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Classification of hematopoietic neoplasms

Classification of hematopoietic neoplasms
Authors:
Arnold S Freedman, MD
Jonathan W Friedberg, MD
Jon C Aster, MD, PhD
Sandeep Gurbuxani, MBBS, PhD
Mikkael A Sekeres, MD, MS
Section Editors:
Andrew Lister, MD, FRCP, FRCPath, FRCR
Bob Lowenberg, MD, PhD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 30, 2022.

INTRODUCTION — Classification of hematopoietic neoplasms is essential for making proper evidence-based treatment decisions and accurately assessing prognosis. The earliest classification schemes for hematologic malignancies were based on tissue architecture and cytologic appearance, but beginning in the 1990s, newer schemes increasingly incorporated immunophenotypic, cytologic, and molecular findings. Contemporary classification schemes of hematopoietic neoplasms are based on cellular lineage (according to immunophenotype), clinical attributes (eg, acute versus chronic, cytopenias/cytoses), and genetic features (eg, gene fusions, rearrangements, mutations).

Beginning with the third World Health Organization (WHO) Classification of Hematologic Malignancies in 2001, successive editions of the WHO classification scheme have been used by consensus among pathologists. However, in 2022, in addition to publication of a newly revised WHO fascicle, another classification scheme was published. Despite some differences, both schemes incorporate additional genetic findings and it is likely that most pathologists will provide diagnoses using both of the following new schemes:

International Consensus Classification (ICC) [1,2]

World Health Organization 5th edition (WHO5) [3,4]

This topic compares the ICC and WHO5 classification schemes with each other. Earlier nosologic schemes are included in the discussion to enable interpretation of data in the older literature and for care of patients previously treated for conditions with now-outdated names.

Details of classification, pathogenesis, evaluation, diagnosis, treatment, and prognosis of specific disease entities are presented separately.

OVERVIEW — Classification schemes for hematologic malignancies continue to evolve with greater insight into pathologic features, pathophysiology, management, and outcomes. Two distinct classification schemes for hematopoietic neoplasms were published in 2022: the International Consensus Classification (ICC) [1,2] and the World Health Organization 5th edition (WHO5) [3,4]. We favor use of either of these new schemes, rather than the WHO revised 4th edition (WHO4R) [5] and earlier nosologic schemes.

International Consensus Classification (ICC) — The ICC was created under the auspices of the United States-based Society for Hematopathology (SH) and the European Association for Haematopathology (EAHP), with input from clinical advisory committees (CACs), which included pathologists, hematologists, oncologists, geneticists, and bioinformaticians. Many of the contributors to ICC participated in WHO4R, but they objected when a proposed WHO 5th edition did not include involvement by SH, EAHP, and CACs. ICC is not affiliated with the WHO.

World Health Organization 5th edition (WHO5) — WHO5 is a successor to earlier editions of the WHO classification scheme (so-called "blue book" monographs) that were prepared under the aegis of the International Agency for Research on Cancer (IARC). Rather than seek input from CACs, WHO5 created subject content by directly engaging multidisciplinary author teams that included hematopathologists, hematologists, oncologists, geneticists, epidemiologists, molecular biologists, and others. As described above, because of the schism in hematopathology, the WHO5 was produced without input from SH, EAHP, and CACs.

Previous classification schemes — The earliest classification systems were primarily based on tissue architecture and histologic appearance. Later models incorporated immunophenotypic, cytologic, and molecular features as key findings were validated. Familiarity with earlier classification schemes is valuable for interpreting older literature and to care for patients treated for conditions that used these now-outdated disease names.

Multiple classification schemes have been employed over the years; prominent earlier schemes include:

Rappaport classification [6]

Kiel classification [7]

Lukes-Collins classification [8]

Working Formulation [9]

Revised European-American classification (REAL) [10]

French-American-British (FAB) system [11]

WHO 3rd edition (2001) [12], 4th edition (2008) [13], and revised 4th edition (2016) [5]

Comparison of ICC and WHO5 — Both the ICC and WHO5 schemes continue to classify hematopoietic neoplasms by integrating morphology (cytology, histology, tissue architecture), clinical attributes (eg, acute versus chronic, cytopenias/cytoses), lineage (based on immunophenotype), and cytogenetic and molecular features [1-4,14].

Most major differences between ICC and WHO5 involve the organization of myeloid neoplasms into different disease categories. In addition, there are differences throughout both schemes in naming otherwise identical entities and in diagnostic criteria for particular neoplasms [1-4,14]. Similarities and differences between the ICC and the WHO5 schemes are described under the following broad categories:

Myeloid neoplasms – Include myeloproliferative neoplasms (such as chronic myeloid leukemia), acute myeloid leukemia, myelodysplastic neoplasms/syndromes, and other myeloid disorders. (See 'Myeloid neoplasms' below.)

Lymphoid neoplasms – Include acute lymphoblastic leukemia/lymphoblastic lymphoma, mature B cell neoplasms (eg, chronic lymphocytic leukemia, follicular lymphomas, multiple myeloma, diffuse large B cell lymphoma), mature T cell neoplasms, Hodgkin lymphoma, and other lymphoid neoplasms. (See 'Lymphoid neoplasms' below.)

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions – (See 'Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions' below.)

Mastocytosis – (See 'Mastocytosis' below.)

Histiocytic/dendritic neoplasms – (See 'Histiocytic/dendritic neoplasms' below.)

Mixed myeloid and lymphoid neoplasms – (See 'Neoplasms with mixed or ambiguous lineage' below.)

MYELOID NEOPLASMS — Myeloid neoplasms are primarily derived from marrow progenitor cells that can differentiate into erythrocytes, granulocytes, monocytes, or megakaryocytes. An exception is chronic myeloid leukemia (CML), in which the cell of origin is a pluripotent hematopoietic stem cell that can also give rise to lymphoid cells.

Overview of the ICC and WHO5 myeloid classification schemes

Similarities – Both the International Consensus Classification (ICC) [1] and World Health Organization 5th edition (WHO5) [3] include the following broad clinicopathologic classes of myeloid neoplasms:

Myeloproliferative neoplasms (MPN) – (See 'Myeloproliferative neoplasms' below.)

Myelodysplastic neoplasms/syndromes (MDS) – (See 'Myelodysplastic neoplasms/syndromes' below.)

Acute myeloid leukemias (AML) – (See 'Acute myeloid leukemia' below.)

Myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) – (See 'Myelodysplastic neoplasms/syndromes' below.)

Differences – ICC [1] and WHO5 [3] differ in how they account for particular cytogenetic/molecular findings, group certain distinctive myeloid malignancies, and distinguish between AML and MDS with increased blasts. They also differ in how they describe phases of CML; classify cases with mutated TP53; and address neoplasms that arise during disease evolution, following cytotoxic treatment, or that are associated with germline pathogenic gene variants.

Key differences in classification of myeloid disorders between ICC and WHO5 include:

Distinction between MDS and AML – Emerging data suggest that the biology and treatment response of MDS with high blast counts (ie, 10 and 19 percent) represent a continuum with AML. ICC recognizes this by creating "MDS/AML," a new diagnostic category for such myeloid neoplasms. While WHO5 retains the name "MDS with increased blasts-2" for these neoplasms, it acknowledges that this category "may be regarded as AML-equivalent for therapeutic considerations and from a clinical trial design perspective when appropriate." (See 'Myelodysplastic neoplasms/syndromes' below.)

Myeloid neoplasms with TP53 mutations – Certain combinations of TP53 abnormalities influence prognosis of myeloid neoplasms, independent of the blast count. ICC recognizes this by creating new categories for MDS, MDS/AML, or AML with TP53 abnormalities. While the WHO5 does not create specific categories for myeloid malignancies with TP53 mutations, the WHO5 monograph acknowledges that MDS with multiple TP53 abnormalities may be regarded as being equivalent to AML for treatment purposes. (See 'Myeloid neoplasms with mutated TP53' below.)

Disorders associated with germline pathogenic gene variants – Certain germline pathogenic variants are associated with unique biological attributes that maybe seen across all age groups. In response, ICC grouped disorders such as juvenile myelomonocytic leukemia (JMML) in a new category, "Pediatric and/or germline mutation-associated disorders." While such disorders continue to be grouped with other myeloid neoplasms (eg, MPN, AML) in WHO5, the modifier "associated with germline (gene) variant" is used to indicate an association with a germline pathogenic variant. (See 'Pediatric and/or germline mutation-associated disorders' below.)

Treatment-related myeloid neoplasms – Both ICC and WHO5 acknowledge the role of genetics and exposure to prior cytotoxic therapy in determining the biology of myeloid malignancies that arise after exposure to prior cytotoxic therapy. However, to reduce redundancy in describing what might be biologically overlapping entities, ICC uses the diagnostic qualifier, "therapy-related" following the diagnosis of MDS, AML, or MDS/AML. By contrast, WHO5 groups treatment-related myeloid neoplasms in a new category, "Myeloid neoplasms post-cytotoxic therapy"; assignment to this category is based on medical history, rather than the specific disease and/or genetic features. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

These and other differences in classification of specific disorders are discussed below and in separate topics.

Categories of myeloid neoplasms

Myeloproliferative neoplasms — MPNs are clonal stem cell disorders associated with excessive proliferation of one or more myeloid progenitors (eg, granulocytic, erythroid, or megakaryocytic). Hematopoiesis is usually effective and, combined with increased numbers of progenitors, typically leads to an increase in one or more of the cellular elements in peripheral blood. Bone marrow cellularity is usually increased and the percentage of blasts in marrow may be increased, but the blast percentage is always <20 percent. Most MPNs are associated with mutations that cause abnormal activation of pro-growth signaling pathways, leading to growth factor-independent proliferation of marrow progenitor cells.

The following entities are included in the MPN category by both ICC [1] and WHO5 [3]:

Chronic myeloid leukemia – In CML, excessive proliferation of the granulocytic lineage leads to increases at all stages of myeloid maturation. CML is always associated with a BCR::ABL1 fusion gene, which is usually created by a (9;22) chromosomal translocation the leads to formation of a derivative chromosome 22, known as the Philadelphia chromosome, after the city in which it was discovered. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

ICC and WHO5 include the same diagnostic criteria for CML, but their labels for disease phases of CML differ; ICC describes three phases (ie, chronic phase, accelerated phase, and blast phase), while WHO5 describes two phases (ie, chronic phase, blast phase).  

Classic BCR::ABL1-negative MPNs – The following "classic" MPNs lack the BCR::ABL1 fusion gene:

Polycythemia vera (PV) PV presents with an increased hematocrit/red blood cell mass. In virtually all cases, PV is associated with a gain-of-function mutation in the gene encoding the tyrosine kinase JAK2 (usually JAK2 V617F). Diagnostic criteria are the same in ICC and WHO5. (See "Clinical manifestations and diagnosis of polycythemia vera".)

Essential thrombocythemia (ET) – ET is a clonal disorder associated with thrombocytosis. Activating mutations in the gene encoding the non-receptor tyrosine kinase JAK2 are found in about half of cases. Other cases are associated with activating mutations in MPL (which encodes the thrombopoietin receptor [TPO-R]; 5 percent of cases), or in CALR (which encodes a protein, that when mutated, is secreted and binds and activates TPO-R; 25 to 35 percent of cases) [15].

Diagnostic criteria for ET are the same in both systems. (See "Diagnosis and clinical manifestations of essential thrombocythemia".)

Primary myelofibrosis (PMF) – PMF (previously called agnogenic myeloid metaplasia or chronic idiopathic myelofibrosis) is characterized by bone marrow fibrosis caused by a polyclonal increase in fibroblasts. Like ET, it is associated with mutations in JAK2, MPL, and CALR in approximately 50, 5, and 30 percent of cases, respectively.

PMF may manifest as an early/prefibrotic phase associated with high granulocyte and/or platelet counts and minimal bone marrow fibrosis, or as an overt fibrotic phase associated with increased bone marrow reticulin and/or collagen fibrosis, osteosclerosis, and extramedullary hematopoiesis. ICC and WHO5 apply the same criteria for early/prefibrotic phase PMF and overt fibrotic PMF. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

Chronic neutrophilic leukemia (CNL) – CNL is a rare entity characterized by overproduction of mature granulocytes and the absence of the BCR::ABL1 fusion gene; >60 percent of cases are associated with CSF3R mutations.

Diagnostic criteria are similar in ICC and WHO5. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

Chronic eosinophilic leukemia (CEL) – CEL is a multisystem disorder characterized by clonal proliferation of morphologically abnormal eosinophils and eosinophil precursors that results in persistent hypereosinophilia in blood and marrow.

WHO5 requires proof of clonality (eg, cytogenetic abnormalities or pathogenic mutations) to diagnose CEL, whereas ICC relies on clinical and morphologic features to establish the diagnosis and to differentiate CEL from other hypereosinophilic syndromes. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

Myeloproliferative neoplasm, unclassifiable – This category describes cases with clinical, laboratory, morphologic, and molecular features of an MPN that do not satisfy diagnostic criteria for any specific category of MPN or have features that overlap distinct MPN types.

This category is referred to as "MPN, unclassifiable" in ICC, while such cases are labeled "MPN, not otherwise specified (NOS)" in WHO5. (See "Overview of the myeloproliferative neoplasms".)

Myelodysplastic neoplasms/syndromes — MDS refers to hematopoietic neoplasms that exhibit morphologic dysplasia, persistent cytopenia(s) due to ineffective blood cell production, and a variable risk of progression to AML or bone marrow failure. Bone marrow cellularity is often increased, but it may be normocellular or hypocellular; the percentage of blasts in the bone marrow is normal or increased, and dysplasia is generally noted in one or more myeloid lineages.

Both ICC and WHO5 recognize the significance of bone marrow blast count, degree of dysplasia, and genetic abnormalities for categorizing MDS. However, their labels for specific MDS subtypes, diagnostic criteria, and distinctions between MDS and AML differ considerably. Both systems use the abbreviation "MDS," but ICC retains the name "Myelodysplastic syndromes," whereas WHO5 renames these entities "Myelodysplastic neoplasms."

MDS subtypes are organized differently in the two classification schemes:

ICC – A distinction is drawn between MDS with low blast counts (<5 percent blasts in bone marrow) versus higher blast counts (≥5 percent in bone marrow):

MDS with blasts <5 percent – Three distinct entities are recognized by ICC among cases with low blast counts: "MDS with mutated SF3B1," "MDS with del(5q)," and "MDS with mutated TP53."

Other cases of MDS with <5 percent blasts are classified as "MDS, NOS" and are further classified as having no dysplasia, single lineage dysplasia, or multilineage dysplasia. In the absence of dysplasia, the category of "MDS, unclassifiable" was eliminated and replaced by "MDS, NOS," which is used only for cases of MDS with cytopenias, -7/del(7q), or complex karyotype.

MDS with higher blast counts – Cases of MDS with 2 to 9 percent blasts in peripheral blood and 5 to 9 percent blasts in bone marrow are classified as "MDS with excess blasts." Cases with 10 to 19 percent blasts that lack a defining AML genetic feature are labeled "MDS/AML."

Cases with MDS-defining genetic abnormalities in association with cytopenia(s), but without dysplasia, are now considered "Clonal cytopenia of undetermined significance (CCUS)." (See "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)".)

WHO5 – MDS subtypes are grouped according to the presence of a defining genetic abnormality versus no such abnormality; the latter group (ie, "MDS, morphologically defined") classifies cases according to blast count, hypoplasia, and/or fibrosis.

WHO5 recognizes a new entity, "Hypoplastic MDS," renames "MDS with low blasts" (previously, simply MDS) and "MDS with increased blasts" (previously, "MDS with excess blasts"), and eliminates distinctions for unilineage versus multilineage dysplasia.

The entity previously known as refractory cytopenia of childhood (RCC) is now labeled "Childhood MDS" in WHO5, while in ICC, it is included in "Pediatric and/or germline mutation-associated disorders" (rather than MDS). (See 'Pediatric and/or germline mutation-associated disorders' below.)

Details of MDS subtypes are presented separately. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Diagnosis and classification'.)

MDS/MPN syndromes — MDS/MPNs are disorders in which both dysplastic and proliferative features coexist.

Chronic myelomonocytic leukemia (CMML) – Both ICC and WHO5 include CMML as an MDS/MPN. In the revised 4th edition of WHO (WHO4R), CMML was subdivided into three groups, CMML-0, CMML-1, and CMML-2, based on blast counts in peripheral blood and marrow [5].

Both ICC and WHO5 eliminated CMML-0 because of its limited prognostic significance, but both schemes acknowledge the significance of clonal genetic abnormalities that permit a diagnosis of CMML with a relatively lower absolute monocyte count (ie, 0.5 x 109/L) [1,3].

The significance of RAS pathway mutations and their association with a proliferative type of CMML is recognized by both classifications, but only WHO5 distinguishes cases according to the peripheral white blood cell (WBC) count: "Myeloproliferative CMML" with WBC count ≥13 x 109/L versus "Myelodysplastic CMML" (WBC count <13 x 109/L). The rationale for creating these two CMML subtypes in WHO5 is that the myeloproliferative subtype is generally associated with activating mutations in RAS pathway components and inferior clinical outcomes. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

Atypical chronic myeloid leukemia – This BCR::ABL1-negative MDS/MPN was called "Atypical CML, BCR::ABL1-negative" in WHO4R. It continues to be called "Atypical CML" in ICC, whereas in WHO5 it is renamed "MDS/MPN with neutrophilia" to avoid potential confusion with CML. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Atypical CML'.)

MDS/MPN with SF3B1 mutation/ring sideroblasts and thrombocytosis – This new category was called "MDS/MPN with ring sideroblasts and thrombocytosis" in WHO4R.

The WHO5 recognizes a single category of MDS/MPN with SF3B1 mutation and thrombocytosis. In the ICC scheme, most such cases are labeled "MDS/MPN with thrombocytosis and SF3B1 mutation," but cases that have SF3B1 mutations but no ring sideroblasts are labeled "MDS/MPN with SF3B1 mutation and thrombocytosis, NOS."

Further discussion of MDS/MPNs is provided separately. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

Acute myeloid leukemia — AML comprises a group of aggressive, genetically heterogeneous myeloid malignancies. Both ICC and WHO5 have made significant changes in AML classification from WHO4R. We consider both ICC or WHO5 classifications acceptable and favor their use rather than WHO4R [5] and the earlier French-American-British (FAB) system [11]. (See 'Previous classification schemes' above.)

Changes from WHO4R — Both ICC [1] and WHO5 [3] place greater emphasis on genetically defined criteria for classification of AML. Differences include:

AML subtypes – Many of the AML subtypes from WHO4R are retained by both ICC and WHO5, but some labels have changed and/or differ between ICC and WHO5. Specific AML subtypes are described separately. (See "Classification of acute myeloid leukemia (AML)".)

Myeloblast threshold – Importantly, both ICC and WHO5 no longer require ≥20 percent myeloid blasts in bone marrow or blood for many subtypes of AML that have defining genetic abnormalities. Subtypes without a defining genetic abnormality and 10 to 19 percent blasts have been renamed "MDS/AML" in the ICC, whereas these cases are classified as "MDS with increased blasts-2" in the WHO5.

Subtypes eliminated – ICC and WHO5 both eliminated AML with somatic RUNX1 mutation, because RUNX1 mutations in AML overlap with a broad range of defining molecular features. Both also eliminated AML with myelodysplasia-related changes (a subtype of AML defined by morphologic features) and created new categories of AML defined by the presence of cytogenetic and/or genetic changes associated with MDS.

Other changes include:

ICC – Other AML subtypes eliminated in the ICC scheme include:

-Categories associated with prior therapy, antecedent myeloid neoplasms (ie, MDS or MDS/MPN), or underlying germline genetic disorders that predispose to AML are no longer considered specific disease categories. Rather, these descriptors are added as qualifiers to specific AML subtypes to reduce overlap between former specific AML categories.

-Pure erythroid leukemia was subsumed into AML with TP53 mutation to increase use of objective genetic findings in AML subtyping.

WHO5 – Other AML subtypes eliminated in WHO5 include:

-AML, NOS was replaced by subtypes based on the stage of differentiation.

Differences between ICC and WHO5 — Key differences between ICC [1] and WHO5 [3] for AML classification include:

Treatment-related and inherited disorders – ICC adds these terms as qualifiers to the specific category of AML. By contrast, WHO5 includes them in a new category, "Secondary myeloid neoplasms."

AML with defining genetic characteristics – ICC distinguishes some subtypes according to more specific categories. As an example, acute promyelocytic leukemia (APML) with t(15;17)/PML::RARA is distinct from APML with other RARA rearrangements; by contrast, all cases of APML are grouped as a single subtype by WHO5.

WHO5 created a category, "AML with other defined genetic abnormalities," as a placeholder for AML with as-yet-undescribed findings.

AML without defining genetic abnormalities – With the increase of AML subtypes based on distinctive genetic characteristics, the fraction of cases assigned to "AML, NOS" has decreased substantially.

ICC retained the category "AML, NOS" for cases that have ≥20 percent blasts, but no defining genetic abnormality; such cases with 10 to 19 percent blasts are now described as "MDS/AML." WHO5 replaced "AML, NOS" with eight subtypes that are defined by the stage and type of differentiation.

Pure erythroid leukemia, which almost always has mutated TP53, was eliminated in ICC and, instead, is subsumed in AML with TP53 mutation. WHO5 retained this as a differentiation-based category, with the preferred label being "Acute erythroid leukemia."

Myeloid proliferations related to Down syndrome (DS) – Myeloid proliferations associated with DS comprise a new category in ICC that includes "Transient abnormal myelopoiesis (TAM) associated with DS" and "Myeloid leukemia associated with Down syndrome (ML-DS)." (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)" and "Myeloid leukemia associated with Down syndrome (ML-DS)".)

In WHO5, these disorders are included in "Myeloid neoplasms associated with germline predisposition."

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".)

Myeloid neoplasms with mutated TP53 — This is a new category of myeloid neoplasms in the ICC scheme [1] that subclassifies myeloid conditions (ie, MDS, MDS/AML, or AML) with TP53 mutations according to blast count. This category was created in recognition of shared biology and treatment responses between these entities.

MDS with mutated TP53 (<10 percent blasts)

MDS/AML with mutated TP53 (10 to 19 percent blasts)

AML with mutated TP53 (>20 percent blasts)

While multi-hit TP53 mutation (ie, mutations of both TP53 alleles) is required to diagnose MDS with mutated TP53, any pathogenic TP53 mutation with variant allele frequency (VAF) >10 percent is sufficient for the diagnosis of AML and MDS/AML with mutated TP53.

There is no corresponding category of myeloid disorders with TP53 mutations in WHO5; instead, these disorders are included in the specific disease categories (ie, MDS, AML). WHO5 does include a subtype of MDS with TP53 mutations and does not distinguish such cases according to blast percentages.

LYMPHOID NEOPLASMS — Lymphoid neoplasms arise from cells that normally develop into T lymphocytes (eg, cytotoxic T lymphocytes, helper T lymphocytes, regulatory T lymphocytes) or B lymphocytes (lymphocytes or plasma cells). Lymphoid neoplasms are grouped according to whether they are of B or T cell derivation and are further divided into those that correspond to lymphoid precursors versus neoplasms of mature lymphocytes and plasma cells.

It should be recognized that lymphoid tumor masses (ie, lymphomas) can progress to involve marrow and blood (ie, a leukemia), and vice versa. As a result, lymphoid neoplasms are described according to the cell of origin (based on morphology, immunophenotype, and genetic findings), rather than anatomic location, per se (ie, extramedullary mass versus blood/bone marrow). Thus, different clinical presentations of certain lymphoid malignancies, such as acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL), are considered a single disease entity.

Comparison of lymphoid classification systems — Both the International Consensus Classification (ICC) [1,2] and the World Health Organization 5th edition (WHO5) [4] organize lymphoid malignancies according to immunophenotype (ie, B cell lineage versus T cell and NK cell-associated neoplasms); these categories are further divided into precursor neoplasms versus mature neoplasms.

Similarities – There are no major changes in the broad categories of lymphoid malignancies in ICC and WHO5, compared with the WHO revised 4th edition (WHO4R) [5].

Differences – Both schemes include changes in nomenclature and classification of certain lymphoid neoplasms. Notable changes include:

WHO5 – WHO5 added two new categories of lymphoid malignancies ("Transformations of indolent B cell lymphomas," "Primary large B cell lymphoma of immune-privileged sites") and a category of tumors and tumor-like lesions with B cell predominance ("Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation").

WHO5 also created "Splenic B cell lymphoma/leukemia with prominent nucleoli" by merging two rare entities from WHO4R, "Hairy cell leukemia variant" (a provisional entity) and "B prolymphocytic leukemia."

ICC – ICC retained "B prolymphocytic leukemia" and "Hairy cell leukemia variant" (a provisional entity in need of further study).

Further details of terminology and diagnostic criteria are discussed separately in disease-specific topics.

Categories of lymphoid neoplasms — Both ICC [2] and WHO5 [4] group lymphoid neoplasms according to whether they are of B cell versus T cell/NK cell derivation and whether they correspond to lymphoid precursors versus neoplasms of mature lymphocytes and plasma cells.

Precursor lymphoid neoplasms — These aggressive precursor lymphoid neoplasms are referred to as "Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL)" because individual cases can evolve from lymphoma to leukemia (and vice versa) and because leukemic and lymphomatous clinical presentations are biologically indistinguishable.

There are two main categories of ALL/LBL:

B cell ALL/LBL – This category includes most cases of ALL/LBL. Individual cases are classified according to genetic features, including whether the lymphoblasts have abnormal numbers of chromosomes (ie, hyperdiploid, hypodiploid) and the presence of specific cytogenetic/molecular features.

T cell ALL/LBL – Approximately 15 percent of ALL/LBL corresponds to precursor T cells. While most cases have identifiable genetic abnormalities, these findings are not used to define T cell ALL/LBL subtypes. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Both ICC and WHO5 have added new cytogenetic and molecular subtypes of ALL/LBL and they use different labels and/or diagnostic criteria for certain categories. Classification of B cell and T cell ALL/LBL are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "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 according to tissue architecture; morphology, immunophenotype, and genetic features of the tumor cells; and their apparent correspondence to normal stages of B cell development (eg, naïve B cells, germinal center B cells, post-germinal center memory B cells, plasma cells).

The most common B cell neoplasms are derived from cells that have experienced a germinal center reaction, which is initiated when antigen-stimulated B cells migrate into the germinal centers of secondary lymphoid organs (eg, lymph nodes, spleen, and mucosa associated lymphoid tissues) [16]. Germinal center B cells proliferate and undergo diversification of immunoglobulin (Ig) genes via somatic hypermutation and heavy chain class-switching. Most tumors of mature B cells show evidence of somatic hypermutation; errors that can occur during somatic hypermutation and class-switching are thought to be responsible for many of the acquired mutations that lead to B cell transformation. (See "Normal B and T lymphocyte development".)

Broad categories of mature B cell neoplasms include:

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) – CLL/SLL is a malignancy of small, mature-appearing lymphocytes that can present either as a leukemia (CLL) or a corresponding lymphoma (SLL). CLL is the most common leukemia in Western countries, accounting for approximately 30 percent of all leukemias in the United States. In most cases, Ig genes are somatically hypermutated; the remaining cases appear to derive from naïve B cells.

There is no change in classification of CLL/SLL by ICC [2] or WHO5 [4]. (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; the tumor comprises small lymphocytes, plasmacytoid lymphocytes, and plasma cells and is usually associated with a serum monoclonal protein. Waldenström macroglobulinemia is a clinicopathologic entity usually associated with LPL with levels of IgM monoclonal gammopathy that are sufficiently high to produce symptoms related to hyperviscosity.

There are no major changes in diagnostic criteria for LPL. Both ICC and WHO5 include a category, "IgM monoclonal gammopathy of undetermined significance," which is divided into two subtypes in ICC. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma" and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

Monoclonal gammopathies – Both ICC and WHO5 added a new category for primary cold agglutinin disease and there are differences in labels for various monoclonal gammopathies.

Primary cold agglutinin disease – This is a new entity in both ICC and WHO5. (See "Cold agglutinin disease".)

Monoclonal gammopathy (MGUS) of non-IgM type – There are no major changes in classification of non-IgM MGUS, but both systems add descriptors for MGUS with renal or clinical significance. (See "Diagnosis of monoclonal gammopathy of undetermined significance".)

Amyloidosis – ICC distinguishes Ig light chain (AL) amyloidosis from localized AL amyloidosis. In WHO5, the term, "Immunoglobulin-related (AL) amyloidosis," is preferred rather than "Primary amyloidosis." (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Plasma cell neoplasms – Multiple myeloma, solitary plasmacytoma of blood, and extraosseous plasmacytoma result from clonal expansion of terminally differentiated germinal center-derived B lymphocytes that typically secrete a monoclonal immunoglobulin (M protein).

Both ICC and WHO5 distinguish multiple myeloma with specific genetic findings (eg, hyperdiploidy; translocation of CCND family genes, MAF family genes, or NSD2) from "Multiple myeloma, not otherwise specified (NOS)." (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

Both ICC and WHO5 assign amyloid-related disorders to a new category, "Monoclonal immunoglobulin deposition diseases." (See "Monoclonal immunoglobulin deposition disease".)  

Hairy cell leukemia – This indolent B cell lymphoproliferative neoplasm of post-germinal center B cell origin usually has circulating tumor cells with characteristic prominent irregular ("hairy") cytoplasmic projections and unique immunophenotypic features. (See "Clinical features and diagnosis of hairy cell leukemia".)

Marginal zone lymphoma (MZL) – The neoplastic cells of MZL are small mature B cells that are typically negative for CD5 and CD10. There are no major changes in diagnostic criteria for MZL.

Both systems include "Splenic MZL" as a distinct category and, among cases of extranodal MZL, both distinguish mucosa-associated lymphoid tissue (MALT lymphoma) from cutaneous MZL. In WHO5, these cutaneous proliferations retain the name, "Cutaneous MZL," whereas in ICC, the name was revised to "Primary cutaneous marginal zone lymphoproliferative disorder," in recognition of their extremely indolent behavior and excellent clinical outcomes without aggressive therapy. (See "Nodal marginal zone lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Follicular lymphoma – Follicular lymphoma (FL) is composed of neoplastic germinal center B cells that recapitulate the appearance of normal germinal centers of secondary lymphoid follicles. FL is the second most common category of lymphoma in the United States and Europe.

The WHO5 made several changes in the classification of FL:

Classic FL – The majority of cases are in a group called, "Classic FL subtype," a follicular proliferation of small and larger neoplastic cells (centrocytes and centroblasts, respectively) that have the t(14;18)/IGH::BCL2 fusion gene.

Grading of classic FL is based on the number of centroblasts, but this is no longer considered mandatory in WHO5 because of poor reproducibility.

FL grade 3B – WHO5 renamed FL grade 3B, a follicular proliferation of centroblasts, as "Follicular large B cell lymphoma," recognizing that this neoplasm behaves and responds to therapy like diffuse large B cell lymphoma. By contrast, the ICC retained the name, "FL grade 3B" for these lesions.

FL with unusual features – WHO5 created this new category, which includes two subtypes:

-FL with blastoid features – This subtype has high-grade morphologic features, may have atypical immunophenotypic or genetic features, and appears to follow a more aggressive course than classic FL. No mention is made of this subtype in the ICC.

-FL with predominantly diffuse growth pattern – This subtype typically presents with localized inguinal involvement, often expresses CD23, lacks the t(14;18), and instead harbors 1p36 deletions and/or TNFRSF14 mutations and STAT6 mutations. This subtype is recognized in the ICC under the name, "BCL2 rearrangement-negative, CD23-positive follicle center cell lymphoma."

Details of diagnosis and classification of FL are described separately. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

Mantle cell lymphoma (MCL) – MCL comprises 7 percent of adult non-Hodgkin lymphoma (NHL) in the United States and Europe. In approximately 80 percent of cases of MCL, the cell of origin is a naïve B cell, while the remaining cases are somatically hypermutated and apparently derived from antigen-stimulated B cells. Translocation of CCND1 (which encodes cyclin D1) with Ig genes is the genetic hallmark of MCL.

Both the ICC and WHO5 added "Leukemic non-nodal MCL" as a new MCL subtype; this typically presents with peripheral blood involvement and follows an indolent course. WHO5 also added "In situ mantle cell neoplasm" as a new category. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma".)

Diffuse large B cell lymphoma (DLBCL) – This is the largest category of mature B cell lymphomas. Despite >150 recurrently mutated genetic drivers in DLBCL [17], the significance of specific genetic subgroups of DLBCL is not well-established; as a result, "DLBCL, not otherwise specified (NOS)" accounts for most cases.

There are no new diagnostic criteria for DLBCL in either ICC or WHO5, but the classification schemes differ in the names and numbers of subtypes. Both systems continue to endorse designation of cell-of-origin (COO) status of DLBCL, NOS; COO status is referred to as germinal center B cell (GCB) origin versus activated B cell-like (ABC, or non-GCB). Both ICC and WHO5 added "Large B cell lymphoma with IRF4 rearrangement" as a new subtype.

Diagnosis and classification of DLBCL are discussed separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

High-grade B cell lymphomas – This category includes Burkitt lymphoma; high-grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement; high-grade B cell lymphoma, NOS; and aggressive B cell lymphomas with 11q aberration.

Burkitt lymphoma (BL) – This is a highly aggressive B cell neoplasm with rapidly growing tumor masses and/or evidence of tumor lysis, which can present in one of three distinct clinical forms: endemic, sporadic, and immunodeficiency associated. This is a well-defined clinicopathologic entity and there are no major differences in diagnostic criteria among WHO4R, ICC, and WHO5. Classification of Burkitt lymphoma is discussed separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)

Other high-grade B cell lymphomas – Classification of other high-grade lymphomas is less settled, resulting in some similarities and other differences between the ICC and WHO5.

-Both schemes consider "High-grade B cell lymphoma with MYC and BCL-2 rearrangements" to be a distinct, highly aggressive entity.

-ICC retains "High-grade B cell lymphoma with MYC and BCL-6 rearrangements" as a provisional entity, whereas WHO5 reclassifies these lesions, according to morphology, as either "Diffuse B cell lymphoma" or "High-grade B cell lymphoma."

-In WHO4R, aggressive lymphomas with 11q aberrations were labeled "Burkitt-like lymphoma with 11q aberration." In the ICC, based on new genetic and molecular data, these tumors are renamed "Large B cell lymphoma with 11q aberration" (a provisional entity), whereas WHO5 refers to them as "High-grade B cell lymphoma with 11q aberration."

Hodgkin lymphoma (HL) — HL (formerly Hodgkin's disease) is divided into two major categories: classic HL and nodular lymphocyte-predominant HL. Pathologically, HL comprises a minority of neoplastic cells (Reed-Sternberg cells and their variants, which are derived from germinal center or post-germinal center B cells) in a mixed inflammatory cell background.

Classic HL (cHL) – Based on the appearance of the tumor cells and composition of the reactive background, cHL is further divided into the following four subtypes:

Nodular sclerosis cHL

Mixed cellularity cHL

Lymphocyte-rich cHL

Lymphocyte-depleted cHL

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

Nodular lymphocyte-predominant HL (NLPHL) – This is an uncommon, favorable prognosis category of HL. It has long been recognized that the malignant cells (so-called lymphocytic & histiocytic variants [LP cells]) of this entity differ from the malignant cells of cHL, as they retain the immunophenotypic features of germinal center B cells. In recognition of this, the ICC has changed the name of this entity to "Nodular lymphocyte-predominant B cell lymphoma," whereas, to avoid confusion amongst clinicians, the WHO5 retains the name "NLPHL." (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)

Mature T cell or NK cell lineage — There are no major differences between ICC and WHO5 regarding lymphoid neoplasms of mature T cells or NK cells, but there are some changes in nomenclature and some new entities (all rare) have been added. This category of neoplasms includes:

Peripheral T cell lymphoma (PTCL) – PTCL is a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all NHLs in adults. Among the numerous categories of PTCL that are included in both ICC and WHO5 are:

Peripheral T cell lymphoma, NOS – Both ICC and WHO5 retain this category, which encompasses a heterogeneous group of neoplasms that do not fit the criteria for specific subtypes of T cell lymphoma (described below). (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified".)

Anaplastic large cell lymphoma (ALCL) – In both ICC and WHO5, this category includes systemic ALCL, which is subcategorized according to expression of the anaplastic lymphoma kinase (ALK) gene as "ALCL, ALK-positive" or "ALCL, ALK-negative"; and "Breast implant-associated ALCL." (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".)

A separate category, "Primary cutaneous ALCL" is included among primary cutaneous lymphomas (described below).

Follicular helper T cell lymphoma – In both ICC and WHO5, this category includes "Angioimmunoblastic T cell lymphoma (AITL)" and related follicular helper T cell subtypes. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

Extranodal NK/T cell lymphoma, nasal type – WHO5 (but not ICC) dropped the descriptor "nasal type," as this Epstein-Barr virus (EBV)-associated neoplasm may arise in numerous extranodal sites. Both ICC and WHO5 also added a provisional subtype, "Primary nodal EBV-positive T/NK-cell lymphoma," in recognition of the existence of a rare, identical or closely related neoplasm that arises in lymph nodes. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

Subcutaneous panniculitis-like T cell lymphoma – Both ICC and WHO5 retain this entity essentially unchanged from WHO4. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

Hepatosplenic T cell lymphoma – Both ICC and WHO5 retain this entity, which is aggressive and occurs more frequently in the setting of immunosuppression. (See "Clinical manifestations, pathologic features, and diagnosis of hepatosplenic T cell lymphoma".)

Primary intestinal T cell lymphomas – Both ICC and WHO5 recognize two major subtypes of aggressive T cell lymphomas involving the intestinal tract: "Enteropathy-associated T cell lymphoma," which is often preceded by celiac disease; and "Monomorphic epitheliotropic intestinal T cell lymphoma," which is unrelated to celiac disease and has different morphologic and immunophenotypic features.

Both the ICC and WHO5 also added two newly recognized, indolent clonal neoplasms involving the gastrointestinal (GI) tract: "Indolent T cell lymphoma of the GI tract" and "Indolent NK cell lymphoproliferative disorder of the GI tract." Indolent T cell lymphoma of the GI tract may cause significant morbidity and spread to other sites, whereas indolent NK cell lymphoma of the GI tract tends to follow a benign course. (See "Clinical manifestations, pathologic features, and diagnosis of enteropathy-associated T cell lymphoma".)

Primary cutaneous peripheral T cell lymphomas – There are numerous cutaneous T cell lymphomas, of which "Mycosis fungoides (MF)" is the most common; "Sézary syndrome" is an erythrodermic, leukemic variant of MF. Another distinct subtype is "Cutaneous anaplastic large cell lymphoma," which despite its name follows an indolent clinical course.

Other rare subtypes of primary cutaneous peripheral T cell lymphomas are classified according to clinicopathologic features or T cell phenotype. In both ICC5 and WHO5, the following rare subtypes are now considered distinct entities: "Primary cutaneous gamma-delta T cell lymphoma," "Aggressive epidermotropic cytotoxic T cell lymphoma," "Acral CD8-positive T cell lymphoproliferative disorder," and "CD4-positive small and medium T cell lymphoproliferative disorder." (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) – Both ICC and WHO5 retain this highly aggressive peripheral T cell malignancy derived from CD4-positive T cells that are latently infected with the human T cell leukemia virus (HTLV) type 1. ATL 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 (LGL) leukemia – Both ICC and WHO5 retain "T cell LGL leukemia," 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 – Both ICC and WHO5 retain "T cell prolymphocytic leukemia," an aggressive tumor composed of small to medium-sized mature T cells. (See "Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia".)

NK cell large granular lymphocyte (LGL) leukemia – Both ICC and WHO5 retain this entity, also called "Chronic lymphoproliferative disorder of NK cells," 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 NK cell leukemia – Both ICC and WHO5 retain this entity, a very rare leukemia derived from NK cells that is most prevalent among Asian populations. It is often EBV-associated and may represent a leukemic variant of "Extranodal NK/T cell lymphoma, nasal type." (See "Natural killer (NK) cell large granular lymphocyte leukemia".)

OTHER CATEGORIES — Labels and diagnostic criteria for most other categories of hematologic malignancies are similar in the International Consensus Classification (ICC) [1] and the World Health Organization 5th edition (WHO5) [3], but they differ in how they assign various conditions to disease categories. Similarities and differences between the two systems are summarized below:

Similarities – Both ICC and WHO5 include the following categories:

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions – Both ICC and WHO5 include these disorders as a distinct category; the modest differences between the classification schemes are described below. (See 'Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions' below.)

Mastocytosis – There are only modest differences in classification of mastocytosis. (See 'Mastocytosis' below.)

Histiocytic and dendritic cell neoplasms – Both systems add Rosai-Dorfman disease as a new entity. (See 'Histiocytic/dendritic neoplasms' below.)

Differences – ICC and WHO5 assign various disorders to different categories or apply different labels. Significant differences include:

Pediatric and/or germline-associated disorders – These entities are included in a separate category in ICC, but they are included among "Secondary myeloid neoplasms" in WHO5. (See 'Pediatric and/or germline mutation-associated disorders' below.)

Neoplasms with mixed/ambiguous lineage – ICC and WHO5 apply different labels to these disorders. (See 'Neoplasms with mixed or ambiguous lineage' below.)

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions — These disorders are categorized in both ICC and WHO5 according to the underlying gene fusion, including rearrangements of PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ETV6::ABL1. WHO5 also created a subtype for other defined tyrosine kinase fusions [1,3].

Evaluation, diagnosis, and classification of eosinophilic neoplasms are discussed separately. (See "Eosinophil biology and causes of eosinophilia" and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

Mastocytosis — Mastocytosis refers to rare, heterogeneous neoplasms characterized by accumulation of neoplastic mast cells in various organs or tissues. These disorders are typically driven by constitutive activation of the KIT receptor and may be associated with various comorbid conditions (eg, IgE-dependent allergies; psychiatric, psychological, or mental disorders).

Both ICC and WHO5 include "Cutaneous mastocytosis" and "Systemic mastocytosis (SM)" as distinct categories, and both include multiple subtypes (variants) of SM, including "Indolent SM," "Smoldering SM," "Aggressive SM," "Mast cell leukemia," and "SM with an associated hematologic/myeloid neoplasm." WHO5 also includes "Mast cell sarcoma (MCS)" and "Bone marrow mastocytosis" as new subtypes of SM. Both classification schemes modified some of the minor criteria for diagnosis of mastocytosis.

Clinical manifestations, diagnosis, and classification of mastocytosis are discussed separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Histiocytic/dendritic neoplasms — Histiocytic/dendritic neoplasms are derived from cells that normally develop into accessory antigen-presenting cells (dendritic cells) or connective tissue macrophages (histiocytes). Many of the histiocytic neoplasms bear mutations in the MAPK signaling pathway, albeit with variable frequencies.

Both ICC and WHO5 include ALK-positive histiocytosis and Rosai-Dorfman disease (called Rosai-Dorfman-Destombes disease by ICC) as new entities among the histiocytic neoplasms. WHO5 includes "Blastic plasmacytoid dendritic cell neoplasm (BPDCN)" among histiocytic and dendritic cell neoplasms, whereas BPDCN is a distinct category in ICC.

Details of clinical presentation, diagnosis, and classification of histiocytic neoplasms are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Erdheim-Chester disease" and "Histiocytic sarcoma" and "Blastic plasmacytoid dendritic cell neoplasm".)

Neoplasms with mixed or ambiguous lineage — Some hematologic malignancies express markers of both myeloid and lymphoid lineages or neither. Examples of such neoplasms include "Acute undifferentiated leukemia" and "Mixed phenotype acute leukemia (MPAL)."

Both ICC and WHO5 classify MPAL subtypes according to genetic findings (eg, t(9;22) rearrangement/BCR::ABL1; KMT2A rearrangement) or immunophenotype (B cell, T cell, myeloid). Details of diagnosis and classification of these leukemias are discussed separately. (See "Mixed phenotype acute leukemia".)

Pediatric and/or germline mutation-associated disorders — These neoplasms are associated with germline gene variants and include disorders such as juvenile myelomonocytic leukemia (JMML), myeloproliferative disorders associated with Noonan-syndrome, and other hematologic neoplasms.

Certain other inherited disorders are also predisposed to hematologic malignancies. Examples include Bloom syndrome, ataxia-telangiectasia, Nijmegen breakage syndrome, Noonan syndrome, constitutional mismatch repair deficiency syndrome, and germline mutations in DNMT3A, ERCC6L2, MBD4, and XPC, and others. These conditions are subsumed in a new category in ICC, called "Pediatric and/or germline mutation-associated disorders" [1].

In ICC, subcategories of these disorders include:

Hematologic neoplasms with germline predisposition associated with a constitutional platelet disorder

Hematologic neoplasms with germline predisposition with a constitutional disorder affecting multiple organ systems

Hematologic neoplasms with germline predisposition without a constitutional disorder affecting multiple organ systems

Acute lymphoblastic leukemia with germline predisposition

In WHO5, JMML, JMML-like neoplasms, and Noonan syndrome-associated myeloproliferative disorder are included in the "MDS/MPN" category, while "Refractory cytopenia of childhood (RCC)," characterized by dysplasia and frequently marrow hypocellularity, is referred to as "Childhood MDS with low blasts" [3]. In WHO5, myeloid neoplasms arising in individuals with Fanconi anemia, Down syndrome, and RASopathies are categorized according to the myeloid disease phenotype, with the predisposing germline genotype (eg, AML with germline pathogenic variants in RUNX1). (See 'MDS/MPN syndromes' above and 'Myelodysplastic neoplasms/syndromes' above.)

Further description of these disorders is provided separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes" and "Juvenile myelomonocytic leukemia".)

SUMMARY

Classification systems – Classification of hematologic neoplasms is needed for evidence-based treatment decisions and assessing prognosis. Two distinct classification systems were published in 2022. Both schemes are acceptable and we favor use of either, or both, rather than previous schemes (see 'Overview' above):

International Consensus Classification (ICC)

World Health Organization 5th edition (WHO5)

Comparison of ICC and WHO5 – Important aspects include (see 'Comparison of ICC and WHO5' above):

Similarities – Both ICC and WHO5 classify hematologic malignancies by morphology (tissue architecture/histology), clinical attributes (eg, acute versus chronic, cytopenias/cytoses), lineage (immunophenotype), and cytogenetic/molecular features.

Differences – There are numerous differences in disease labels, subtypes, and details of diagnostic criteria. Additionally, there are major differences in categorization of:

-Myeloid malignancies

-Inherited germline-associated disorders

-Treatment-related malignancies

Details of classification of specific entities are discussed in disease-specific topics.

Myeloid neoplasms – ICC and WHO5 differ regarding (see 'Categories of myeloid neoplasms' above):

Myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) – MDS and AML are divided differently. ICC created a new category, "MDS/AML" (ie, 10 to 19 percent blasts and no defining AML genetic features), while WHO5 divides MDS (<19 percent blasts) from AML (≥20 percent blasts), even while recognizing substantial clinical overlap.  

Myeloproliferative neoplasms (MPNs) (see 'Myeloproliferative neoplasms' above):

-Chronic myeloid leukemia (CML) – ICC considers three phases ("Chronic," "Accelerated," and "Blast" phases), while WHO5 subsumes the latter two into "Accelerated phase."

-Other MPNs – ICC and WHO5 apply similar labels and criteria for "Essential thrombocythemia," "Myelofibrosis," and other MPNs.

MDS/MPN – There are modest differences in diagnostic criteria and labels for subtypes of "Chronic myelomonocytic leukemia" and other MDS/MPNs. (See 'MDS/MPN syndromes' above.)

AML – Genetic findings and blast morphology are used for classification in both schemes. Importantly, neither system requires ≥20 percent myeloid blasts in marrow or blood for many subtypes with AML-defining genetic abnormalities. (See 'Acute myeloid leukemia' above.)

The models classify myeloid malignancies with TP53 mutations, germline gene variants, and treatment-related conditions differently.

Lymphoid neoplasms – Both systems organize lymphoid malignancies by immunophenotype (ie, B versus T/NK cell) and further divide them into precursor neoplasms versus mature neoplasms. There are modest differences between ICC and WHO5 in classification of lymphoid malignancies.

Major categories include:

Precursor lymphoid neoplasms – Includes "Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL)" of B cell or T cell lineage. B cell ALL/LBL is further subtyped based on genetic and cytogenetic findings, whereas these have little role in T cell ALL/LBL. The ICC and WHO5 are largely concordant in subtyping these entities. (See 'Precursor lymphoid neoplasms' above.)

Mature B cell neoplasms – Includes "Chronic lymphocytic leukemia," "Lymphoplasmacytic lymphoma," monoclonal gammopathies, plasma cell neoplasms, "Follicular lymphoma," "Diffuse large B cell lymphoma," high-grade lymphomas, and others. ICC and WHO5 are largely concordant in subtyping these entities. (See 'Mature B cell neoplasms' above.)  

Hodgkin lymphoma (HL) – Four categories of "Classic HL" and "Nodular lymphocyte predominant HL (NLPHL)" are largely unchanged. ICC changed the name of NLPHL to "Nodular lymphocyte- predominant B-cell lymphoma”. (See 'Hodgkin lymphoma (HL)' above.)

Mature T cell or NK cell neoplasms – Includes various cutaneous and systemic T cell and NK cell neoplasms. Subtyping is largely concordant between systems. (See 'Mature T cell or NK cell lineage' above.)

Other categories  

Eosinophilic neoplasms – (See 'Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions' above.)

Mastocytosis – (See 'Mastocytosis' above.)

Mixed or ambiguous lineage – (See 'Neoplasms with mixed or ambiguous lineage' above.)

Germline mutation-associated – (See 'Pediatric and/or germline mutation-associated disorders' above.)

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Topic 4716 Version 20.0

References