Leukemias
Definitions
1) Leukemia – malignant neoplasm of hematopoietic stem cells
2) Lymphoma – malignant neoplasm of lymphocytes which usually arises in lymph nodes but can arise from lymphoid tissue anywhere in the body
3) Leukocytosis – increased numbers of WBCs in the peripheral blood
4) Granulocytopenia – absolute decrease in the number of neutrophils in the peripheral blood
5) Thrombocytopenia – decrease in the # of platelets in the peripheral blood
6) Pancytopenia – coexistence of anemia, granulocytopenia, and thrombocytopenia
General Information on Leukemias
- usually classifies on basis of cell type involved and the state of maturity of the leukemic cells
Ø acute leukemias – characterized by the presence of very immature cells (blasts) and by a rapidly fatal course in untreated patients
q replacement of normal marrow elements with proliferating “blast cells” that do not undergo normal maturation
q loss of normal mature marrow elemants (i.e. red cells, granulocytes, and platelets)
q Clinical picture: anemia, infection, hemorrhage
q Abrupt, stormy onset (most patients within 3 months of symptoms
q May have organ infiltration resulting in lymphadenopathy, splenomegaly, and hepatomegaly
q Diagnosis – 30% or more blasts in the bone marrow; high peripheral white count with circulating blasts
Ø chronic leukemias – associated with well=differentiated leukocytes and with a relatively indolent course
q not rapidly fatal, clinical and morphological features that unite the acute leukemias are lacking
Ø two major variants of acute and chronic leukemias are recognized : lymphocytic and myelocytic
Ø Thus ALL, CLL, AML, CML.
For board purposes, you can usually determine the type of leukemia based on patient age alone.
Disease Age
ALL 0-15
AML 15-40
CLL 40-65
CML 65+
Pathophysiology
- block in differentiation of leukemic stem cells and the leukemic blasts have a prolonged generation time; there is a failure of maturation into functional end cells
- as the leukemic blasts accumulate, they suppress the normal hematopoietic stem cells by incompletely understood mechanisms
- the suppression of the normal hematopoietic stem cells clinically shows: anemia, infection, bleeding
- Treatment: the aim is to reduce the population of the leukemic clone enough to allow recovery of normal stem cells.
Acute Lymphoblastic Leukemia (ALL)
Epidemiology
- 1o children and young adults
- most common type of cancer in children under 15 years of age.
- Children between the ages of 1-10 have the best prognosis
- Remission rate for childhood ALL – 85% (over ½ are cured)
Classification of ALL
- L1,L2,L3 subtypes
Ø 85% of children with ALL have the L1 subtype
Ø <15% have the L2 subtype (seen commonly in adults)
Ø L3 subtype = leukemic manifestation of Burkitt’s lymphoma
Ø CNS is frequent site of relapse
- Immunologic subclassification is based on the origin of the leukemic lymphoblasts and their stage of differentiation
Ø vast majority of ALLs are B cell in origin (80%)
Ø T lymphoblasts in patients with T cell ALL seem to be arrested in early introthymic stages of maturation (aggressive lymphoma relation)
Ø Prognostic difference exist among the immunologic subtypes
- most favorable – precursor B-cell ALL
- poorest prognosis – B cell ALL- corresponding to the leukemic phase of Burkitt’s lymphoma
- Chromosomal changes
Ø 60% have cytogenetic abnormalities in their leukemic cells
Ø Hyperdiploidy is fairly common in early precursor B cell ALL and is present in about 20-30% of all cases of ALL – associated with a good prognosis
Ø Philadelphia chromosome (translocation of protions of chromosome 9 and 22) is found in about 15% of adult cases of ALL and 5% of childhood cases and is associated with a poorer prognosis
Ø t(8:14) seen in ALL-L3 and a t(1:19) are associated with a poor prognosis.
Acute Myelocytic Leukemia
Epidemiology
- AML affects 1o adults between the ages of 15 and 40 years
- Only 20% of all childhood leukemias
Pathogenesis and Classification
- extremely heterogenous because of the complexity of myeloid cell differentiation.
- FAB classification
Ø 7 categories (M1-M7) depending on the amount of maturation (M1-M3) and the predominant line of differentiation of the leukemic stem cells (M4-M7)
- Morphological features, special stains, and surface markers
Ø characteristics of myeloblasts
1) delicate nuclear chromatin
2) 3-5 nucleoli
3) fine granules in the cytoplasm
4) Auer rods – red staining intracytoplasmic rodlike structures
Ø Myeloperoxidase
- cytochemical stain + in myeloblasts and – in lymphoblasts
Ø Acute Promyelocytic Leukemia (AML-M3)
- two types associated with an increased risk for DIC with bleeding, skin, mucosal, uterine, and GI hemorrhage, as well as intracranial or pulmonary hemorrhage
Ø AML-M4 and AML-M5 (monoblastic component)
- proneness to tissue infiltration by the leukemic blasts
Ø AML-M6 (Erythroleukemia)
- has ben associated with radiation and toxin-induce leukemia
Ø AML-M7 (Megakaryocytic Leukemia)
- increased incidence in Down’s patients and following myeloproliferative disorders
- Chromosomal Abnormalities
Ø demonstrated in 90% of patients with AML
Ø see chart on p. 966
- Myelodysplastic Syndromes
Ø small group of stem cell disorders characterized by maturation defects resulting in ineffective hematopoiesis and an increased risk of transformation to acute myeloblstic leukemias
Ø bone marrow retains capacity in a small clone of stem cells to differentiate into red cells, granulocytes, and platelets, but is ineffective
Ø this clone of cells is genetically unstable and can lose ability for differentiation and thus gives rise to an acute leukemia
Ø Most patients with myelodysplsia are elderly males between 60-70 yoa.
- present with weakness, infections, hemorrhages
Chronic Lymphocytic Leukemia
Epidemiology and Presentation
- predominantly a disease of older adults (40-65)
- male:female 2:1
- more than ½ have disease discovered on routine blood study
- involves the proliferation of a clone of small, immunologically incompetent lymphocytes in the bone marrow, lymph nodes, and spleen
Ø if extensively in the marrow with circulating lymphocytosis = CLL
Ø If predominantly in lymph nodes w/o a peripheral lymphocytosis = small lymphocytic lymphoma
Laboratory diagnosis
q persistent peripheral blood lymphocytosis
q 40% or more lymphocytes in the marrow
q both of above required for diagnosis of CLL
Ø 95% of CLLs are of B lymphocyte origin with the cells staining with a monoclonal immunoglobulin pattern
Therapy and Prognosis
¨ CLL usually very indolent
¨ In small # of patients, the disease undergoes “prolymphocytic transformation” = more fulminant clinical course
Chronic Leukemias
Chronic Myelocytic Leukemia
Epidemiology and Natural History
- predominantly affects adults over 65 years old (at least for board purposes)
- CML inevitably transforms into an acute leukemia
- It is the most common leukemia, accounting for 15-20% of total.
- Chronic phase lasts 3-5 years, then evolves into acute blast crisis with death in a few months.
Genetics
- More than 95% have Philadelphia Chromosome t(9;22)(q34;q11) with the gene product Bcr-Abl, making the cell resistant to chemotherapy and apoptosis.
- Those that don’t have the Philadelphia Chromosome have developed the same Bcr-Abl fusion protein through a different mechanism. The result is the same.
Treatment
- Hydrozyurea and Busulfan reduce myeloid numbers, reducing symptoms, in the chronic phase but don’t delay the acute phase.
- Interferon-α prolongs survival, inducing remissions in 60-80%. These 2 therapies are somewhat additive.
- Imatinib mesylate [Glivac/Gleevac (formerly STI-571)] is a competitive inhibitor of bcr-abl, platelet derived growth factor, and c-kit tyrosine receptor kinases. It helps even in those that have failed interferon therapy.
Hairy Cell Leukemia
- HCL – rare leukemia composed of B cells with a less mature morphology that the B cells of CLL
- Distinctive appearance on peripheral blood smears
Ø cytoplasmic projections (hairy cell)
Laboratory
- leukemic cells stain for acid phosphatase which is resistant to treatment with tartrate – distinctive laboratory finding
Presentation
- most commonly in middle aged males who present with pancytopenia and spleenomegaly
- infections are very common
- new therapies have prolonged survival.
Tags: Acute Lymphoblastic Leukemia, Acute Myelocytic Leukemia, anemia, blast cells, granulocytes, Granulocytopenia, Hairy Cell Leukemia, hemorrhage, Hepatomegaly, infection, leukocytosis, lymphadenopathy, Lymphocytic Leukemia, malignant neoplasm, Pancytopenia, splenomegaly, thrombocytopenia
