2013
, vol. 
37
 
8
(pg. 
1173
-
1181
)
108
Saggini
A
Gulia
A
Argenyi
Z
, et al. 
A variant of lymphomatoid papulosis simulating primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Description of 9 cases.
Am J Surg Pathol
2010
, vol. 
34
 
8
(pg. 
1168
-
1175
)
109
Kempf
W
Kazakov
DV
Schärer
L
, et al. 
Angioinvasive lymphomatoid papulosis: a new variant simulating aggressive lymphomas.
Am J Surg Pathol
2013
, vol. 
37
 
1
(pg. 
1
-
13
)
110
Thompson
PA
Lade
S
Webster
H
Ryan
G
Prince
HM
Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity.
Haematologica
2010
, vol. 
95
 
11
(pg. 
1977
-
1979
)
111
Keech
JA
Jr
Creech
BJ
Anaplastic T-cell lymphoma in proximity to a saline-filled breast implant.
Plast Reconstr Surg
1997
, vol. 
100
 
2
(pg. 
554
-
555
)
112
Miranda
RN
Aladily
TN
Prince
HM
, et al. 
Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients.
J Clin Oncol
2014
, vol. 
32
 
2
(pg. 
114
-
120
)
113
Clemens
MW
Medeiros
LJ
Butler
CE
, et al. 
Complete surgical excision is essential for the management of patients with breast implant-associated anaplastic large-cell lymphoma.
J Clin Oncol
2016
, vol. 
34
 
2
(pg. 
160
-
168
)
114
Laurent
C
Delas
A
Gaulard
P
, et al. 
Breast implant associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes.
Ann Oncol
2016
, vol. 
27
 
2
(pg. 
306
-
314
)
115
Swerdlow
SH
Jaffe
ES
Brousset
P
, et al. 
International Lymphoma Study Group
Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies.
Am J Surg Pathol
2014
, vol. 
38
 
10
(pg. 
e60
-
e71
)
116
Perry
AM
Warnke
RA
Hu
Q
, et al. 
Indolent T-cell lymphoproliferative disease of the gastrointestinal tract.
Blood
2013
, vol. 
122
 
22
(pg. 
3599
-
3606
)
117
Petrella
T
Maubec
E
Cornillet-Lefebvre
P
, et al. 
Indolent CD8-positive lymphoid proliferation of the ear: a distinct primary cutaneous T-cell lymphoma?
Am J Surg Pathol
2007
, vol. 
31
 
12
(pg. 
1887
-
1892
)
118
Macon
WR
Levy
NB
Kurtin
PJ
, et al. 
Hepatosplenic alphabeta T-cell lymphomas: a report of 14 cases and comparison with hepatosplenic gammadelta T-cell lymphomas.
Am J Surg Pathol
2001
, vol. 
25
 
3
(pg. 
285
-
296
)
119
Toro
JR
Liewehr
DJ
Pabby
N
, et al. 
Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma.
Blood
2003
, vol. 
101
 
9
(pg. 
3407
-
3412
)
120
Guitart
J
Weisenburger
DD
Subtil
A
, et al. 
Cutaneous γδ T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas.
Am J Surg Pathol
2012
, vol. 
36
 
11
(pg. 
1656
-
1665
)
121
Rodríguez-Pinilla
SM
Ortiz-Romero
PL
Monsalvez
V
, et al. 
TCR-γ expression in primary cutaneous T-cell lymphomas.
Am J Surg Pathol
2013
, vol. 
37
 
3
(pg. 
375
-
384
)
122
Endly
DC
Weenig
RH
Peters
MS
Viswanatha
DS
Comfere
NI
Indolent course of cutaneous gamma-delta T-cell lymphoma.
J Cutan Pathol
2013
, vol. 
40
 
10
(pg. 
896
-
902
)
123
Koskela
HL
Eldfors
S
Ellonen
P
, et al. 
Somatic STAT3 mutations in large granular lymphocytic leukemia.
N Engl J Med
2012
, vol. 
366
 
20
(pg. 
1905
-
1913
)
124
Jerez
A
Clemente
MJ
Makishima
H
, et al. 
STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia.
Blood
2012
, vol. 
120
 
15
(pg. 
3048
-
3057
)
125
Bergmann
AK
Schneppenheim
S
Seifert
M
, et al. 
Recurrent mutation of JAK3 in T-cell prolymphocytic leukemia.
Genes Chromosomes Cancer
2014
, vol. 
53
 
4
(pg. 
309
-
316
)
126
Kiel
MJ
Velusamy
T
Rolland
D
, et al. 
Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia.
Blood
2014
, vol. 
124
 
9
(pg. 
1460
-
1472
)
127
Rajala
HL
Eldfors
S
Kuusanmäki
H
, et al. 
Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia.
Blood
2013
, vol. 
121
 
22
(pg. 
4541
-
4550
)
128
Nicolae
A
Xi
L
Pittaluga
S
, et al. 
Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas.
Leukemia
2014
, vol. 
28
 
11
(pg. 
2244
-
2248
)
129
Küçük
C
Jiang
B
Hu
X
, et al. 
Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells.
Nat Commun
2015
, vol. 
6
 pg. 
6025
 
130
Deleeuw
RJ
Zettl
A
Klinker
E
, et al. 
Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes.
Gastroenterology
2007
, vol. 
132
 
5
(pg. 
1902
-
1911
)
131
Tan
SY
Ooi
AS
Ang
MK
, et al. 
Nuclear expression of MATK is a novel marker of type II enteropathy-associated T-cell lymphoma.
Leukemia
2011
, vol. 
25
 
3
(pg. 
555
-
557
)
132
Tomita
S
Kikuti
YY
Carreras
J
, et al. 
Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan.
Mod Pathol
2015
, vol. 
28
 
10
(pg. 
1286
-
1296
)
133
Chan
JK
Chan
AC
Cheuk
W
, et al. 
Type II enteropathy-associated T-cell lymphoma: a distinct aggressive lymphoma with frequent γδ T-cell receptor expression.
Am J Surg Pathol
2011
, vol. 
35
 
10
(pg. 
1557
-
1569
)
134
Rodríguez Pinilla
SM
Roncador
G
Rodríguez-Peralto
JL
, et al. 
Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers.
Am J Surg Pathol
2009
, vol. 
33
 
1
(pg. 
81
-
90
)
135
Garcia-Herrera
A
Colomo
L
Camós
M
, et al. 
Primary cutaneous small/medium CD4+ T-cell lymphomas: a heterogeneous group of tumors with different clinicopathologic features and outcome.
J Clin Oncol
2008
, vol. 
26
 
20
(pg. 
3364
-
3371
)
136
Grogg
KL
Jung
S
Erickson
LA
McClure
RF
Dogan
A
Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma: a clonal T-cell lymphoproliferative disorder with indolent behavior.
Mod Pathol
2008
, vol. 
21
 
6
(pg. 
708
-
715
)
137
Beltraminelli
H
Leinweber
B
Kerl
H
Cerroni
L
Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases.
Am J Dermatopathol
2009
, vol. 
31
 
4
(pg. 
317
-
322
)
138
Cohen
JI
Kimura
H
Nakamura
S
Ko
YH
Jaffe
ES
Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8-9 September 2008.
Ann Oncol
2009
, vol. 
20
 
9
(pg. 
1472
-
1482
)
139
Kimura
H
Ito
Y
Kawabe
S
, et al. 
EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases.
Blood
2012
, vol. 
119
 
3
(pg. 
673
-
686
)
140
Ohshima
K
Kimura
H
Yoshino
T
, et al. 
CAEBV Study Group
Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in children and young adults: overlap with chronic active EBV infection and infantile fulminant EBV T-LPD.
Pathol Int
2008
, vol. 
58
 
4
(pg. 
209
-
217
)
141
Quintanilla-Martinez
L
Ridaura
C
Nagl
F
, et al. 
Hydroa vacciniforme-like lymphoma: a chronic EBV+ lymphoproliferative disorder with risk to develop a systemic lymphoma.
Blood
2013
, vol. 
122
 
18
(pg. 
3101
-
3110
)
142
Swerdlow
SH
T-cell and NK-cell posttransplantation lymphoproliferative disorders.
Am J Clin Pathol
2007
, vol. 
127
 
6
(pg. 
887
-
895
)
143
Kato
S
Asano
N
Miyata-Takata
T
, et al. 
T-cell receptor (TCR) phenotype of nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL): a clinicopathologic study of 39 cases.
Am J Surg Pathol
2015
, vol. 
39
 
4
(pg. 
462
-
471
)
144
Fan
Z
Natkunam
Y
Bair
E
Tibshirani
R
Warnke
RA
Characterization of variant patterns of nodular lymphocyte predominant Hodgkin lymphoma with immunohistologic and clinical correlation.
Am J Surg Pathol
2003
, vol. 
27
 
10
(pg. 
1346
-
1356
)
145
Hartmann
S
Eichenauer
DA
Plütschow
A
, et al. 
The prognostic impact of variant histology in nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG).
Blood
2013
, vol. 
122
 
26
(pg. 
4246
-
4252
)
146
Boudová
L
Torlakovic
E
Delabie
J
, et al. 
Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma.
Blood
2003
, vol. 
102
 
10
(pg. 
3753
-
3758
)
147
Hartmann
S
Döring
C
Jakobus
C
, et al. 
Nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma--endpoints of a spectrum of one disease?
PLoS One
2013
, vol. 
8
 
11
pg. 
e78812
 
148
Xing
KH
Connors
JM
Lai
A
, et al. 
Advanced-stage nodular lymphocyte predominant Hodgkin lymphoma compared with classical Hodgkin lymphoma: a matched pair outcome analysis.
Blood
2014
, vol. 
123
 
23
(pg. 
3567
-
3573
)
149
Hartmann
S
Döring
C
Vucic
E
, et al. 
Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma.
Br J Haematol
2015
, vol. 
169
 
3
(pg. 
415
-
422
)
150
Nam-Cha
SH
Montes-Moreno
S
Salcedo
MT
Sanjuan
J
Garcia
JF
Piris
MA
Lymphocyte-rich classical Hodgkin’s lymphoma: distinctive tumor and microenvironment markers.
Mod Pathol
2009
, vol. 
22
 
8
(pg. 
1006
-
1015
)
151
Haroche
J
Abla
O
Uncommon histiocytic disorders: Rosai-Dorfman, juvenile xanthogranuloma, and Erdheim-Chester disease.
Hematology Am Soc Hematol Educ Program
2015
, vol. 
2015
 
1
(pg. 
571
-
578
)
152
Feldman
AL
Arber
DA
Pittaluga
S
, et al. 
Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone.
Blood
2008
, vol. 
111
 
12
(pg. 
5433
-
5439
)
153
Shao
H
Xi
L
Raffeld
M
, et al. 
Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases.
Mod Pathol
2011
, vol. 
24
 
11
(pg. 
1421
-
1432
)
154
Chen
W
Jaffe
R
Zhang
L
, et al. 
Langerhans cell sarcoma arising from chronic lymphocytic lymphoma/small lymphocytic leukemia: lineage analysis and BRAF V600E Mutation Study.
N Am J Med Sci
2013
, vol. 
5
 
6
(pg. 
386
-
391
)
155
Ratei
R
Hummel
M
Anagnostopoulos
I
, et al. 
Common clonal origin of an acute B-lymphoblastic leukemia and a Langerhans’ cell sarcoma: evidence for hematopoietic plasticity.
Haematologica
2010
, vol. 
95
 
9
(pg. 
1461
-
1466
)
156
Dalia
S
Jaglal
M
Chervenick
P
Cualing
H
Sokol
L
Clinicopathologic characteristics and outcomes of histiocytic and dendritic cell neoplasms: the Moffitt Cancer Center experience over the last twenty five years.
Cancers (Basel)
2014
, vol. 
6
 
4
(pg. 
2275
-
2295
)
157
Dalia
S
Shao
H
Sagatys
E
Cualing
H
Sokol
L
Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment.
Cancer Control
2014
, vol. 
21
 
4
(pg. 
290
-
300
)
158
Go
H
Jeon
YK
Huh
J
, et al. 
Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms.
Histopathology
2014
, vol. 
65
 
2
(pg. 
261
-
272
)