SPECIAL ARTICLE
`World Health Organization Classification of Neoplastic Diseases
`of the Hematopoietic and Lymphoid Tissues: Report of the
`Clinical Advisory Committee Meeting—Airlie House, Virginia,
`November 1997
`
`By Nancy Lee Harris, Elaine S. Jaffe, Jacques Diebold, Georges Flandrin, H. Konrad Muller-Hermelink, James Vardiman,
`T. Andrew Lister, and Clara D. Bloomfield
`
`Purpose: The European Association of Hemato-
`pathologists and the Society for Hematopathology have
`developed a new World Health Organization (WHO)
`classification of hematologic malignancies, including
`lymphoid, myeloid, histiocytic, and mast cell neo-
`plasms.
`Design: Ten committees of pathologists developed
`lists and definitions of disease entities. A clinical advi-
`sory committee (CAC) of international hematologists
`and oncologists was formed to ensure that the classifica-
`tion would be useful to clinicians. The CAC met in
`November 1997 to discuss clinical issues related to the
`classification.
`Results: The WHO uses the Revised European-Ameri-
`can Lymphoma (REAL) classification, published in 1994
`by the International Lymphoma Study Group, to catego-
`rize lymphoid neoplasms. The REAL classification is
`based on the principle that a classification is a list of
`‘‘real’’ disease entities, which are defined by a combina-
`tion of morphology, immunophenotype, genetic fea-
`tures, and clinical features. The relative importance of
`each of these features varies among diseases, and there
`
`THE SOCIETY FOR Hematopathology and the Euro-
`
`pean Association of Hematopathologists jointly devel-
`oped a classification of hematologic neoplasms for the
`World Health Organization (WHO). A steering committee
`composed of members of both societies was formed, and 10
`committees were assigned the task of arriving at a consensus
`list of myeloid, lymphoid, and histiocytic neoplasms, with
`descriptions and criteria for diagnosis. A new classification
`for lymphoid neoplasms was recently proposed,1 and the
`goals of the WHO project were to update and revise that
`classification, with input from additional experts in order to
`broaden the consensus, and to extend the principles of
`disease definition and consensus building to the myeloid and
`histiocytic neoplasms. More than 50 pathologists from
`around the world were involved in the project, which began
`in 1995. Proponents of all major lymphoma and leukemia
`classifications agreed that if a reasonable consensus emerged
`from this effort, they would accept the WHO classification
`of hematologic malignancies as the standard.
`
`is no one gold standard. The WHO classification applies
`the principles of the REAL classification to myeloid and
`histiocytic neoplasms. The classification of myeloid neo-
`plasms recognizes distinct entities defined by a combina-
`tion of morphology and cytogenetic abnormalities. At
`the CAC meeting, which was organized around a series
`of clinical questions, participants reached a consensus
`on most of the questions posed. They concluded that
`clinical groupings of lymphoid neoplasms were neither
`necessary nor desirable. Patient treatment is deter-
`mined by the specific type of lymphoma, with the
`addition of grade within the tumor type, if applicable,
`and clinical prognostic factors, such as the International
`Prognostic Index.
`Conclusion: The WHO classification has produced a
`new and exciting degree of cooperation and communi-
`cation between oncologists and pathologists from
`around the world, which should facilitate progress in
`the understanding and treatment of hematologic malig-
`nancies.
`J Clin Oncol 17:3835-3849. r 1999 by American
`SocietyofClinicalOncology.
`
`The proposed WHO classification of hematologic malig-
`nancies stratifies neoplasms primarily according to their
`lineage: myeloid neoplasms (Table 1), lymphoid neoplasms
`(Tables 2 and 3), mast cell disorders (Table 4), and
`histiocytic neoplasms (Table 5). Variants and subtypes of
`selected neoplasms are listed in Tables 6 through 15. Within
`each category, distinct diseases are defined according to a
`
`From the Departments of Pathology, Massachusetts General Hospi-
`tal and Harvard Medical School, Boston, MA; National Cancer
`Institute, Bethesda, MD; Hotel Dieu and Hopital Necker, Paris, France;
`University of Wurzburg, Wurzburg, Germany; Pritzker School of
`Medicine, University of Chicago, Chicago, IL, Department of Medical
`Oncology, St Bartholomew’s Hospital, London, UK; and Ohio State
`University Comprehensive Cancer Center, Columbus, OH.
`Submitted October 4, 1999; accepted November 3, 1999.
`Address reprint requests to Nancy Lee Harris, MD, Pathology,
`Warren 2, Massachusetts General Hospital, Fruit St, Boston, MA
`02114; email nlharris@partners.org.
`r 1999 by American Society of Clinical Oncology.
`0732-183X/99/1712-3835
`
`JournalofClinicalOncology, Vol 17, No 12 (December), 1999: pp 3835-3849
`
`3835
`
`Downloaded from ascopubs.org by 66.44.48.84 on November 13, 2017 from 066.044.048.084
`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1010, p. 1
`
`

`

`3836
`
`Table 1. Proposed WHO Classification of Myeloid Neoplasms
`
`Myeloproliferative diseases
`Chronic myelogenous leukemia, Philadelphia chromosome positive (t(9;
`22)(qq34;q11), BCR/ABL)
`Chronic neutrophilic leukemia
`Chronic eosinophilic leukemia/hypereosinophilic syndrome
`Chronic idiopathic myelofibrosis
`Polycythemia vera
`Essential thrombocythemia
`Myeloproliferative disease, unclassifiable
`Myelodysplastic/myeloproliferative diseases
`Chronic myelomonocytic leukemia
`Atypical chronic myelogenous leukemia
`Juvenile myelomonocytic leukemia
`Myelodysplastic syndromes
`Refractory anemia
`With ringed sideroblasts
`Without ringed sideroblasts
`Refractory cytopenia (myelodysplastic syndrome) with multilineage dys-
`plasia
`Refractory anemia (myelodysplastic syndrome) with excess blasts
`5q2 syndrome
`Myelodysplastic syndrome, unclassifiable
`Acute myeloid leukemias*
`AMLs with recurrent cytogenetic translocations
`AML with t(8;21)(q22;q22), AML1(CBF-alpha)/ETO
`Acute promyelocytic leukemia (AML with t(15;17)(q22;q11-12) and
`variants, PML/RAR-alpha)
`AML with abnormal bone marrow eosinophils (inv(16)(p13q22) or
`t(16;16)(p13;q11), CBFb/MYH11X)
`AML with 11q23 (MLL) abnormalities
`AML with multilineage dysplasia
`With prior myelodysplastic syndrome
`Without prior myelodysplastic syndrome
`AML and myelodysplastic syndromes, therapy-related
`Alkylating agent–related
`Epipodophyllotoxin-related (some may be lymphoid)
`Other types
`AML not otherwise categorized
`AML minimally differentiated
`AML without maturation
`AML with maturation
`Acute myelomonocytic leukemia
`Acute monocytic leukemia
`Acute erythroid leukemia
`Acute megakaryocytic leukemia
`Acute basophilic leukemia
`Acute panmyelosis with myelofibrosis
`Acute biphenotypic leukemias
`
`NOTE: Only major disease categories are listed; subtypes and variants will
`be discussed in detail in the WHO book.2
`Abbreviation: AML, acute myeloid leukemia.
`*Acute lymphoid leukemias are included under lymphoid neoplasms and in
`Table 6.
`
`HARRIS ET AL
`
`immunophenotype, genetic
`combination of morphology,
`features, and clinical syndromes. The relative importance of
`each criterion differs among the neoplasms, and there is no
`one gold standard for classification of all hematologic
`malignancies. The goal was to define disease entities that
`could be recognized by pathologists and that have clinical
`relevance.
`To ensure that the proposed classification would be of
`maximal use to oncologists, the steering committee invited
`expert hematologists and oncologists to form a clinical
`advisory committee (CAC), with American and European
`co-chairs. The charge to the CAC was to review the
`proposed classification and advise the pathologists on its
`clinical utility. More than 40 hematologists and oncologists
`from around the world agreed to participate. The proposed
`classification was circulated, and all participants were invited to
`submit topics and questions for discussion. A meeting was held
`in November 1997, at Airlie House, VA, involving the CAC, all
`pathologists involved in the WHO committees, and the
`executive committees of the two hematopathology societies.
`The meeting was organized around a series of questions
`developed from those submitted by CAC members and
`posed by the pathologists. Only controversial issues were
`discussed; diseases were accepted as previously defined if
`there were no new questions or data. Only lymphoid and
`myeloid neoplasms were discussed at the meeting; histio-
`cytic and mast cell tumors were not considered. Participants
`were invited to present data relevant to each question, and
`open discussion followed. At the end of each session, the
`clinicians were asked to arrive at a consensus regarding each
`question (as well as other issues raised at the meeting); if
`necessary, a show of hands was taken as a vote. After the
`meeting, participants were polled to resolve residual ques-
`tions; several additional meetings of the pathology steering
`committee and the CAC co-chairs were held for the same
`purpose. The final classification will be published under the
`auspices of the WHO.2
`
`MYELOID NEOPLASMS
`Despite advances in the understanding of genetic factors
`in the biology of the myeloid neoplasms, particularly the
`acute leukemias, the classification of these disorders has not
`been recently updated. Thus, discussion of these disorders
`generated considerable controversy. At several subsequent
`meetings of pathologists and the clinical co-chairs, a consen-
`sus on the classification emerged. The following summary
`includes issues raised at the CAC meeting and resolutions
`achieved subsequently.
`In the French-American-British (FAB) classification, three
`main categories of myeloid neoplasms are recognized: acute
`myeloid leukemias, myelodysplastic syndromes, and myelo-
`
`Downloaded from ascopubs.org by 66.44.48.84 on November 13, 2017 from 066.044.048.084
`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1010, p. 2
`
`

`

`CLASSIFICATION OF HEMATOLOGIC MALIGNANCIES
`
`3837
`
`Table 2. Proposed WHO Classification of Lymphoid Neoplasms
`
`B-Cell neoplasms
`Precursor B-cell neoplasm
`Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell
`acute lymphoblastic leukemia)
`Mature (peripheral) B-cell neoplasms*
`B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
`B-cell prolymphocytic leukemia
`Lymphoplasmacytic lymphoma
`Splenic marginal zone B-cell lymphoma (1/2 villous lymphocytes)
`Hairy cell leukemia
`Plasma cell myeloma/plasmacytoma
`Extranodal marginal zone B-cell lymphoma of MALT type
`Nodal marginal zone B-cell lymphoma (1/2 monocytoid B cells)
`Follicular lymphoma
`Mantle-cell lymphoma
`Diffuse large B-cell lymphoma
`Mediastinal large B-cell lymphoma
`Primary effusion lymphoma
`Burkitt’s lymphoma/Burkitt cell leukemia
`T-cell and NK-cell neoplasms
`Precursor T-cell neoplasm
`Precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell
`acute lymphoblastic leukemia)
`Mature (peripheral) T-cell neoplasms*
`T-cell prolymphocytic leukemia
`T-cell granular lymphocytic leukemia
`Aggressive NK-cell leukemia
`Adult T-cell lymphoma/leukemia (HTLV11)
`Extranodal NK/T-cell lymphoma, nasal type
`Enteropathy-type T-cell lymphoma
`Hepatosplenic gamma-delta T-cell lymphoma
`Subcutaneous panniculitis-like T-cell lymphoma
`Mycosis fungoides/Sezary syndrome
`Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type
`Peripheral T-cell lymphoma, not otherwise characterized
`Angioimmunoblastic T-cell lymphoma
`Anaplastic large-cell lymphoma, T/null cell, primary systemic type
`Hodgkin’s lymphoma (Hodgkin’s disease)
`Nodular lymphocyte-predominant Hodgkin’s lymphoma
`Classical Hodgkin’s lymphoma
`Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
`Lymphocyte-rich classical Hodgkin’s lymphoma
`Mixed cellularity Hodgkin’s lymphoma
`Lymphocyte depletion Hodgkin’s lymphoma
`
`NOTE: Only major categories are included. Subtypes and variants will be
`discussed in the WHO book2 and are listed in Tables 7 through 16. Common
`entities are shown in boldface type.
`leukemia virus; MALT, mucosa-
`Abbreviations: HTLV11, human T-cell
`associated lymphoid tissue; NK, natural killer.
`*B- and T-/NK-cell neoplasms are grouped according to major clinical
`presentations (predominantly disseminated/leukemic, primary extranodal,
`predominantly nodal).
`
`Table 3. Categories of Posttransplant Lymphoproliferative Disorders
`
`Early lesions
`Reactive plasmacytic hyperplasia
`Infectious mononucleosis-like
`PTLD, polymorphic
`Polyclonal (rare)
`Monoclonal
`PTLD, monomorphic (classify according to lymphoma classification)
`B-cell lymphomas
`Diffuse large B-cell lymphoma (immunoblastic, centroblastic, ana-
`plastic)
`Burkitt’s/Burkitt-like lymphoma
`Plasma cell myeloma
`T-cell lymphomas
`Peripheral T-cell lymphoma, not otherwise categorized
`Other types (hepatosplenic, gamma-delta, T/NK)
`Other types, rare
`Hodgkin’s disease-like lesions (associated with methotrexate therapy)
`Plasmacytoma-like lesions
`
`proliferative disorders.3 The blast count, lineage commit-
`ment, and level of differentiation of the neoplastic cells are
`the major determinants of the categories recognized, using
`morphologic, cytochemical, and immunophenotypic fea-
`tures. Recently, genetic features (cytogenetic and molecular
`genetic), as well as other features, such as prior therapy and
`a history of myelodysplasia, have been shown to have a
`significant impact on the clinical behavior of these disorders,
`and these features do not always correlate perfectly with the
`FAB categories. Thus, a major focus of debate was how to
`integrate genetic and clinical features with morphology,
`cytochemistry, and immunophenotype into a classification
`that could be used by pathologists and have clinical relevance. A
`key issue, as with the lymphoid neoplasms, was to discriminate
`between disease entities and prognostic factors. Some genetic
`abnormalities seem to define distinct diseases, whereas others
`are prognostic factors within a given disease. Also debated
`was whether all diseases fit into one of the three major
`categories or whether additional broad categories are needed.
`After discussion, it seemed that a paradigm similar to that
`adopted for the Revised European-American Lymphoma
`(REAL) classification could at least tentatively apply to the
`myeloid disorders; namely, a combination of morphology,
`immunophenotype, genetic features, and clinical features
`could be used to define distinct disease entities. The
`technology of genetic analysis is evolving rapidly, and it is
`likely that advances in this field will necessitate revisions to
`
`Table 4. Mast Cell Diseases
`
`Cutaneous mastocytosis
`Systemic mast cell disease (1/2 skin involvement)
`Systemic mast cell disease with associated hematologic disorder (1/2 skin
`involvement)
`Mast cell leukemia/sarcoma
`
`Downloaded from ascopubs.org by 66.44.48.84 on November 13, 2017 from 066.044.048.084
`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1010, p. 3
`
`

`

`3838
`
`Table 5. Histiocytic and Dendritic Cell Neoplasms
`
`Macrophage/histiocytic neoplasm
`Histiocytic sarcoma
`Dendritic Cell neoplasms
`Langerhans cell histiocytosis
`Langerhans cell sarcoma
`Interdigitating dendritic cell sarcoma/tumor
`Follicular dendritic cell sarcoma/tumor
`Dendritic cell sarcoma, not otherwise specified
`
`any current classification in the near future. The pathologists
`proposed four major groups of myeloid diseases: myelopro-
`liferative diseases (MPDs), myelodysplastic/myeloprolifera-
`tive diseases (MD/MPDs), myelodysplastic syndromes
`(MDSs), and acute myeloid leukemias (AMLs). Within the
`category of AML, four main groups are recognized: (1)
`AML with recurrent cytogenetic translocations; (2) AML
`with myelodysplasia-related features; (3) therapy-related
`AML and MDS; and (4) AML not otherwise specified.
`
`Myeloproliferative Diseases
`
`MPDs are clonal stem-cell disorders characterized by
`‘‘effective’’ hematopoiesis that results in elevated peripheral-
`blood levels of one or more cell lines and hepatospleno-
`megaly; the marrow is hypercellular with maturation and
`without dysplasia. Among the MPDs,
`the prototype is
`Philadelphia chromosome (Ph1)–positive (BCR/ABL1)
`chronic myelogenous leukemia (CML). The other accepted
`entities are polycythemia vera, idiopathic myelofibrosis, and
`essential thrombocythemia. Controversies within this group
`include the definitions and classification of juvenile myelo-
`monocytic leukemia (JMML; also known as juvenile chronic
`myeloid leukemia and juvenile chronic myelomonocytic
`leukemia), chronic myelomonocytic leukemia (CMML),
`and atypical CML.
`Should JMML be a separate category? Should it be
`classified as an MDS or an MPD? The CAC accepted the
`conclusions of the International Study Group for Pediatric
`MDS that JMML is a separate disorder, distinct from adult
`chronic myeloid or myelomonocytic leukemia. CAC mem-
`bers proposed that the term JMML be adopted. They favored
`including it in the MPDs; however, the pathologists recom-
`
`Table 6. Acute Lymphoid Leukemias
`
`Precursor B-cell acute lymphoblastic leukemia (cytogenetic subgroups)
`t(9;22)(a34;q11); BCR/ABL
`t(v;11q23); MLLrearranged
`t(1;19)(q23;p13) E2A/PBX1
`t(12;21)(p12;q22) ETV/CBF-alpha
`Precursor T-cell acute lymphoblastic leukemia
`Burkitt-cell leukemia
`
`HARRIS ET AL
`
`Table 7. B-Cell Neoplasms, Predominantly Disseminated/Leukemic
`Types, Variants
`
`B-cell CLL/SLL
`Variant: with monoclonal gammopathy/plasmacytoid differentiation
`Hairy cell leukemia
`Variant: hairy cell leukemia variant
`
`mended that a separate category be formed to include JMML
`and other disorders that combine features of myeloprolifera-
`tive and myelodysplastic syndromes.
`Should CMML be divided into MDS and MPD types?
`CMML has long been recognized as a disorder that has
`features of both myelodysplastic and myeloproliferative
`syndromes. Nearly half the patients present with low or
`normal neutrophil counts, multilineage marrow dysplasia,
`no organomegaly, and bone marrow morphology that re-
`sembles refractory anemia with excess blasts (RAEB) but
`with monocytosis. Other patients have marked neutrophilia,
`monocytosis, and splenomegaly. It has been debated whether
`this is really two diseases—one an MDS and the other an
`MPD. However, studies to date have shown no differences in
`cytogenetic abnormalities, oncogene mutations, in vitro colony
`growth patterns, or clinical outcome between the two types of
`CMML. It was the consensus at the meeting that CMML is one
`disease. The CAC concluded that CMML fits better in the MPD
`than in the MDS category, but after subsequent discussions, the
`pathologists recommended that it be included in a separate
`category, along with JMML, of disorders with both myeloprolif-
`erative and myelodysplastic features.
`What should the nomenclature and category be for
`atypical CML (aCML)? Atypical CML was first recognized
`as a disease involving predominantly the neutrophil series
`and lacking Ph1 or the BCR/ABL translocation. It has
`dysplastic as well as proliferative features and often occurs
`with multilineage dysplasia. The prognosis is significantly
`worse than that for Ph11 CML. It is clear that it is clinically,
`genetically, and morphologically distinct from Ph11 CML;
`therefore, the term aCML is suboptimal, implying both a
`
`Table 8. Follicular and Mantle-Cell Lymphomas: Grading and Variants
`
`Follicular lymphoma
`Grade 1, 0-5 centroblasts/hpf
`Grade 2, 6-15 centroblasts/hpf
`Grade 3, . 15 centroblasts/hpf
`3a, . 15 centroblasts, but centrocytes are still present
`3b, Centroblasts form solid sheets with no residual centrocytes
`Variants
`Cutaneous follicle center lymphoma
`Diffuse follicle center lymphoma
`Grade 1, 0-5 CB/hpf
`Grade 2, 6-15 CB/hpf
`Mantle-cell lymphoma
`Variant: blastoid
`
`Downloaded from ascopubs.org by 66.44.48.84 on November 13, 2017 from 066.044.048.084
`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1010, p. 4
`
`

`

`CLASSIFICATION OF HEMATOLOGIC MALIGNANCIES
`
`3839
`
`Table 9. DLBCL, Morphologic Variants and Subtypes
`
`Table 11. Plasma Cell Disorders: Subtypes and Variants
`
`Morphologic variants
`Centroblastic
`Immunoblastic
`T-cell/histiocyte-rich
`Lymphomatoid granulomatosis type
`Anaplastic large B-cell
`Plasmablastic
`Subtypes
`Mediastinal (thymic) large B-cell lymphoma
`Primary effusion lymphoma
`Intravascular large B-cell lymphoma
`
`relationship to Ph11 CML and a chronic process. The CAC
`was unable to agree on another name, and thought the term
`aCML could be retained, provided the disease was clearly
`defined so as to prevent confusion. The pathologists recom-
`mended placing aCML with JMML and CMML in a
`category of MD/MPD.
`Should there be a separate category for cases that are
`neither MDS nor MPD? For reasons mentioned above, the
`pathologists recommended a fourth category of myeloid
`neoplasms to contain those cases that are inherently prolifera-
`tive but show dysplastic features, such as JMML, CMML,
`and aCML. It was the opinion of the clinicians that such a
`category was not desirable and that these diseases could be
`placed in the MPD category. The pathologists contended that
`these disorders have many common features, including abnormali-
`ties of both the granulocytic and monocytic lines and a relatively
`aggressive course, that distinguish them from the MDS and
`MPD categories and argued for placing them together.
`MPDs: Summary.
`1. Should JMML be a separate category? YES
`2. Should CMML be divided into MDS and MPD types?
`NO
`3. What should we call aCML? aCML
`4. Should there be a separate category for cases that are
`neither MDS nor MPD? NO CONSENSUS
`c Pathologists proposed a category of MDS/MPD to
`include JMML, CMML, and aCML.
`
`Monoclonal gammopathy of undetermined significance
`Plasma cell myeloma variants
`Indolent myeloma
`Smoldering myeloma
`Osteosclerotic myeloma (POEMS syndrome)
`Plasma cell leukemia
`Nonsecretory myeloma
`Plasmacytoma variants
`Solitary plasmacytoma of bone
`Extramedullary plasmacytoma
`
`Abbreviation: POEMS, polyneuropathy, organomegaly, endocrinopathy,
`M-component, skin changes.
`
`with 20% to 30% blasts (classified as RAEB in transforma-
`tion) have a prognosis similar to that of patients with more
`than 30% blasts. Thus, there was a consensus that the blast
`count for the diagnosis of AML should be 20% and the
`RAEB in transformation category should be dropped.
`Should cytogenetic/molecular categories of AML be recog-
`nized as distinct diseases? Several specific cytogenetic
`abnormalities in AML are associated with characteristic
`morphology and have distinctive clinical features. With the
`exception of promyelocytic leukemia/M3 with t(15;17),
`these genetic abnormalities do not correlate precisely with
`FAB categories. The consensus of the CAC was that these
`categories should be recognized as distinct entities within
`the classification. After discussion, the pathologists agreed
`that it would be possible to develop morphologic criteria for
`these categories that would permit them to be recognized, or
`at least suspected, by pathologists, who should then suggest
`confirmation by genetic analysis. The following specific
`categories will be defined: (1) AML with t(8;21)(q22;q22),
`AML1(CBF-alpha)/ETO; (2) acute promyelocytic leukemia
`(AML with t(15;17)(q22;q11-12) and variants, PML/RAR-
`alpha); (3) AML with abnormal bone marrow eosinophils
`(inv(16)(p13q22) or t(16;16)(p13;q22), CBF-beta/MYH11);
`and (4) AML with 11q23 (MLL) abnormalities.
`
`Table 12. Immunosecretory Disorders (clinical manifestations of diverse
`lymphoid neoplasms)
`
`Acute Myeloid Leukemia and Myelodysplastic Syndrome
`
`Clinical Syndrome
`
`Underlying Neoplasm
`
`What blast count should define AML? According to the
`FAB standard, AML is defined by the presence of 30%
`blasts. However, recent studies have indicated that patients
`
`Waldenstro¨m’s macroglobulinemia
`Heavy-chain diseases
`Gamma HCD
`Alpha HCD
`
`Table 10. Burkitt’s Lymphoma, Morphologic Variants and Subtypes
`
`Lymphoplastmacytic lymphoma
`
`Lymphoplasmacytic lymphoma
`Extranodal marginal zone lymphoma
`(immunoproliferative small intes-
`tinal disorder)
`B-cell CLL
`
`Plasma cell myeloma, monoclonal
`gammopathy
`Plasma cell myeloma, monoclonal
`gammopathy
`
`Morphologic variants
`Burkitt-like
`With plasmacytoid differentiation (AIDS-associated)
`Subtypes, clinical and genetic
`Endemic
`Sporadic
`Immunodeficiency-associated
`
`Mu HCD
`Immunoglobulin deposition diseases
`Systemic light-chain disease
`
`Primary amyloidosis
`
`Abbreviation: HCD, heavy-chain disease.
`
`Downloaded from ascopubs.org by 66.44.48.84 on November 13, 2017 from 066.044.048.084
`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1010, p. 5
`
`

`

`3840
`
`Table 13. T-Cell Neoplasms, Disseminated Leukemic Types: Variants
`
`T-cell prolymphocytic leukemia, morphologic variants
`Small cell
`Cerebriform cell
`Adult T-cell leukemia/lymphoma (HTLV11), clinical variants
`Acute
`Lymphomatous
`Chronic
`Smoldering
`Hodgkin-like
`
`The specific morphologic features of these disorders will
`be described in the classification,2 and these entities will be
`excluded from the FAB categories used for cases that lack these
`abnormalities. In addition, cases with these specific cytogenetic
`abnormalities with low blast counts, which in the past might have
`been diagnosed as MDS, will now be classified as AML.
`Should multilineage dysplasia, prior MDS, and/or prior
`therapy be included in the classification of AML? Severe
`multilineage dysplasia, defined as the presence of dysplastic
`features in two or more cell lines, has been shown to be
`associated with poor outcome in AML. Similarly, AML
`arising in patients with a history of MDS also has a poor
`prognosis. Therapy-related leukemias secondary to alkylat-
`ing-agent therapy are clearly different from many de novo
`acute leukemias;
`they are associated with characteristic
`cytogenetic abnormalities (3q2, 25, 5q2, 27, 7q2, 18,
`19, 11q2, 12p2, 218, 219, 20q2, 121, t(1;7), t(2;11),
`complex karyotypes) and a worse prognosis and often show
`multilineage dysplasia or are preceded by a hypoprolifera-
`tive state with multilineage dysplasia, resembling MDS.
`Similar cytogenetic abnormalities are often seen in MDS not
`associated with prior therapy and in de novo acute leuke-
`mias, particularly in the elderly. It has been suggested that all
`of these disorders reflect similar genetic damage, which may
`be either environmental or iatrogenic. There was a consen-
`sus that the presence of multilineage dysplasia at the time of
`the diagnosis of acute leukemia, a history of myelodysplasia,
`and prior alkylating-agent therapy were all adverse prognos-
`tic factors, which may reflect a common pathogenesis. The
`committee concluded that multilineage dysplasia, a history
`
`Table 14. Peripheral T-cell Neoplasms, Primary Extranodal Types:
`Variants and Subtypes
`
`Mycosis fungoides variants
`Pagetoid reticulosis
`MF-associated follicular mucinosis
`Granulomatous slack skin disease
`Primary cutaneous CD301 T-cell lymphoproliferative disorders
`Lymphomatoid papulosis, types A and B*
`Primary cutaneous ALCL
`Borderline lesions
`
`*Lymphomatoid papulosis is not considered a neoplasm.
`
`HARRIS ET AL
`
`Table 15. Peripheral T-Cell Neoplasms, Predominantly Nodal Types:
`Variants
`
`Peripheral T-cell lymphoma not otherwise categorized, variants
`Lymphoepithelioid (Lennert’s)
`T-zone
`Anaplastic large cell lymphoma T-null cell type, variants
`Lymphohistiocytic
`Small cell
`
`of MDS, and a history of alkylating-agent therapy should be
`included in the classification of AML.
`The specific cytogenetic abnormalities common to MDS,
`alkylating-agent–related AML, and poor-prognosis AML
`(3q2, 25, 5q2, 27, 7q2, 18, 19, 11q2, 12p2, 218,
`219, 20q2, 121, t(1;7), t(2;11), complex karyotypes) likely
`reflect a common pathogenesis of these lesions, distinct
`from that of other de novo AMLs. However, there was no
`consensus on the role of these abnormalities in defining
`disease entities within the classification. Our understanding
`of this issue will likely improve in the near future, necessitat-
`ing a change in the major groupings. However, for the present,
`cytogenetic abnormalities indicative of poor prognosis should be
`recognized as prognostic factors within each category of AML.
`Therapy with topoisomerase II inhibitors (epipodophyllo-
`toxins and doxorubicin) is also associated with secondary
`leukemias, which are often myeloid but may be lymphoid.
`They typically show cytogenetic abnormalities associated
`with de novo AML—most commonly translocations involv-
`ing 11q23 (MLL) but also occasionally t(8;21), inv(16), or
`t(15;17). These cases should also be recognized in the
`classification as distinct from alkylating-agent–related sec-
`ondary leukemias.
`Should refractory cytopenia with multilineage dysplasia
`be a separate category? MDSs are clonal stem-cell disor-
`ders characterized by ineffective hematopoiesis that results
`clinically in peripheral-blood cytopenias; the marrow is
`variably hypercellular, and patients show poor responses to
`chemotherapy and have an increased risk of progression to
`acute leukemia. Refractory anemia and refractory anemia
`with ring sideroblasts were defined in the FAB classification
`as having dysplasia largely restricted to the erythroid line.
`Recent studies have shown that patients with MDS and less
`
`Table 16. Proposed Categories of Unclassifiable Hematologic Malignancies
`
`Hematologic malignancy, unclassifiable
`Myeloid neoplasm, unclassifiable
`Myeloproliferative disease, unclassifiable
`Myelodysplastic syndrome, unclassifiable
`Acute myeloid leukemia, unclassifiable
`Lymphoid neoplasm/lymphoma, unclassifiable
`B-cell lymphoma, unclassifiable
`T-cell lymphoma, unclassifiable
`Hodgkin’s disease, unclassifiable
`Histiocytic neoplasm, unclassifiable
`
`Downloaded from ascopubs.org by 66.44.48.84 on November 13, 2017 from 066.044.048.084
`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1010, p. 6
`
`

`

`CLASSIFICATION OF HEMATOLOGIC MALIGNANCIES
`
`than 5% blasts but with significant dysplasia involving
`granulocytic and megakaryocytic lines have a worse progno-
`sis and are more likely to die of marrow failure or progress to
`acute leukemia (similar to RAEB) than patients with MDS
`who lack these features. Thus, the committee agreed that a
`separate category is needed for these cases. Multilineage
`dysplasia is defined as the presence of dysplastic features in
`two or more cell lines. Refractory anemia (with or without
`ring sideroblasts) will continue to be defined as a disorder
`involving the erythroid line only. MDS will exclude cases of
`low-blast-count leukemias that show one of the following
`AML type cytogenetic abnormalities: t(8;21), inv(16), or
`t(15;17). Because of the distinctive morphologic and clinical
`features of the 5q2 syndrome, the pathologists agreed that
`this should be a separate category within MDS.
`AML and MDS: Summary.
`1. What blast count should define AML? 20%
`c (eliminate RAEB in transformation)
`2. Should cytogenetic/molecular categories be recog-
`nized as distinct diseases? YES
`c t(8;21)(q22;q22), AML1(CBF-alpha)/ETO
`c Acute promyelocytic leukemia t(15;17)(q22;q11-
`12), PML/RAR-alpha and variants
`c AML with abnormal bone marrow eosinophils
`(inv(16)(p13q22) and variants, CBF-beta/MYH11)
`c 11q23, MLL abnormalities
`3. Should severe multilineage dysplasia, prior therapy,
`and/or prior MDS be included in classification of
`AML? YES
`4. Should MDS with multilineage dysplasia be a separate
`category? YES
`
`LYMPHOID NEOPLASMS
`The proposed WHO classification of lymphoid neoplasms
`adopts the REAL classification, proposed by the Interna-
`tional Lymphoma Study Group. The REAL classification is
`based on the premise that a classification should attempt to
`define distinct disease entities, using all available informa-
`tion, including morphology, immunophenotype, genetic fea-
`tures, and clinical features. There is no single gold standard,
`and the importance of various criteria for both definition and
`diagnosis differs among different diseases. On the basis of 3
`years of experience with the REAL classification and input
`from the committees, several changes were proposed for the
`WHO classification. These included changes in nomenclature,
`division of heterogeneous categories, and adoption of ‘‘provi-
`sional’’ entities as ‘‘real.’’ The proposed WHO classification
`recognizes B-cell neoplasms, T-cell/natural-killer (NK)–cell
`neoplasms, and Hodgkin’s disease (HD). The T- and B-cell
`neoplasms were stratified into precursor, or lymphoblastic,
`neoplasms (acute lymphoblastic leukemia [ALL] and lym-
`phoblastic lymphoma) and mature (peripheral) B- and T-cell
`
`3841
`
`neoplasms. The mature B- and T-cell neoplasms were infor-
`mally grouped according to their major clinical presentations:
`predominantly disseminated/leukemic, primary extranodal,
`and predominantly nodal diseases. The pathologists sought
`input from the clinicians on these changes as well as on issues
`that remained controversial or problematic, such as grading of
`follicular lymphoma, how to define Burkitt-like