ABSTRACT: Myeloproliferative disorders originate in the clonal expansion of a transformed pluripotential hematopoietic progenitor cell. This results in a group of syndromes that include polycythemia vera, essential thrombocythemia, chronic myelocytic leukemia, and agnogenic myeloid metaplasia. Diagnostic criteria for polycythemia vera and essential thrombocythemia were codified by the Polycythemia Vera Study Group in 1967 and 1977. Subsequent modifications include criteria for evidence of clonal proliferation by abnormal bone marrow karyotype and demonstration of erythropoietin(Drug information on erythropoietin)-independence of erythropoiesis or reduced serum erythropoietin. Phlebotomy is the mainstay of treatment for polycythemia vera. The defining characteristic of essential thrombocythemia is a sustained elevation of the platelet count above 600,000/mL in an untreated patient. Symptoms and risk factors are the main determinants of treatment options for patients with essential thrombocythemia. High-risk patients are candidates for cytoreduction, whereas lower-risk patients receive either no treatment, low-dose aspirin(Drug information on aspirin), or another antithrombotic therapy. The availability of newer nonleukemogenic and megakaryocyte-specific agents warrants a reassessment of current treatment options. [ONCOLOGY 15(8):989-1008, 2001]
Myeloproliferative disorders are chronic malignant conditions that originate in the clonal expansion of a pluripotential hematopoietic precursor cell. This proliferating progenitor retains its ability to self-renew, commit, differentiate, and mature to produce increased numbers of functioning cells of the hematic trilineage (ie, red blood cells, white blood cells, and platelets).[1,2] The resulting group of syndromes that comprise chronic myeloproliferative disorders include polycythemia vera, essential thrombocythemia, chronic myelocytic leukemia (CML), and agnogenic myeloid metaplasia.
Chronic myelocytic leukemia meets some of the criteria of a chronic myeloproliferative disease. Because CML is more homogeneous in its features, is uniquely associated with a particular chromosomal abnormality, has a relatively short chronic phase, and almost invariably progresses to acute leukemia within a decade, it is best treated as distinct from a non-CML myeloproliferative disorder. Myelofibrosis is an epiphenomenon in myeloproliferative disorders that occurs most often in agnogenic myeloid metaplasia and may complicate late-stage essential thrombocythemia or polycythemia vera. Its etiology and pathophysiology are poorly understood, and it is both unpredictable and resistant to treatment.
The non-CML myeloproliferative disease syndromes are more heterogeneous than CML, and "hybrid" phenotypes are common and diagnostically challenging. The phenotype determines both the pathophysiology and management of each syndrome during the long period of chronic, indolent proliferation. When appropriately treated, survival is measured in decades. Both essential thrombocythemia and polycythemia vera have a predictable but low incidence of transformation to acute leukemia or myelodysplastic disease. These tendencies increase with the use of potentially leukemogenic drug therapy.
The sine qua non for the diagnosis of polycythemia vera is erythrocytosis, but the diagnosis also requires demonstration of the involvement of at least one additional cell type of the hematic trilineage. Approximately 50% of cases involve thrombocytosis. The Polycythemia Vera Study Group (PVSG) first codified diagnostic criteria in 1967.[4-6] No single marker is diagnostic for polycythemia vera, so the PVSG chose major and minor criteria that, in certain combinations, establish the diagnosis. The principal subsequent modifications include the addition of an abnormal marrow karyotype as a clonality marker to the primary diagnostic criteria and the demonstration of erythropoietin-independent burst-forming unit growth or reduced serum erythropoietin as minor criteria.[8,9] The modified criteria are listed in Table 1. The inclusion of bone marrow histopathology has been proposed by the European Working Group on Myeloproliferative Diseases. The robustness of histopathological criteria will depend on the definition of morphological changes that are without significant inter- or intra-observer error.
Because the kidneys release erythropoietin in response to hypoxic signals, elevated serum levels of erythropoietin appear in secondary erythrocytosis. Erythroid proliferation in polycythemia vera is not driven by erythropoietin, however, and serum levels are typically low. To date, no specific genetic marker has been associated with polycythemia vera, although evidence of a familial incidence has been accrued.[11,12]
It is essential that any occult bleeding and/or iron deficiency that might mask polycythemia vera be corrected before red blood cell mass is measured. A hematocrit of 60% or greater is always indicative of polycythemia vera if other criteria are met, so the need to measure the red blood cell mass directly can be omitted for patients with hematocrit measurements at this level.
Wasserman has suggested that the natural history of polycythemia vera may consist of five stages (Table 2). Only about 15% of patients are diagnosed in stage 1. Michiels has proposed criteria for distinguishing the stages as a patient’s symptoms progress. These distinctions involve progressive changes in the primary and secondary criteria, including findings on bone marrow biopsy, with gradation of myelofibrosis as well as cellularity and megakaryocytes. The characteristic features of bone marrow sections of untreated polycythemia vera patients include increased cellularity due to hyperplasia of all marrow elements and an increase in enlarged megakaryocytes with hyperploid nuclei.
In 1977, the PVSG defined the original essential thrombocythemia diagnostic criteria and subsequently revised them. The defining characteristic is sustained elevation of the platelet count above 600,000/µL in an untreated patient. In approximately 50% of cases, patients also have elevated white cell counts. Essential thrombocythemia is a diagnosis of exclusion, requiring the requisite platelet count, laboratory evidence excluding other myeloproliferative disorders, and a clinical evaluation finding no cause for reactive thrombocytosis. More specific criteria based on laboratory findings—eg, increased platelet size and heterogeneity, ratio of adenosine(Drug information on adenosine) triphosphate to adenosine diphosphate, and spontaneous growth of erythroid or megakaryocytic colonies in vitro—were excluded from the revisions because they are not uniformly present in patients with essential thrombocythemia.
Although understanding of the molecular biology of myeloproliferative disorders has advanced, no genetic lesion has thus far been associated with essential thrombocythemia. A clonal karyotypic anomaly (5q-) was identified, but it appears in no more than 5% of patients with essential thrombocythemia. The human megakaryocyte growth and development factor thrombopoietin (TPO) was cloned, and the TPO receptor c-Mpl has been characterized. Studies have shown that expression of c-Mpl protein and m-RNA is markedly reduced in the platelets of patients with essential thrombocythemia. Hepatic production of TPO is signal independent, and serum levels are determined primarily by the efficiency of c-Mpl binding and clearance. In polycythemia vera and essential thrombocythemia patients, serum TPO is normal to elevated, suggesting that an intrinsic defect of c-Mpl transcription may cause decreased receptor expression and, consequently, ineffective TPO clearance. In view of the apparent lack of specificity, the diagnostic value of TPO and c-Mpl assays remain to be determined. The revised (1997) diagnostic criteria for essential thrombocythemia are shown in Table 3.
If the measurements in criterion 3 (iron in marrow, serum ferritin, or red blood cell mean corpuscular volume) suggest iron deficiency, polycythemia vera cannot be excluded unless a trial of iron therapy fails to raise the red blood cell mass into the polycythemic range. A normal or elevated serum ferritin level along with a normal red blood cell mean corpuscular volume effectively excludes both reactive thrombocytosis secondary to iron deficiency and the possibility of polycythemia vera masked by iron deficiency. Furthermore, a hematocrit of 60% or greater is invariably indicative of polycythemia vera and excludes essential thrombocythemia.
Polycythemia vera is a relatively rare disorder, with an annual incidence of 1 to 3 cases per 100,000 population. According to reports, it occurs least frequently in Japan and most frequently in Sweden and among Ashkenazim in northern Israel. The median age of onset is approximately 65 years, but the disorder is occasionally seen in younger individuals. Median survival for patients whose disorder is not effectively controlled is reported to be 1.5 to 3 years. Among those who receive appropriate treatment, median survival is extended to 10 years or more, depending on age at diagnosis.
As with other myeloproliferative disorders, the clinical manifestations of polycythemia vera are determined by the degree of proliferation of the pluripotential hematopoietic precursor cell (PHPC) progenies. The principal complication is thrombosis resulting from increased proliferation of erythrocytes and platelets. Blood viscosity increases exponentially as the hematocrit exceeds 50%. Platelets in polycythemia vera patients show increased adhesiveness and aggregability. This explains the frequency of thromboembolic events in untreated patients with polycythemia vera, with incidence varying among several series studied.
One series found that 14% of essential thrombocythemia patients experienced thromboembolic events prior to diagnosis, and in 20%, such events were the presenting symptoms of the disorder.[18,21] Similar events develop in an additional 30% during the course of treatment. The most common risk factors for vascular complications of polycythemia vera are age and previous history of vascular events. The greatest risk of thrombosis occurs in the first 3 years following diagnosis in patients treated with phlebotomy.
With moderate elevations of viscosity, stasis develops most frequently in the small vessels of the digits, vestibular apparatus, and retinae and may be experienced as erythromelalgia, vertigo, or scotomata. Because of the reversibility of platelet aggregation, these symptoms are usually transient. At higher levels of viscosity and thrombocythemia, however, involvement of arterial circulation may result in transient ischemic attacks, angina, or bowel ischemia. In one series, cerebral ischemia accounted for 70% of arterial thromboses at diagnosis and was as prevalent as myocardial infarction (30%) prior to diagnosis of polycythemia vera.[18,21]
These extreme events are most common in older patients with underlying atherosclerotic conditions. Patients with uncontrolled polycythemia vera are also prone to deep venous thrombosis of the extremities and the hepatic, portal, and splenic veins. Arterial and venous thromboses occur with about equal frequency in polycythemia vera patients. Hemorrhage, the second most common complication of polycythemia vera, develops in approximately 20% of uncontrolled patients.
The principal long-term risk associated with polycythemia vera among patients who survive thromboembolic and hemorrhagic events is progression to stage IV, or postpolycythemic myeloid metaplasia. This condition has a profile indistinguishable from agnogenic myeloid metaplasia. It is reported that 10% of patients transform in approximately 15 years, and 50% after 20 years, regardless of treatment. Approximately 2% of long-term survivors of polycythemia vera progress to stage V, acute myelocytic leukemia.