INTRODUCTION — Malignancies of the hematopoietic and lymphoid tissues include the lymphomas, leukemias, myeloproliferative neoplasms, mast cell neoplasms, plasma cell neoplasms, histiocytic tumors, and dendritic cell neoplasms. Multiple classification schemes have been employed for these diseases over the years. These have included:

●Gall and Mallory classification

●Rappaport classification

●Kiel classification

●Lukes-Collins classification

●Working Formulation

●Revised European-American classification (REAL)

●French-American-British system

●World Health Organization (WHO) classification 2001

●World Health Organization (WHO) classification 2008, revised in 2016

The earliest classification systems were based upon tissue architecture and the cytologic appearances of the neoplastic cells. For a few entities (eg, follicular lymphoma), these morphologic features are often sufficient to establish the diagnosis. However, with the development and application of immunophenotyping and cytogenetic and molecular genetic testing, it was recognized that many distinct entities existed that could not be distinguished reliably by morphology alone. This appreciation led to the incorporation of immunophenotype and genetic criteria into the REAL classification of lymphoid neoplasms in 1994. Numerous subsequent analyses demonstrated that the REAL classification had "added value" over older systems for determining prognosis and patient stratification. In 2001, immunophenotype and genetic findings were incorporated into a new WHO classification, which subsumed the REAL classification and included tumors of myeloid or mixed lineage origin.

The latest WHO classification, updated in 2016, further refined and expanded upon the use of objective diagnostic criteria (eg, particular molecular markers) for clearly defined entities and is widely used and accepted (table 1 and table 2) [1]. However, it remains important for clinicians to be familiar with prior classification systems in order to interpret the older literature and to care for patients who were previously treated for hematopoietic neoplasms with now outdated names. A nested classification of lymphoid neoplasms proposed by the Pathology Working Group of the International Lymphoma Epidemiology Consortium, which is based on the WHO classification and the third edition of the International Classification of Diseases-Oncology, provides a guide for translation of previous classification systems into the present [2].

This topic review will discuss the current classification system, the 2016 revisions to the WHO classification, the biology of which is discussed separately. (See "Normal B and T lymphocyte development".)

OVERVIEW — The 2016 World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues uses morphologic, immunophenotypic, genetic, and clinical features to define distinct diagnoses [1]. In addition, there are borderline categories for cases that do not fit into a defined entity. This approach has been adapted to improve the accurate assessment of patient outcomes in "typical" disease and to enable the study of borderline cases.

When possible, the different tumor types are grouped by lineage into:

●Myeloid neoplasms (table 2) – Derived from bone marrow progenitor cells that normally develop into erythrocytes, granulocytes (neutrophils, basophils, and eosinophils), monocytes, or megakaryocytes.

●Lymphoid neoplasms (table 1) – Derived variously from B cell progenitors (bone marrow derived), T cell progenitors (thymus-derived), mature T lymphocytes (cytotoxic T cells, helper T cells, or T regulatory cells) or mature B lymphocytes (B cells or plasma cells).

●Histiocytic/dendritic neoplasms (table 1) – Derived from cells that normally develop into "professional" antigen presenting cells (dendritic cells) or tissue macrophages (histiocytes).

There are also neoplasms that show evidence of both myeloid and lymphoid differentiation, presumably because they are derived from multipotent progenitor cells. Such cases are given their own category, neoplasms of myeloid and lymphoid lineage.

MYELOID NEOPLASMS — Myeloid neoplasms are usually derived from bone marrow progenitors that are restricted to developing into erythrocytes, granulocytes (neutrophils, basophils, and eosinophils), monocytes, or megakaryocytes. An exception is chronic myeloid leukemia (CML), in which the cell of origin is a pluripotent hematopoietic stem cell capable of giving rise to lymphoid cells as well. These neoplasms can be subgrouped into three broad clinicopathologic classes (table 2):

●Acute myeloid leukemias (AML)

●Myeloproliferative neoplasms (MPN)

●Myelodysplastic syndromes (MDS)

Some myeloid neoplasms show features that overlap between those of an MPN and an MDS, and all MPNs and MDS have the potential to transform into AML.

AML and related entities inevitably pursue a very aggressive course and need immediate therapy, whereas the clinical behavior of MPNs and MDS is varied and can be quite indolent.

Acute myeloid leukemia and related aggressive myeloid neoplasms — AML is defined by ≥20 percent myeloid blasts in the bone marrow or peripheral blood, or the presence of particular cytogenetic abnormalities, regardless of the blast count. This group of entities includes (table 2):

●AML with recurrent genetic abnormalities

●AML with myelodysplasia-related changes

●Therapy-related myeloid neoplasms

●AML, not otherwise specified

●Myeloid sarcoma (extramedullary AML)

●Myeloid proliferations related to Down syndrome — This includes transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome. (See "Down syndrome: Clinical features and diagnosis", section on 'Transient myeloproliferative disorder'.)

●Blastic plasmacytoid dendritic cell neoplasm (see "Blastic plasmacytoid dendritic cell neoplasm")

Details on the biology, cytogenetics, clinical presentation, and diagnosis of AML are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Cytogenetic abnormalities in acute myeloid leukemia".)

Myeloproliferative neoplasms — The MPNs are a group of clonal stem cell disorders associated with the proliferation of one or more of the myeloid lineages (eg, granulocytic, erythroid, or megakaryocytic). These diseases are often associated with mutations that cause abnormal increases in activity of pro-growth signaling pathways, leading to the growth factor-independent proliferation of bone marrow progenitors. Bone marrow cellularity is usually increased, but may be normal. The percentage of blasts in the bone marrow may be normal or slightly increased, but is always <20 percent. Although some skewing of differentiation may be seen (producing increases in the proportion of certain cell types, such as eosinophils or basophils), hematopoiesis usually is effective. The combination of effective hematopoiesis and increased numbers of progenitors typically leads to an increase in the number of one or more formed elements in the peripheral blood.

The following entities are included under the category of MPNs (table 2):

●Chronic myeloid leukemia (CML) – CML demonstrates excessive proliferation of the granulocytic lineage at all stages of maturation and is always associated with the presence of a BCR-ABL1 fusion gene, which is usually created by a reciprocal translocation that results in the formation of the Philadelphia chromosome, t(9;22). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

●Chronic neutrophilic leukemia (CNL) – CNL is rare entity characterized by the overproduction of mature granulocytes and the absence of the BCR-ABL1 fusion gene. Previously, the name CNL was also applied to an unusual MPN associated with a variant BCR-ABL1 fusion gene and pure neutrophilia, but such cases are considered to be forms of CML in the current WHO classification. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

●Polycythemia vera (PV) – PV presents with an otherwise unexplained increased hematocrit/red blood cell mass and is associated in virtually all cases with gain-of-function mutations in the gene encoding the tyrosine kinase JAK2. (See "Clinical manifestations and diagnosis of polycythemia vera".)

●Essential thrombocythemia (ET) – ET demonstrates clonal or autonomous thrombocytosis and is associated with JAK2 mutations in about 50 percent of cases. Additional subsets of cases are associated with mutations in a different tyrosine kinase, MPL (about 5 percent of cases), which encodes the thrombopoietin receptor; or in CALR (25 percent to 35 percent of cases), which encodes a protein that when mutated is secreted and binds and activates the thrombopoietin receptor [3]. (See "Diagnosis and clinical manifestations of essential thrombocythemia".)

●Primary myelofibrosis (PMF) – PMF (previously called agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis) is characterized by otherwise unexplained bone marrow fibrosis. Like ET, it is associated with mutations in JAK2, MPL, and CALR in approximately 50 percent, 5 percent, and 30 percent of cases, respectively. Some data suggest that PMF may be best viewed as a stage of MPN progression, rather than a distinct entity. Indeed, CML, PV, and ET can all evolve to a picture that mimics PMF. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

●Myeloid neoplasms with eosinophilia – This group of neoplasms characteristically present with eosinophilia, anemia, thrombocytopenia, hepatomegaly, and splenomegaly. They are often associated with gene fusions that activate the tyrosine kinase activity of PDGFR-alpha, PDGFR-beta, FGFR1, or JAK2, in which case they fall into the category of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFR-alpha, PDGFR-beta, FGFR1, or JAK2 (discussed later), in order to recognize that in a subset of cases these disorders present with features compatible with acute lymphoblastic leukemia/lymphoma. A minor subset of myeloid neoplasms with eosinophilia lack these gene rearrangements and are classified as chronic eosinophilic leukemia, not otherwise specified. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

●Myeloproliferative neoplasm, unclassifiable – Although most of the MPNs are classifiable, some are difficult to categorize; these may also be referred to as atypical MPNs.

Further discussion of the classification of MPN is provided separately. (See "Overview of the myeloproliferative neoplasms".)

Mastocytosis — Mastocytosis describes a group of neoplasms in which pathologic mast cells accumulate in the bone marrow and other tissues. These neoplasms were previously included under the broader category of MPNs, but are now classified as a distinct category in the current WHO classification (table 2) [4]. Mastocytosis is often associated with mutations that activate the tyrosine kinase activity of the KIT receptor and may be seen together with another myeloid neoplasm, such as chronic myelomonocytic leukemia or acute myeloid leukemia; such tumors are classified as systemic mastocytosis with associated hematologic neoplasm. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Myelodysplastic syndromes (MDS) — The myelodysplastic syndromes (MDS) refer to hematopoietic neoplasms that exhibit dysplasia, ineffective blood cell production leading to cytopenias, and a variable risk of transformation to acute leukemia. Bone marrow cellularity is often increased, but may be normocellular or hypocellular. The percentage of blasts in the bone marrow is normal or increased, but <20 percent. Maturation is present, but dysplasia is noted in one or more myeloid lineages.

The following entities are included as categories of MDS (table 2) [4]:

●MDS with single lineage dysplasia (previously called "refractory cytopenia with unilineage dysplasia," which included refractory anemia, refractory neutropenia, and refractory thrombocytopenia)

●MDS with ring sideroblasts, which includes subgroups with single lineage dysplasia and multilineage dysplasia (previously called "refractory anemia with ring sideroblasts")

●MDS with multilineage dysplasia (previously called "refractory cytopenia with multilineage dysplasia")

●MDS with excess blasts (previously called "refractory anemia with excess blasts")

●MDS with isolated del(5q)

●MDS, unclassifiable

●Childhood MDS – Includes a provisional entity called refractory cytopenia of childhood

The classification of MDS is discussed in more detail separately. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'WHO classification'.)

MDS/MPN syndromes — The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) include disorders where both dysplastic and proliferative features co-exist. These include (table 2):

●Chronic myelomonocytic leukemia (see "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis")

●Atypical chronic myeloid leukemia, BCR-ABL1 negative

●Juvenile myelomonocytic leukemia (see "Juvenile myelomonocytic leukemia")

●MDS/MPN with ring sideroblasts and thrombocytosis

●MDS/MPN, unclassifiable

The classification of MDS/MPN is discussed in more detail separately. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'WHO classification'.)

LYMPHOID NEOPLASMS — Lymphoid neoplasms are derived from cells that normally develop into T lymphocytes (cytotoxic T lymphocytes, helper T lymphocytes, or regulatory T lymphocytes) or B lymphocytes (lymphocytes or plasma cells). In general, the lymphoid neoplasms are divided into neoplasms derived from lymphoid precursors (eg, acute lymphoblastic leukemia/lymphoma) and neoplasms of mature lymphocytes and plasma cells. These are further grouped depending upon whether they are of B or T cell derivation (table 1).

Historically, lymphoid neoplasms that present with bone marrow and blood involvement (leukemia) have been segregated from those that present as a mass (lymphoma). However, it is now appreciated that any "lymphoma" can present with or evolve to a leukemic picture, and any "leukemia" may occasionally present as a mass lesion. In the current World Health Organization (WHO) classification, the diagnosis of the various lymphoid neoplasms depends not on the anatomic location of tumor cells, but rather on the cell of origin of the tumor, as judged by morphology, immunophenotype, and genetic findings [1] . As a result, several entities previously considered distinct are now grouped together under single diagnostic categories. As examples:

●Chronic lymphocytic leukemia and small lymphocytic lymphoma

●Precursor B cell lymphoblastic leukemia and pre-B cell lymphoblastic lymphoma

●Pre-T cell lymphoblastic leukemia and pre-T cell lymphoblastic lymphoma

The WHO classification makes no effort to order lymphoid neoplasms according to their aggressiveness, in part due to recognition that the natural history of these tumors shows significant patient-to-patient variability. However, some clinical trials have separated histologic subtypes according to the usual clinical behavior of each of the lymphoid neoplasms, which can be roughly segregated into three groups, as follows (table 3) [5]:

●Indolent – Survival of untreated indolent lymphoid neoplasms is generally measured in years. Indolent lymphomas represent 35 to 40 percent of the non-Hodgkin lymphomas (NHLs). The most common subtypes include follicular lymphoma; chronic lymphocytic leukemia/small lymphocytic lymphoma; some cases of mantle cell lymphoma; extramedullary, nodal, and splenic marginal zone lymphoma; lymphoplasmacytic lymphoma; and mycosis fungoides [5].

●Aggressive – Survival of untreated aggressive lymphoid neoplasms is usually measured in months. About half of the NHLs are aggressive [5]. The most common subtypes include diffuse large B cell lymphoma and various types of peripheral T cell lymphoma, including anaplastic large cell lymphoma [6,7].

●Highly aggressive – Survival of untreated highly aggressive lymphoid neoplasms is measured in weeks. Highly aggressive lymphomas, as a group, represent about 5 percent of the NHLs. These diseases are all uncommon. The highly aggressive lymphomas can arise from B cells or T cells.

●Hodgkin lymphomas are pathologically and clinically distinct from the other lymphoid neoplasms and fall into a separate diagnostic group with a generally excellent prognosis.

Whenever possible, we try to avoid grouping these lymphomas into indolent, aggressive, and highly aggressive histologies in our discussions and instead focus on the individual lymphoma histologies as defined by the WHO.

Precursor lymphoid neoplasms — These highly aggressive precursor lymphoid neoplasms include two main categories:

●Precursor B lymphoblastic leukemia/lymphomas are neoplastic disorders of immature lymphoblasts committed to the B cell lineage. Precursor B cells arise in the bone marrow, and most patients with this tumor present with bone marrow involvement and a leukemic peripheral blood picture (ie, precursor B cell acute lymphoblastic leukemia). (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

●Precursor T lymphoblastic leukemia/lymphomas are neoplastic disorders of immature lymphoblasts committed to the T cell lineage that may arise within the thymus or the bone marrow. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Mature B cell neoplasms — Lymphoid neoplasms of mature B cells are classified in part based upon a comparison of the immunophenotype and genotype of the tumor cells to normal stages of B cell development as well as other characteristic immunophenotypic and genetic features. (See "Normal B and T lymphocyte development".)

These tumors can be derived from any stage of mature B cell development, including naive B cells, germinal center B cells, post-germinal center memory B cells, or plasma cells. Of note, the most common B cell neoplasms derive from cells that have experienced a germinal center reaction, which is initiated when antigen stimulated B cells migrate into the germinal centers (or follicles) of secondary lymphoid organs (eg, lymph nodes, spleen, and mucosa associated lymphoid tissues) [8]. Germinal center B cells proliferate and undergo two events that permit the diversification of immunoglobulin (Ig) genes, somatic hypermutation and heavy chain class switching. Most tumors of mature B cells, including plasma cell neoplasms, show evidence of somatic hypermutation, and it is thought that "mistakes" that occur during somatic hypermutation and class switching are responsible for many of the acquired mutations that lead to B cell transformation.

Specific diagnostic entities derived from mature B cells include the following (table 1):

●Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) – CLL/SLL is the most common leukemia in Western countries, accounting for approximately 30 percent of all leukemias in the United States. It is a malignancy of small, mature-appearing lymphocytes, presenting primarily either as a leukemia (CLL) or a lymphoma (SLL). In roughly 60 percent of cases, the Ig genes are somatically hypermutated; the remaining cases appear to derive from naive B cells. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

●Lymphoplasmacytic lymphoma (LPL) – LPL is a neoplasm derived from post-germinal center B cells that is comprised of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. It is usually associated with the presence of a serum monoclonal protein. Waldenstrom macroglobulinemia is a clinicopathologic entity usually associated with LPL and levels of IgM monoclonal gammopathy that are sufficiently high to produce symptoms related to hyperviscosity. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma" and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

●Mantle cell lymphoma (MCL) – MCL has been previously referred to as intermediate lymphocytic lymphoma, mantle zone lymphoma, centrocytic lymphoma, and lymphocytic lymphoma of intermediate differentiation. MCL comprises about 7 percent of adult NHLs in the United States and Europe. In about 80 percent of cases, the cell of origin is a naive B cell, while the remaining cases are somatically hypermutated and apparently derived from antigen-stimulated B cells. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma".)

●B cell prolymphocytic leukemia (B-PLL) – B-PLL is a rare B cell neoplasm characterized by a predominance of activated lymphocytes referred to as prolymphocytes in the bone marrow. True B-PLL presents de novo and must be distinguished from CLL (chronic lymphocytic leukemia) with a high number of circulating prolymphocytes. Approximately 50 to 60 percent of cases are somatically hypermutated while the remainder may arise from naive B cells. (See "B cell prolymphocytic leukemia".)

●Follicular lymphoma (FL) – FL, previously called follicle center lymphoma, is the second most common lymphoma in the United States and Western Europe. Patients usually present with painless peripheral adenopathy. FL is comprised of neoplastic germinal center B cells and recapitulates the appearance of normal germinal centers of secondary lymphoid follicles. Primary cutaneous follicle center lymphoma resembles FL morphologically, but is usually confined to the skin and has distinctive immunophenotypic and genotypic features. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma" and "Primary cutaneous follicle center lymphoma".)

●Diffuse large B cell lymphoma (DLBCL) – DLBCL, previously diffuse histiocytic lymphoma, is the most common subtype of NHL, accounting for approximately 25 percent of cases. DLBCL encompasses a heterogeneous group of tumors that have as a common feature diffuse effacement of involved tissues by a proliferation of large neoplastic B cells. Pathologic evaluation should include immunohistochemical or gene expression studies and cytogenetic analyses that permit further classification of cases into germinal center B cell DLBCL and non-germinal center B cell DLBCL (including activated B cell lymphoma), and to identify so-called double hit B cell lymphomas with MYC gene rearrangements and rearrangements involving BCL2 and/or BCL6, as some double hit B cell lymphomas are morphologically indistinguishable from DLBCL. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

●The current WHO classification includes several rare B cell lymphomas that were previously included as subtypes of DLBCL [1]:

•Intravascular large B cell lymphoma (see "Intravascular large cell lymphoma")

•Primary mediastinal (thymic) large B cell lymphoma, a lymphoma with distinct clinicopathologic features that may be derived from an unusual subset of B cells that are resident in the thymus. (See "Primary mediastinal large B cell lymphoma".)

•DLBCL associated with chronic inflammation

•Large B cell lymphoma, lymphomatoid granulomatosis type, an Epstein-Barr virus (EBV)-associated large cell lymphoma that usually presents at extranodal sites.

•T cell rich/histiocyte-rich large B cell lymphoma

•Primary DLBCL of the central nervous system

•Primary cutaneous DLBCL, leg type (see "Primary cutaneous large B cell lymphoma, leg type")

•EBV-positive DLBCL, not otherwise specified (see "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'EBV-positive DLBCL, NOS')

•EBV-positive mucocutaneous ulcer, a provisional entity that is important to recognize because, despite the presence of very pleomorphic malignant-appearing large cells, it typically follows an indolent course and may remit with cessation of immunosuppression. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'EBV-positive mucocutaneous ulcer'.)

•Human herpesvirus-8 (HHV-8) positive DLBCL, not otherwise specified

•Large B cell lymphoma with IRF4 rearrangements, a provisional entity that mainly occurs in the head and neck region (frequently Waldeyer's ring) of children.

•Plasmablastic lymphoma – This distinctive type of large cell lymphoma is usually AIDS-related, typically presents in the oral cavity and jaws, and is frequently EBV-associated. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)

•Primary effusion lymphoma (PEL) – PEL is an uncommon large cell lymphoma associated with AIDS and other immunodeficiency states. Latent gene products of HHV-8 appear to play a role in the pathogenesis. Occasionally, a similar HHV8-positive lymphoma arises out of a background of multicentric Castleman's disease. (See "Primary effusion lymphoma" and "HHV-8-associated multicentric Castleman disease".)

•ALK-positive large B cell lymphoma – This is a rare B cell lymphoma with plasmablastic features associated with translocations or rearrangements of the ALK (anaplastic lymphoma kinase) gene.

●High grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements – This subtype includes the so-called double or triple hit lymphomas with a spectrum of histologic features ranging from DLBCL to BL to "blastoid." Previously, these cases were often categorized as either DLBCL or grey zone lymphoma with features intermediate between Burkitt lymphoma and DLBCL. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Burkitt lymphoma'.)

●Burkitt lymphoma (BL) – BL is a highly aggressive B cell neoplasm of germinal center B cell origin that can present in one of three distinct clinical forms: endemic, sporadic, and immunodeficiency-associated. Patients present with rapidly growing tumor masses and often have evidence of tumor lysis. In the prior FAB classification, BL involving bone marrow and peripheral blood was referred to as acute lymphoblastic leukemia, L3 subtype, but such tumors are now considered leukemic presentations of BL. A large majority of BL is associated with chromosomal translocations involving the MYC oncogene, but in the 2016 WHO revision, a Burkitt-like lymphoma with an alternative 11q aberration is included as a provisional entity. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)

●Marginal zone B cell lymphoma (MZL) – The MZL usually arise from post-germinal center marginal zone B cells surrounding normal lymphoid follicles. Three subtypes are recognized:

•Extranodal MZL of mucosa-associated lymphoid tissue (MALT) or MALT-type lymphoma, most commonly involves the gastrointestinal tract. This condition refers only to the low-grade tumor and not to DLBCL, which can also occur in these tissues. Primary cutaneous marginal zone lymphoma is included in this broader category. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)" and "Primary cutaneous marginal zone lymphoma".)

•Splenic MZL is the tissue counterpart of splenic lymphoma with circulating villous lymphocytes. Patients typically present with splenomegaly, lymphocytosis, and cytopenias (most often due to hypersplenism). Unlike most other NHLs, lymphadenopathy and involvement of extralymphatic organs is uncommon. (See "Splenic marginal zone lymphoma".)

•Nodal MZL tumor cells cytologically resemble "normal" monocytoid B cells and often involve marginal zones around B cell follicles. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

●Hairy cell leukemia (HCL) – HCL, previously called "leukemic reticuloendotheliosis," is an uncommon indolent B cell lymphoproliferative disorder that usually has a post-germinal center B cell origin. The tumor cells in the blood have characteristic prominent irregular ("hairy") cytoplasmic projections. (See "Clinical features and diagnosis of hairy cell leukemia".)

●Plasma cell neoplasms – Plasma cell neoplasms (previously often referred to as plasma cell dyscrasias) result from clonal expansion of terminally differentiated germinal center-derived B lymphocytes that typically secrete a monoclonal immunoglobulin (M protein).

•Plasma cell myeloma/plasmacytoma – These are neoplastic proliferation of plasma cells that present as multiple lesions (multiple myeloma) or a single lesion (plasmacytoma of bone or extramedullary plasmacytoma). Most cases are associated with an M protein in serum and/or urine. In the bone marrow, these cells proliferate and often produce extensive skeletal destruction, osteolytic lesions, osteopenia, and/or fractures. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis" and "Diagnosis and management of solitary plasmacytoma of bone" and "Diagnosis and management of solitary extramedullary plasmacytoma".)

•Primary (AL) amyloidosis and light and heavy chain deposition diseases are clonal plasma cell disorders characterized by tissue deposits of light chain or heavy chain fragments, leading to organ dysfunction. (See "Pathogenesis of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases".)

•POEMS syndrome is plasma cell disorder associated with polyneuropathy, monoclonal protein, and one or more of the following features: organomegaly, endocrinopathy, skin changes, Castleman disease (angiofollicular lymph node hyperplasia), or other findings. (See "POEMS syndrome".)

Hodgkin lymphoma (HL) — HL, formerly called Hodgkin's disease, arises from germinal center or post-germinal center B cells. HL has a unique cellular composition, containing a minority of neoplastic cells (Reed-Sternberg cells and their variants) in an inflammatory background. It is separated from the other B cell lymphomas based on its unique clinicopathologic features, and can be divided into two major sub-groups, based on the appearance and immunophenotype of the tumor cells (table 1):

●Nodular lymphocyte-predominant HL – The tumor cells in this uncommon subtype retain the immunophenotypic features of germinal center B cells. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)

●Classic HL – The tumor cells in this group are also derived from germinal center B cells, but typically fail to express many of the genes and gene products that define normal germinal center B cells. Based on differences in the appearance of the tumor cells and the composition of the reactive background, classic HL is further divided into the following four subtypes:

•Nodular sclerosis classical HL

•Mixed cellularity classical HL

•Lymphocyte-rich classical HL

•Lymphocyte-depleted classical HL

A significant minority of cases of classical HL are EBV-associated (particularly the lymphocyte depleted and mixed cellularity types), whereas nodular lymphocyte-predominant HL is rarely EBV-associated.

The classification of HL is presented in more detail separately. (See "Hodgkin lymphoma: Epidemiology and risk factors" and "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

Mature T cell or NK cell lineage — Lymphoid neoplasms of mature T cells or NK cells include (table 1):

●Peripheral T cell lymphoma (PTCL) – PTCL are a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all NHLs in adults:

•Peripheral T cell lymphoma, unspecified – (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified".)

•Angioimmunoblastic T cell lymphoma (AITL) – AITL is derived from T follicular helper (TFH) T cells. Some tumors that were previously classified as peripheral T cell lymphoma, unspecified, have immunophenotypic features that resemble AITL, and are included in a provisional category "nodal T cell lymphoma with a TFH phenotype"; their relationship to AITL remains to be defined. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

•Extranodal NK/T cell nasal type lymphoma – (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

•Subcutaneous panniculitis-like T cell lymphoma – (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

•Hepatosplenic T cell lymphoma – (See "Clinical manifestations, pathologic features, and diagnosis of hepatosplenic T cell lymphoma".)

•Enteropathy-associated T cell lymphoma, previously called intestinal T cell lymphoma – (See "Clinical manifestations, pathologic features, and diagnosis of enteropathy-associated T cell lymphoma".)

●Anaplastic large cell lymphoma (ALCL) – ALCL is characterized by large lymphoid cells with pleomorphic nuclei. There are two clinical subtypes: cutaneous and systemic. Primary systemic ALCL is then further subcategorized into tumors that have or do not have rearrangements involving the anaplastic lymphoma kinase (ALK) gene. Breast implant-associated ALCL is a rare entity lacking ALK rearrangements in which the malignant cells are confined to the fluid within the fibrous capsule surrounding the implant. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma" and "Primary cutaneous anaplastic large cell lymphoma" and "Breast implant-associated anaplastic large cell lymphoma".)

●Primary cutaneous peripheral T cell lymphomas – There are numerous cutaneous T cell lymphomas. Mycosis fungoides (MF) is the most common of these. Sézary syndrome is an erythrodermic, leukemic variant of MF. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides" and "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome" and "Primary cutaneous anaplastic large cell lymphoma".)

●Adult T cell leukemia-lymphoma (ATL) – ATL is a highly aggressive peripheral T cell neoplasm most often comprised of highly pleomorphic lymphoid cells. It is derived from CD4-positive T cells that are latently infected with the human T cell leukemia virus (HTLV), type 1 and often presents with generalized lymphadenopathy, hepatosplenomegaly, immunosuppression, hypercalcemia, lytic bone lesions, and skin lesions. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

●T cell large granular lymphocyte leukemia (LGL) – T cell LGL leukemia is a disorder of clonally expanded T cell large granular lymphocytes that invade the bone marrow, spleen, and liver. (See "Treatment of large granular lymphocyte leukemia".)

●T cell prolymphocytic leukemia (T-PLL) – T cell prolymphocytic leukemia is an aggressive tumor comprised of small to medium-sized mature T cells. (See "Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia".)

●Natural killer (NK) cell large granular lymphocyte leukemia (LGL) – NK cell LGL leukemia, also called chronic lymphoproliferative disorder of NK cells, is an indolent NHL variant involving malignant NK cells. Its clinical presentation is more aggressive than that of T cell LGL leukemia. (See "Natural killer (NK) cell large granular lymphocyte leukemia".)

●Aggressive natural killer cell leukemia – Aggressive NK cell leukemia is a very rare aggressive leukemia derived from NK cells. The highest prevalence is among Asians. It is often EBV-associated and may represent a leukemic variant of extranodal NK/T cell nasal type lymphoma. (See "Natural killer (NK) cell large granular lymphocyte leukemia".)

NEOPLASMS WITH MYELOID AND LYMPHOID LINEAGE — Some neoplasms express markers of both myeloid and lymphoid lineages or neither of these:

●Myeloid/lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, or a PCM1-JAK2 fusion gene. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

●Acute leukemias of ambiguous lineage – The acute leukemias of ambiguous lineage include leukemias that either have no features of lymphoid or myeloid lineage (eg, acute undifferentiated leukemia) or features of both lymphoid and myeloid lineages (eg, mixed phenotype or mixed lineage acute leukemia) [9].

HISTIOCYTIC/DENDRITIC NEOPLASMS — Histiocytic/dendritic neoplasms are those derived from those cells that normally develop into accessory antigen presenting cells (dendritic cells) or connective tissue macrophages (histiocytes) (table 1):

●Histiocytic sarcoma

●Tumors derived from Langerhans cells (see "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis")

●Interdigitating dendritic cell sarcoma

●Follicular dendritic cell sarcoma

●Erdheim-Chester disease (see "Erdheim-Chester disease")

●Disseminated juvenile xanthogranuloma

●Other rare dendritic cell tumors

An alternative classification from the Histiocyte Society is presented separately [10]. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Histiocytic disorders'.)

SUMMARY — Most malignancies of the hematopoietic and lymphoid tissues fall into distinct diagnostic categories that are defined by morphologic, immunophenotypic, genetic, and clinical features. Malignancies that do not fit defined entities are placed in categories that capture diverse tumors (eg, peripheral T cell lymphoma, not otherwise specified) or in borderline "grey zone" categories that are used for cases that share features of more than one entity (eg, Hodgkin lymphoma and diffuse large B cell lymphoma). When possible, the different tumor types are grouped by lineage as follows:

●Myeloid neoplasms (table 2) – Derived from those bone marrow progenitor cells that normally develop into erythrocytes, granulocytes (neutrophils, basophils, and eosinophils), monocytes, or megakaryocytes. These neoplasms can be categorized into three broad clinicopathologic classes:

•Acute myeloid leukemia (AML) – AML is defined by greater than 20 percent myeloid blasts in the bone marrow or peripheral blood, or the presence of particular cytogenetic abnormalities, regardless of the blast count. (See 'Acute myeloid leukemia and related aggressive myeloid neoplasms' above.)

•Myeloproliferative neoplasm (MPN) – Clonal stem cell disorders associated with the proliferation of one or more of the myeloid lineages (eg, granulocytic, erythroid, or megakaryocytic). (See 'Myeloproliferative neoplasms' above.)

•Myelodysplastic syndromes (MDS) – Disorders that exhibit dysplasia and ineffective blood cell production. (See 'Myelodysplastic syndromes (MDS)' above.)

Of note, some cases show features that overlap between those of a MPN and a MDS, and all MPN and MDS have the potential to transform into AML. (See 'MDS/MPN syndromes' above.)

•Mastocytosis – Disorders characterized by the accumulation of pathologic mast cells in tissues. These are often associated with mutations that activate the tyrosine kinase activity of the c-KIT receptor. (See 'Mastocytosis' above.)

●Lymphoid neoplasms (table 1) – Derived variously from B cell progenitors (bone marrow derived), T cell progenitors (thymus-derived), mature T lymphocytes (cytotoxic T cells, helper T cells, or T regulatory cells) or mature B lymphocytes (B cells or plasma cells). Historically, lymphoid neoplasms that present with bone marrow and blood involvement (leukemia) have been segregated from those that present as a mass (lymphoma). However, it is now appreciated that any "lymphoma" can present with or evolve to a leukemic picture, and any "leukemia" can occasionally present as a mass. Lymphoid neoplasms are mainly grouped depending upon whether they are of B, T, or natural killer (NK) cell derivation. (See 'Lymphoid neoplasms' above.)

●Histiocytic/dendritic neoplasms (table 1) – Derived from cells that normally develop into "professional" antigen presenting cells (dendritic cells) or tissue macrophages (histiocytes). (See 'Histiocytic/dendritic neoplasms' above.)

There are also neoplasms that show evidence of both myeloid and lymphoid differentiation, presumably because they are derived from multipotent progenitor cells. Such cases are given their own category, neoplasms of myeloid and lymphoid lineage. (See 'Neoplasms with myeloid and lymphoid lineage' above.)