- Last Update On : 2013-01-27
The chronic myeloproliferative diseases represent an acquired defect at the level of the pluripotent stem cell that results in uncontrolled proliferation of one or more of the cellular elements in the bone marrow (i.e. erythroid, granulocytic or megakaryocytic). They are further subclassified based on which of these populations are proliferating, and occasionally show considerable overlap, making subclassification difficult. In the past, there were four distinct entities that were recognized:
- Essential thrombocythemia
- Chronic myelogenous leukemia
- Polycythemia vera
- Myelofibrosis with myeloid metaplasia.
The more recent WHO classification includes seven subgroups:
- Chronic myelogeous leukemia (Philadelphia chromosome, BCR/ABL positive)
- Chronic neutrophilic leukemia
- Chronic eosinophilic leukemia (and the hypereosinophilic syndrome)
- Polycythemia vera
- Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)
- Essential thrombocythemia; and chronic myeloproliferative disease, unclassifiable.
The chronic myeloproliferative diseases are characterized by relatively effective hematopoiesis, which results in a hypercellular bone marrow and elevation of one or more of the cell lines in the peripheral blood. It is clear that many of these diseases are associated with a cytogenetic defect activating a tyrosine kinase receptor. This is most clearly seen in chronic myelogenous leukemia, where the BCR/ABL gene is involved in enhancement of tyrosine kinase activity.Splenomegaly and hepatomegaly are also fairly common, secondary to extramedullary hematopoiesis. This is in contrast to the myelodysplastic syndromes, in which the bone marrow is hypercellular, but the production is ineffective in one or more cell lines, resulting in peripheral cytopenias, and often pancytopenia.
Each of the subgroups of the chronic myeloproliferative diseases has well-defined clinical and pathologic features. However, in some cases the distinctions blur, and the category of chronic myeloproliferative disease, unclassifiable, is used in these instances, until and if the disease further declares itself. Marrow fibrosis can often be seen late in the course of all of these subcategories, and is not related to the clonal proliferation, but instead may be secondary to the production of cytokines and growth factors.If the fibrosis is prominent, it can obscure the underlying disease process, and in these circumstances, the category of chronic myeloproliferative disease, unclassifiable, may again be preferred. Acute myeloid leukemia is another common final pathway.
Chronic myelogenous leukemia is typically recognized by the following constellation of features:
- Leukocytosis with the entire spectrum of granulocytic maturation in both peripheral blood and marrow (often with a slightly more prominent increase in the myelocyte percentage)
- Philadelphia chromosome on cytogenetic examination
- BCR/ABL gene rearrangement
- Clinical fatigue and splenomegaly
- Basophilia is a constant finding
- Eosinophilia is also common in both peripheral blood and bone marrow.
Occasionally, micromegakaryocytes can be seen in the peripheral blood, with their dense, magenta-colored nucleus and sparse cytoplasm, occasionally containing platelet-type granulation. In the bone marrow, the cellularity is markedly increased, and all cell lines are hyperplastic, with the megakaryocytes increased in number, arranged in sheets or clusters, but often smaller in size, showing decreased lobulation of the nucleus. Occasional blasts may be present, but when they reach 10-19% in either peripheral blood or bone marrow, the patient is considered to have entered the accelerated phase, and when the blast count is greater than 20%, they are considered to be in blast crisis. Survival beyond this point is short. Blast crisis can present with blasts of either myeloid or lymphoid origin, with the lymphoid type having a better prognosis. Other criteria for the diagnosis of accelerated phase include:
- Peripheral basophilia greater than 20%
- Persistent thrombocytopenia (<100 x 109/L) unrelated to therapy or persistent thrombocytosis (>1000 x 109/L) unresponsive to therapy;
- Increasing spleen size and WBC count unresponsive to therapy
- Cytogenetic evidence of clonal evolution.
Many patients have shown excellent therapeutic response to imatinib mesylate (Gleevec) in recent years, although the curative choice still remains bone marrow transplantation
Polycythemia vera is also a clonal proliferation resulting in an increased red blood cell mass, often occurring in elderly patients with a male predominance.Many of these patients are found incidentally through an abnormal CBC study, but as many as 25% present with an initial thrombotic episode. Occasionally these patients present with a normal hematocrit, normal to high RBC count, and low MCV, mimicking the findings in thalassemia trait. In this situation, the patient is iron deficient from chronic blood loss, effectively performing auto-phlebotomy.
The WHO criteria for diagnosis of polycythemia vera are somewhat complicated but include:
- increased RBC mass
- clonal genetic abnormality other than Ph chromosome or BCR/ABL fusion gene
- endogenous erythroid colony formation in vitro
- thrombocytosis >400 x 109/L
- WBC>12 x 109/L
- bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation
- low serum erythropoietin levels
After excluding secondary causes of polycythemia, the diagnosis requires elevated red blood cell mass and one other major finding, or elevated red blood cell mass with two other minor findings.
There are two main phases of polycythemia vera, an initial proliferative phase associated with increased red cell mass, and a post-proliferative phase, characterized by marrow fibrosis, cytopenias and extramedullary hematopoiesis. If the patient presents in the second phase, they may be difficult to distinguish from primary idiopathic myelofibrosis. Polycythemia vera can also terminate in acute leukemia.
Chronic idiopathic myelofibrosis (formerly known as myelofibrosis with myeloid metaplasia) is also a disease of the elderly and is characterized by the following:
- Varying degrees of fibrosis in the bone marrow
- Leukoerythroblastosis, often with significant dysmorphic features in all three cell lines
- Splenomegaly, and often hepatomegaly, secondary to extramedullary hematopoiesis.
The blood findings include prominent anisocytosis and poikilocytosis in the red blood cells, with teardrops (dacrocytes) being particularly common and a helpful clue in the differential diagnosis. Nucleated red blood cells are also frequently found. The white cells are usually moderately elevated, although they may be present in normal numbers. A left shift in the white cell series is typical, with immature myeloid cells and even occasional blasts. Basophils are usually increased. Platelets are either normal or decreased in number, and often show dysmorphic features, with giant platelets and uneven or incomplete granularity. Micromegakaryocytes can be seen. The bone marrow is telling in this disease, for there is a progressive increase in reticulin and collagen over time, which can be highlighted with special stains. In most cases, the marrow cannot be aspirated (“dry tap”).
Essential thrombocythemia is characterized by recurrent spontaneous hemorrhage, and the platelet count typically exceeds 1000 x 109/L. Platelets demonstrate an abnormal morphology, and neutrophilic leukocytosis is almost invariably present. The diagnostic criteria for essential thrombocythemia, as listed by the WHO classification, include:
- Sustained platelet count greater than or equal to 600x109/L
- Bone marrow biopsy showing proliferation mainly in the megakaryocyte line with enlarged, mature megakaryocytes.
Although these four subtypes of myeloproliferative disease are well defined and recognized, it is clear that considerable overlap can be seen amongst these different morphologic entities, and individual cases can show transition from one category to another. All of these entities have a chronic course that may terminate in marrow fibrosis, with the attendant complications of pancytopenia, or acute leukemia. Such is the case with our patient, who began his course with polycythemia vera, and ended with myelofibrosis.
The chronic myeloproliferative diseases can also show overlap both clinically and pathologically with the myelodysplastic syndromes, and the WHO classification has defined a separate category called the myelodysplastic/myeloproliferative diseases, which includes:
- Chronic myelomonocytic leukemia,
- Atypical chronic myeloid leukemia,
- Juvenile myelomonocytic leukemia,
- Myelodysplastic/ myeloproliferative disease, unclassifiable.
Thus, in making a diagnosis of a specific myeloproliferative disease, one must take into account the clinical presentation, and the morphologic and cytogenetic findings to correctly classify the patient and ensure proper treatment and follow-up.
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