Definition – group of diseases having as a common denominator the proliferation of one, or usually more than one, of the bone marrow-derived cell lines.  The proliferation may be medullary or extramedullary

Classification of Diseases

1)     Chronic myelogenous leukemia – CML

2)     Agnogenic myeloid metaplasia (myelofibrosis) – AMM

3)     Polycythemia rubra vera – PRV

4)     Primary Thrombocytopenia – PT

• the resulting clinical and morphological findings vary somewhat depending on the cell line that predominates.

General Clinical and Lab features

• anemia, polycythemia, leukocytosis, teardrop erythrocytes, macrocytes, nucleated erythroid precursors in peripheral blood smear, thrombocytosis, thrombocytopenia, purpura, splenomegaly, hepatomegaly.

Chronic Myelogenous Leukemia

• neoplastic multipotential stem cell disorder resulting in the proliferation of granulocytes in the bone marrow, spleen and liver.
• Can have varying proliferation of erythroid and megakaryocytic cells.

Symptoms and Signs

1)     gradual onset of fatigue and weakness

2)     anemia (may be minimal)

3)     splenomegaly, hepatomegaly, or lymphadenopathy

Lab diagnosis

1)     White blood cell count

Ø  very high WBC (30,000 to 100,000), consisting mostly of mature segmented neutrophils

Ø  usually – eosinophilia and basophilia

Ø  elevated platelet count in 50%; decreased in 10%

2)     Leukocyte alkaline phosphatase

Ø  low or zero

3)     Philadelphia chromosome

Ø  translocation t(9:22) present in the granulocytes, erythrocytes, and megakaryocytes, but NOT the stimulated T lymphocytes

Ø  abnormal small G-group chromosome #22

4)     Bone marrow findings

Ø  hypercellularity

Ø  marked granulocytic hyperplasia (high M:E ratio)

Therapy and Prognosis of CML

• Chronic Phase

q  Average survival w/o treatment = 31 mths

q  With aggressive therapy – survival increases to a median of 50 mths

q  Treatment is aimed at lowering the WBC and platelets and consists predominantly of interferon and hydroxyurea

• Blast Crisis

q  After 2-5 years, the CML results in a “blast crisis”

q  Over 30% of the marrow consists of blasts

-        80% of cases – blasts are myeloid

-        20% of cases – blasts are lymphoid

q  treatment is vincristine and prednisone

q  poor response to therapy when in blast crisis

Agnogenic Myeloid Metaplasia

Definition

• also called idiopathic myelofibrosis
• describes a myeloproliferative syndrome characterized by fibrosis and granulocytic hyperplasia in the bone marrow and by proliferation of granulocytes in the spleen and liver.
• Agnogenic = of unknown origin
• it is a monoclonal proliferation

Clinical and Laboratory Findings

• middle or advanced age (sometimes in childhood)
• sometimes associated with Down’s syndrome
• Chief symptoms

1)     progressive anemia – usually normochromic

2)     splenomegaly

3)     hepatomegaly

• blood smear – shows characteristic “teardrop” RBC, or dacryocytes
• as disease progresses – increasing neutrophilic leukocytosis
• later stages – fibrosis in the bone marrow is so severe that osteosclerosis is justified.
• When you biopsy the bone marrow, you either get a dry tap or hypercellular marrow.
• Core biopsy confirms the fibrosis and the cellular hyperplasia
• About 20% of the cases terminate as acute myelogenous leukemia

Primary Thrombocythemia

• 2^o thrombocytosis (not 1^o thrombocythemia)

Ø  when the platelet count is higher than 500,000 there is a thrombocytosis

Ø  the proliferation of megakaryocytes in the bone marrow and the thrombocytosis in the peripheral blood reflect the underlying proliferative disorder; occurs as a result of something else

• 1^o or essential thrombocythemia

Ø  the proliferation of megakaryocytes in the bone marrow and thrombocytosis in the peripheral blood occur as a “primary” disease.

Ø  Thrombocytosis frequently causes either severe bleeding or thrombosis

Ø  Defect is most severe when the platelet concentration is the highest

Ø  It is not possible to predict in advance which patients with a high platelet count will have abnormal bleeding and which will form thrombi

Ø  Treatment: directed primarily at reducing the platelet count.

Polycythemia rubra vera

Definition

• Polycythemia – refers to an increase in concentration of erythrocytes in the peripheral blood to above normal; Can be 1^o or 2^o
• If 1^o usually called polycythemia rubra vera

Ø  Unknown etiology

Ø  Red blood cell precursors proliferate independently of erythropoietin

• If 2^o sometimes called erythrocytosis
• Third class of polycythemia

Ø  relative polycythemia or relative erythrocytosis

Ø  caused by a decreased plasma volume

Clinical Findings

• common signs and symptoms

1)     ruddy cyanosis

2)     headache

3)     dyspnea or orthopnea

4)     dizziness or vertigo

5)     eye complaints

6)     epigastric discomfort

• High hematocrit = high viscosity = higher thrombotic phenomenon

Laboratory findings

• Erythrocytosis

Ø  required for diagnosis

• Leukocytosis and thrombocytosis

Ø  since it is a stem cell disorder

Ø  degree of leukocytosis is usually proportional to the increase in erythrocyte count

Ø  platelet count is usually increased also

Ø  Hyperkalemia from increased release of K⁺ from the excessive # of platelets

• Other findings

Ø  hypercellular bone marrow

Ø  increase in all cell lines

Differential Diagnoses

Secondary Polycythemia (erythrocytosis)

q  usually caused by hypoxia arising from decreased atmospheric pressure, impaired pulmonary ventilation, congenital heart disease, arteriovenous aneurysm, chronic acquired heart disease, or presence of abnormal hemoglobin.

q  Can occasionally be caused by tumor (renal cell CA) or a hormonal disorder

q  LOW O₂ SAT (normal O₂ in PV)

q  High levels of Erythropoietin in 2^o (normal to low normal in PV)

Leukemoid Reactions

q  Definition – peripheral blood findings resemble those found in leukemia

Ø  leukomoid reactions are benign proliferations

Ø  no clear cut division between marked leukocytosis and leukemoid reaction

Ø  more immature cells in leukomoid reactions than in the usual leukocytosis

q  In some cases the differentiation between leukomoid and leukemia is extremely difficult.

Ø  Generally, the bone marrow in a myelocytic leukomoid reaction shows a greater proportion of mature granulocytes than does a myelocytic leukemia.

Ø  Results in the anemia and thrombocytopenia not being present in leukomoid reactions

q  Leukomoids are usually transient, whereas leukemia is usually progressive.

q  Conditions that may cause a leukomoid reaction

Granulocytic reactions, Lymphocytic reactions, Monocytic reactions, Metabolic processes, malignant disease, drugs.

Plasma Cell Dyscrasias

Definition

• group of disorders that have in common the expansion of a single clone of immunoglobulin-secreting cells and a resultant increase in serum levels of a single homogenous immunoglobulin or its fragments
• these dyscrasias generally behave as malignant diseases

Monoclonal Protein

• the monoclonal protein identified in the blood is referred to as an M component or M protein in reference to Myeloma.
• The M components have high molecular weights – restrict them to circulating plasma and extracellular fluid
• These may appear in the urine when there is some form of glomerular damage with heavy proteinuria.
• Sometimes excess light or heavy chains are also synthesized with the complete immunoglogulins.

Ø  They are always identical to those found in the complete immunoglobulin

Ø  Occasionally only light or heavy chains are produced without complete Ig.

Ø  The free light chains, known as Bence Jones proteins, are small enough to be rapidly excreted in the urine.

Classification of Plasma Cell Dyscrasias

• complicated
• includes morphological entities as well as entities classified on the basis of the type of Ig produced

Plasma Cell Myeloma

Epidemiology

• most common among the malignant plasma cell dyscrasias
• also called multiple myeloma
• Characterized by widespread bone marrow involvement by malignant plasma cells
• Always has an associated monoclonal gammopathy
• 50-70 yoa; male predominance; Blacks>whites

Clinical Manifestations

• Normochromic, normocytic anemia found in 80% of patients
• Bone involvement – “punched out” lytic lesions and pathologic compression fractures of the thoracic and lumbar vertebrae – back pain
• Renal Complications are common – Bence Jones proteinuria
• Hypercalcemia – usually due to bone resorption by myeloma tumors
• Increased susceptibility to infections – due to depression of normal immunoglobulins
• Unusual complication – spinal cord compression from epidural masses of plasma cells
• Serum hyperviscosity

Diagnosis of Plasma Cell Myeloma

• do bone marrow biopsy, serum protein electrophoresis, immunoelectrophoresis, quantitative immunoglobulins, protein electrophoresis, immunoelectrophoresis, 24-hour protein quantitation, skeletal radiographic survey to look for lytic lesions

Treatment of Plasma Cell Myeloma

• management of specific complications and chemotherapy for the malignant process

Solitary Plasmacytoma of Bone

• Plasmacytomas – mass lesions composed of neoplastic plasma cells
• Can be part of a disseminated plasma cell malignancy (i.e. myeloma) or can occur as a solitary lesion

Extramedullary Plasmacytoma

• when extramedullary spread of plasma cell myeloma occurs, it is a poor prognostic sign.
• The most common site of occurrence is the subepithelial tissue of the mucous membranes of the upper air passages

Macroglobulinemia

Definition

• macroglobulinemia – usually used to describe the presence of a monoclonal gammopathy of IgM type
• most often associated with lymphoplasmacytoid and lymphoid malignancies

Clinical findings

• lymphadenopathy, hepatosplenomegaly, and anemia
• hyperviscosity – due to the large quantities of IgM

Ø  may lead to visual disturbances, mental confusion, and hemorrhagic tendencies

Ø  can sometimes be relieved by plasmapheresis

Diagnosis

• similar to the work-up of myeloma
• IgM peak is usually identified on serum protein electrophoresis
• On immunoelectrophoresis the protein is identified as monoclonal and of IgM class
• 1/3 of patients will have free light chains in the urine (Bence Jones proteins)

Heavy Chain Disease

• Rare disorders characterized by the presence of monoclonal gammopathy composed of incomplete heavy chains with no associated light chains
• Protein abnormality is usu associated with a lymphoid or plasmacytic proliferation
• Diagnosis

Ø  monoclonal protein on immunoelectrophoresis that reacts with anti-IgG, IgA, or IgM

Benign Monoclonal Gammopathy

• there are monoclonal gammopathies in patients who do not have a B cell malignancy or amyloidosis
• these are called benign monoclonal gammopathies or monoclonal gammopathies of undetermined significance.
• Incidence increases with age
• 30% of those that have benign monoclonal gammopathy have no associated disease
• another 20-30% have cardiovascular or neurologic disease
• remainder have a variety of ailments

q  IgG – 75%

q  IgA – 15%

q  IgM – 10%

q  The size of the serum monoclonal gammopathy is small compared to that in plsma cell myeloma.

Tags: Agnogenic myeloid metaplasia, anemia, granulocytes, Hepatomegaly, Leukemoid Reactions, leukocytosis, macrocytes, myelofibrosis, nucleated erythroid precursors in peripheral blood smear, polycythemia, Polycythemia rubra vera, Primary Thrombocytopenia, purpura, splenomegaly, teardrop erythrocytes, thrombocytopenia, thrombocytosis

This entry was posted on Wednesday, July 15th, 2009 at 5:00 am and is filed under Pathophysiology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.