Hematology Ciulla: Malignant Leukocyte Disorders

malignant clone of cells

They proliferate without responding to normal regulatory mechanisms

leukemia

It originates in the bone marrow and is initially systemic.

lymphoma

It originates in lymphoid tissue and is initially localized.

Oncogene activation potentially involving viral factors, bone marrow damage, chromosome defects, genetic factors, and immune dysfunction.

What are some theories about the etiology of leukemia and lymphoma?

Viruses

They can suppress immune function or activate oncogenes (e.g., HTLV-I, II, V, and HIV-1).

Radiation, chemicals, and secondary malignancies due to cancer treatments

What external factors can damage bone marrow and potentially lead to malignancy?

t(15;17)

Leukemic subtype for acute promyelocytic leukemia

Down syndrome and Fanconi anemia

What genetic conditions are associated with an increased incidence of leukemia?

By the stem cell involved (lymphoproliferative or myeloproliferative) and the length of the clinical course (acute or chronic).

How can leukemia and lymphoma be classified?

Investigation of unexplained peripheral blood abnormalities, staging and management of certain lymphomas or solid tumors, and ongoing monitoring of response to therapy in patients with malignancy.

What are some indications for a bone marrow examination?

aspirate and core biopsy specimen

What is the optimal sample for bone marrow examination?

posterior superior iliac crest

What is the most commonly used site for a bone marrow biopsy?

anterior iliac crest or sternum

What other sites may be used for bone marrow biopsy besides the posterior superior iliac crest?

Cellularity, myeloid to erythroid (M:E) ratio, megakaryocyte evaluation, iron stores, and differential

What routine assessments are performed during a bone marrow examination?

Flow cytometry, cytogenetics, molecular, and microbiology testing

What additional tests may be included in a bone marrow examination?

Weeks to months, with death due to infection and bleeding

What is the duration of survival without treatment for acute leukemia?

Years

What is the duration of survival without treatment for chronic leukemia?

Immature/blast cells

What type of cells predominate in acute leukemia?

Maturing or mature cells

What type of cells predominate in chronic leukemia?

Myeloblasts

What are the predominant cells in Acute Myeloid Leukemia (AML)?

Lymphoblasts

What are the predominant cells in Acute Lymphoblastic Leukemia (ALL)?

Granulocytes

What are the predominant cells in Chronic Myeloid Leukemia (CML)?

Lymphocytes

What are the predominant cells in Chronic Lymphocytic Leukemia (CLL)?

Sudden onset; affects all ages

What is the onset and age range for acute leukemia?

Weakness and fatigue due to anemia, petechiae and bruising due to thrombocytopenia, fever and infection due to neutropenia, and variable leukocyte count.

What are some clinical manifestations of acute leukemia?

Anemia

Weakness and fatigue in acute leukemia is due to

Thrombocytopenia

Petechiae and bruising in acute leukemia is due to

Neutropenia

Fever and infection in acute leukemia is due to

≥20%

What are the bone marrow blast percentages for acute leukemia according to WHO?

>30%, with cellularity >70%.

What are the bone marrow blast percentages for acute leukemia according to FAB classifications?

Frequently asymptomatic initially; affects adults.

What is the onset and age range for chronic leukemia?

Mild or absent anemia, normal to slightly increased platelet count, high WBC count, and marrow cellularity >70%.

What are some clinical manifestations of chronic leukemia?

Unexplained weight loss, night sweats, splenomegaly, hepatomegaly, and lymphadenopathy.

What are common symptoms of both acute and chronic leukemias?

Chemotherapy (dependent on type), radiation, bone marrow/stem cell transplant, and supportive care with transfusions, antibiotics, and growth factors.

What are the treatment options for leukemia?

Hematopoietic malignancy classifications

What do the FAB and WHO classifications relate to?

Cellular morphology and cytochemical stain results

What is the FAB classification based on?

Having >30% bone marrow blasts

How does the FAB classification define acute leukemia?

Information from immunologic probes of cell markers, cytogenetics, molecular abnormalities, and clinical syndrome.

What additional information does the WHO classification use besides cellular morphology and cytochemical stains?

Having ≥20% bone marrow blasts

How does the WHO classification define acute leukemia?

WHO classification

Which classification is now the standard for diagnosis?

It is easier to use

Why is the FAB classification still widely taught?

Cells of the granulocytic series and, to a lesser degree, the monocytic series.

What cells contain the enzyme detected by the Myeloperoxidase (MPO) stain?

Myeloperoxidase (MPO) stain

It differentiates blasts of acute myelogenous leukemias (AMLs) from acute lymphoblastic leukemias (ALLs).

Positive; negative

Auer rods stain ____ in myeloperoxidase stain while lymphocytic cells are ____ for this stain

Phospholipids and lipoproteins.

What does the Sudan black B stain?

They stain positive (blue-black granulation)

How do granulocytic cells and Auer rods appear with Sudan black B stain?

Negative

Lymphocytic cells are ____ for Sudan black B

naphthol AS-D chloroacetate esterase stain

Specific esterase stain is also known as

Esterase enzyme present in primary granules of granulocytic cells.

What do specific esterase stains (naphthol AS-D chloroacetate esterase stain) detect?

alpha-naphthyl acetate and alpha-naphthyl butyrate

Nonspecific esterase stain is also known as

Esterase enzyme present in monocytic cells.

What do nonspecific esterase stains (alpha-naphthyl acetate and alpha-naphthyl butyrate) detect?

esterase stains

They help distinguish acute leukemias of myeloid origin (FAB M1, M2, M3, M4) from those of monocytic origin (FAB M5).

Periodic acid-Schiff (PAS) stain

Stains Intracellular glycogen bright pink.

Immature lymphoid cells, malignant erythroblasts, and megakaryocytic cells.

Which cells stain positive with the PAS stain?

myeloblasts and normal erythrocytic cells

Which cells stain negative with the PAS stain?

Erythroleukemia (FAB M6) and acute lymphoblastic leukemia.

For what conditions is the PAS stain useful in diagnosis?

Leukocyte alkaline phosphatase (LAP) stain

Detects Alkaline phosphatase activity (dark precipitate) in primary granules of neutrophils.

LAP score

Determined by grading 100 neutrophils on a scale from 0 to 4+ based on stain intensity and granule size, and then adding the results. Used to differentiate chronic myelogenous leukemia (CML) from a neutrophilic leukemoid reaction (NLR)

13-130

What is the reference range for the LAP score?

Chronic myelogenous leukemia (CML) or paroxysmal nocturnal hemoglobinuria

What does a decreased LAP score indicate?

CML in remission or with infection, Hodgkin lymphoma in remission, secondary polycythemia

What does a normal LAP score indicate?

Neutrophilic leukemoid reaction, polycythemia vera, CML in blast crisis, or late trimester pregnancy.

What does an increased LAP score indicate?

Tartrate-resistant acid phosphatase stain (TRAP)

Once tartrate is added, staining is inhibited in most cells. Hairy cells from hairy cell leukemia are resistant to _____ to stain positive

Perl's Prussian blue stain

Detects Free iron, which precipitates into small blue/green granules in mature erythrocytes.

siderotic granules or Pappenheimer bodies

Iron inclusions visible with Wright's stain

Siderocytes

mature erythrocytes with iron granules

Sideroblasts

nucleated RBCs in the bone marrow containing iron granules

Severe hemolytic anemias, iron overload, sideroblastic anemia, and post-splenectomy

What conditions show an increased percentage of siderocytes?

In the bone marrow of myelodysplastic syndrome (refractory anemia with ringed sideroblasts [RARS]) and sideroblastic anemias.

Where are ringed sideroblasts seen?

acute lymphoproliferative disorders

It is caused by unregulated proliferation of the lymphoid stem cell, classified morphologically using FAB criteria or immunologically using CD markers to determine cell lineage (T or B cell).

Fever, bone/joint pain, bleeding, and hepatosplenomegaly

What are the clinical symptoms of acute lymphoproliferative disorders?

Neutropenia, anemia, thrombocytopenia, variable WBC count, hypercellular marrow with bone marrow blasts ≥20% (WHO) or >30% (FAB).

What are the laboratory findings in acute lymphoproliferative disorders?

PAS positive, Sudan black B negative, and myeloperoxidase negative.

How do lymphoblasts stain in acute lymphoproliferative disorders?

FAB L1

What is the most common childhood leukemia, according to FAB classification? It is found in children (2- to 10-year peak) and young adults.

Small lymphoblasts, homogeneous appearance, best prognosis, most T cell ALLs are FAB L1.

characteristics of FAB L1

Most common in adults, large lymphoblasts, heterogeneous appearance

characteristics of FAB L2

FAB L3

What is the leukemic phase of Burkitt lymphoma according to FAB classification? It is seen in both adults and children, with lymphoblasts that are large and uniform with prominent nucleoli, cytoplasm stains deeply basophilic, and may show vacuoles.

Poor prognosis, all FAB L3 leukemias are of B cell lineage.

What is the prognosis for FAB L3 leukemia?

Burkitt lymphoma

A high-grade non-Hodgkin lymphoma phase of FAB L3 leukemia, endemic in East Africa (associated with Epstein-Barr virus), presents with jaw/facial bone tumors, U.S. variant presents with abdominal mass.

CD19, CD34, and TdT (terminal deoxynucleotidyl transferase) positive, CD10 (CALLA) negative.

What are the CD marker characteristics of progenitor B cells in ALL?

CD10 (CALLA), CD19, CD34, and TdT positive, the most common subtype of B cell lineage.

What are the CD marker characteristics of early-pre-B cells in ALL?

CD10 (CALLA), CD19, CD20, and TdT positive, the second most common subtype of B cell lineage.

What are the CD marker characteristics of pre-B cells in ALL?

CD19, CD20 positive, TdT negative, the most mature B cell and least common subtype.

What are the CD marker characteristics of B cells (early B) in ALL?

CD19

What is the only marker expressed through all stages of B cells in ALL?

CD2, CD3, CD5, and CD7 (pan T cell markers). Immature T cells are TdT positive.

What CD markers are present on all T cells in T cell ALL?

Immature T cells can have both or neither CD4 and CD8. Mature T cells have one or the other, but not both.

How do immature and mature T cells differ in their CD4 and CD8 expression?

It occurs most often in males, with a mediastinal mass as a common finding.

In which population does T cell ALL occur most often, and what is a common finding?

t(8;14) with a rearrangement of the MYC oncogene.

What genetic translocation is associated with FAB L3/Burkitt lymphoma?

Pre-B cell ALL is associated with t(9;22), and B cell ALL is associated with t(4;11).

What genetic translocations are associated with pre-B cell ALL and B cell ALL?

t(7;11)

What genetic translocation is associated with T cell ALL?