Leukemias 

Malignant Hematopoietic Disorders

 

Definitions and Classification

The spectrum of malignant disorders of hematopoietic origin is broad, both from a pathologic and clinical standpoint. They are clonal proliferations, and may be of single lineage (e.g., B cell chronic lymphocytic leukemia) or multilineage (e.g. chronic myelocytic leukemia). The course may be acute (high grade, aggressive) or chronic (low grade, indolent). The separation into acute and chronic initially reflected survival from diagnosis without specific therapy. From a pathologic standpoint it soon became clear that the chronic or low grade disorders, in most instances, represented a proliferation of mature or well differentiated cells while the acute disorders represented a proliferation of more immature cells (blasts).

Based on the origin of the proliferating cells, the disorders are often grouped as either lymphocytic and nonlymphocytic (myeloid). The term "myeloid" as used here includes all granulocytes (neutrophils, basophils, and eosinophils), monocytes, erythroid elements, and megakaryocytes. The term also is sometimes used to indicate only granulocytes to distinguish from monocytes, erythroid elements, and megakaryocytes. The disorders are now separated in 6 large categories:

Further subclassifications have emerged as new entities are recognized and characterized. These new entities are defined primarily on the basis of immunophenotypic, cytogenetic, and molecular genetic studies.

Outline of Malignant Hematopoietic Disorders

Leukemias

Although the term "leukemia" initially was used to indicate the finding of malignant cells of hematopoietic origin in the peripheral blood, the term as now used, refers to infiltration of the bone marrow, usually in a diffuse pattern, by malignant hematopoietic cells. Early in the course of some leukemias, the malignant cells are detected only in the bone marrow with involvement of the peripheral blood and other organs occurring later in the course of the disease.

  • Chronic leukemias
    • Chronic lymphocytic leukemia
      • B cell lymphocytic leukemias
        • Small lymphocytic B cell chronic lymphocytic leukemia (CLL, B cell CLL)
        • Mantle cell leukemia
        • Hairy cell leukemia
        • Prolymphocytic B cell leukemia (B cell PLL)
        • Leukemic phase of splenic lymphoma with villous lymphocytes
        • Leukemic phase of marginal zone lymphomas
        • Leukemic phase of lymphoplasmic lymphomas
      • T and NK cell lymphocytic leukemias
        • Large granular lymphocyte (LGL) syndrome (leukemia)
        • Leukemic phase of mycosis fungoides
        • Prolymphocytic T cell leukemia (T cell PLL)
        • Small lymphocytic T cell chronic lymphocytic leukemia
    • Chronic myelocytic leukemia (CML)- classified under "myeloproliferative disorders"
    • Chronic myelomonocytic leukemia (CMML)- classified under "myelodysplastic disorders"
  • Acute leukemias

Myeloproliferative Disorders

Clonal proliferation of myeloid progenitor cells that have retained the capacity to differentiate. Even though the proliferation involves more than one lineage within the myeloid compartment, usually only one lineage predominates in the various subtypes. 

  • Polycythemia vera (PV)- Predominant proliferating lineage is erythroid
  • Essential thrombocythemia (ET)- Predominant proliferating lineage is megakaryocytic
  • Myelofibrosis with myeloid metaplasia (MF)  (primary or idiopathic myelofibrosis)- The predominant proliferating lineage is megakaryocytic, but it is the finding of fibrosis in the bone marrow that defines this subset
  • Chronic myelocytic leukemia (CML)- The predominant proliferating lineage is granulocytic, primarily neutrophilic 
  • Other variants:
    • Hypereosinophilic syndrome
    • Systemic mastocytosis
    • Hybrid myeloproliferative-myelodysplastic disorders
    • Juvenile myelomonocytic leukemia

Myelodysplastic Syndromes (MDS)

Like the myeloproliferative disorders, the myelodysplastic disorders are clonal proliferations of myeloid progenitor cells in the bone marrow, but unlike the myeloproliferative disorders, these disorders are characterized by ineffective hematopoiesis. The bone marrow is usually normocellular or hypercellular, and differentiation is observed, but often does not progress to completion; the result is an increased rate of intramarrow death of developing hematopoietic cells. The morphologic appearance of the cellular elements of the involved lineages is abnormal (dysplastic).

Several classifications of these disorders have been proposed, but none encompass the entire spectrum of the various clinopathologic findings. Two classifications have gained widespread use:

  • French-American-British (FAB) Classification
    • Refractory anemia (RA)
    • Refractory anemia with ringed sideroblast (SA)
    • Refractory anemia with excess blasts (RAEB)- 5-20% blasts in bone marrow
    • Refractory anemia with excess blasts in transition (RAEB-t)- 21-30% blasts in bone marrow
    • Transformation to acute leukemia- blasts >30% in bone marrow
    • Chronic myelomonocytic leukemia (CMML)- variable dysplasia in other lineages and up to 20% blasts may be seen in bone marrow
  • World Health Organization (WHO) Classification
    • Refractory anemia (RA)
    • Refractory anemia with ringed sideroblasts (RARS)
    • Refractory cytopenia with multilineage dysplasia (RCMD)
    • Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-s)
    • Refractory anemia with excess blasts-1 (RAEB-1)- 5-9% blasts in bone marrow
    • Refractory anemia with excess blasts-2 (RAEB-2)- 10-19% blasts in bone marrow
    • Myelodysplasia syndrome- unclassified (MDS-U)
    • Unilineage dysplasia of granulocytic or megakaryocytic lineage
    • 5q- syndrome- anemia in the setting of a normal or even elevated platelet count, and the finding of monolobated megakaryocytes in bone marrow.

Lymphomas

In contrast to the leukemias, the myelopriliferative and myelodysplastic disorders which originate in the bone marrow, lymphomas originate in lymph nodes or in lymphocytes that reside in other organs or tissue (extranodal lymphomas). Lymphomas are separated into non-Hodgkins lymphoma (NHL) and Hodgkin's lymphoma/disease.

World Health Organization (WHO) classification of NHLs (adapted from):

  • B Cell Lymphomas
    • Precursor B cell lymphoma
      • Precursor B lymphoblastic lymphoma
    • Mature B cell lymphoma
      • Small lymphocytic lymphoma
      • Lymphoplasmacytic lymphoma
      • Splenic marginal zone lymphoma
      • Marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma, maltoma)
      • Nodal marginal zone B cell lymphoma (monocytoid B cell lymphoma)
      • Follicular lymphoma
      • Mantle cell lymphoma
      • Diffuse large B cell lymphoma
      • Primary mediastinal large B cell lymphoma
      • Intravascular large B cell lymphoma
      • EBV positive senile large cell B cell lymphoma 
      • Primary effusion lymphoma
      • Burkitt's lymphoma
  • T/NK Cell Lymphomas
    • Precursor T cell lymphoma
      • Precursor T cell lymphoblastic lymphoma
      • Blastic NK cell lymphoma
    • Mature T/NK cell lymphoma
      • Adult T cell leukemia/lymphoma
      • Extranodal NK/T cell lymphoma, nasal type
      • Enteropathy-associated T cell lymphoma
      • Hepatosplenic gamma-delta T cell lymphoma
      • Subcutaneous panniculitis-like T cell lymphoma
      • Mycosis fungoides
      • Sezary syndrome
      • Primary cutaneous anaplastic large cell lymphoma
      • Peripheral T cell lymphoma, unspecified
      • Angioimmunoblastic T cell lymphoma
      • Anaplastic large cell lymphoma

WHO Classification of Hodgkin's lymphoma/disease

  • Nodular lymphocyte predominant Hodgkin's lymphoma
  • Classical Hodgkin's lymphoma which includes
    • Nodular schlerosing classical Hodgkin's lymphoma
    • Mixed cellularity classical Hodgkin's lymphoma
    • Lymphocyte-rich classical Hodgkin's lymphoma
    • Lymphocyte-depleted classical Hodgkin's lymphoma

Histiocytic and Dendritic Cell (Antigen Presenting Cell) Malignant Neoplasms: Who Classification (adapted from) 

  • Langerhans cell histiocytosis (Histiocytosis X, Eosinophilic granuloma, Hand-Schiiller-Christian disease, Letterer-Siwe disease)
  • Langerhans cell sarcoma (malignant neoplasma)
  • Histiocytic sarcoma (malignant neoplasm)
  • Erdheim-Chester disease
  • Interdigitating dendritic cell sarcoma (malignant neoplasm)
  • Follicular dendritic cell sarcoma (malignant neoplasm)

Multiple Myelomas and other Monoclonal Gammopathies

  • Multiple myeloma
  • Plasmacytomas
  • Waldenstrom's macroglobulinemia
  • Primary amyloidosis
  • Heavy chain diseases
    • IgG heavy chain disease
    • IgA heavy chain disease
    • IgM heavy chain disease
  • Monoclonal gammopathy of undetermined significance (MGUS)

General References:

  • Bennett JM, Catovsky D, Daniel MT, et al: FAB Cooperative Group: Proposal for the classification of the myelodysplastic syndrome. Br J Haematol 51:189, 1982
  • Bennett JM, Catovsky D, Daniel MT, et al: French-American-British (FAB) Cooperative Group: The morphological classification of acute lymphoblastic leukemia- concordance among observers and clinical correlations. Br J Haematol 47:553, 1981
  • Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Am Intern Med 103:620, 1985
  • Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IRAC Press: Lyon 2001
Charles  E.  Hess,  M.D.,FACP    [more information]
Professor of Internal Medicine
Department: Medicine
Division: Hematology/Oncology