Idiopathic Myelofibrosis : Historical Review, Diagnosis and Management
I . M . Weinstein S UMMA R Y. Idiopathic myelofibrosis is reviewed from several aspects . The historical development of knowledge about this disorder is discussed, from early descriptions of extramedullary hematopoiesis associated with numerous etiologies, a debate over pathogenetic mechanisms, followed by newer evidence which placed this disorder with the myeloproliferative disorders . Evidence is presented showing that idiopathic myelofibrosis is an acquired clonal disorder in terms of the hematopoietic abnormalities, but that the marrow fibrosis is a result of non-clonal disordered fibrogenesis . The clinical, laboratory and pathologic features of idiopathic myelofibrosis are discussed . The features which distinguish this disorder from the other myeloproliferative disorders, particularly chronic myelogenous leukemia are emphasized . The natural history is described together with an evaluation of accepted and experimental therapy .
Idiopathic myelofibrosis is defined as a chronic myeloproliferative disorder, characterized by marrow fibrosis, splenomegaly, peripheral blood leukoerythroblastosis and red cell poikilocytes (teardrops) . This disorder has been described under at least 37 different names, primarily that aspect of the syndrome that most impressed the authors ." The most commonly used alternative name for this disorder is agnogenic myeloid metaplasia . 3 In this review only the term idiopathic myelofibrosis will be used . Historical Review In 1879, 13 years before Vaquez described polycythemia vera,a Heuck described `two cases of leukemia with peculiar blood and bone marrow findings' .' This is the first acceptable report of this disorder . Heuck noted osteofibrosis of the bone marrow and extramed1 . M. Weinstein, MD, Clinical Professor of Medicine, Department of Medicine, Division of Hematology-Oncology, UCLA School of Medicine ; Attending Physician and Member, Board of Governors, Cedars-Sinai Medical Center, Los Angeles, California 90024-1678, USA . Correspondence to : 1 . M . Weinstein, MD, 8635 W . Third Street, Suite 1165, Los Angeles, California 90048, USA . Blood Rervwr (1991) 5, 9s-Ie4 !© 1991 W nginan Group UK Ltd
ullary hematopoiesis of the liver and spleen . Beginning with the turn of the 20th century other authors published case reports of patients with splenomegaly, osteosclerosis and 'leukemic' blood pictures .' , ' From 1905-1930 most published reports on this subject depicted patients with massive splenomegaly, myeloid metaplasia and osteosclerosis, often in association with tuberculosis and cancer .' , ' There was confusion in these early attempts to distinguish secondary myeloid metaplasia from the idiopathic variety ; a dilemma that still exists today . It was generally held that the development of extramedullary hematopoiesis in the liver and spleen was compensatory to bone marrow fibrosis . In the 1930's and 1940's more careful studies were reported, attempting to codify this ill-defined clinical pathological syndrome into a single entity . Several authors emphasized the co-existence of myeloid metaplasia and infection or metastatic cancer . Others emphasized a similarity of the extramedullary blood formation to the normal embryological 9-, t In 1950, Block and Jacobsen published an state . important paper arguing that idiopathic myeloid metaplasia was an entity of unknown origin, closely related to polycythemia vera but fundamentally
BLOOD different from chronic myelogenous leukemia ." In 1951, Damashek introduced the concept of the 'myeloproliferative syndrome', speculating that chronic myelogenous leukemia, polycythemia vera and agnogenic myeloid metaplasia were all closely related neoplastic marrow disorders with a common propensity to transform into acute leukemia ." In the ensuing decade, this concept became widely accepted Despite the elegant publication by Ward and Block' on the natural history of agnogenic myeloid metaplasia in which they presented clinical, pathological and embryological data refuting the neoplastic nature of the disorder, by 1970 most authorities agreed that idiopathic myelofibrosis was a neoplastic disorder . In 1975, studies on patients who had idiopathic myelofibrosis and G6PD heterozygosity were shown to have only one type of G6PD in their red cells, white cells and platelets ." In the same year, Silverstein's timely monograph presented all the known pertinent historical, clinical and laboratory features of this disorder up to that time . The report clearly established that idiopathic myelofibrosis was a chronic myeloproliferative syndrome ." Etiology and Pathogenesis In the past decade, investigators have confirmed the clonal nature of this disorder in the hematopoietic cells, but the fibroblastic proliferation in the marrow appears to be a secondary phenomenon .26,2 . The type of collagen primarily involved in myelofibrosis (Type 111) has been reported ." Of great significance is the evidence that the increased collagen content of the marrow in idiopathic myelofibrosis is the result of release of growth factors, primarily derived from platelets and megakaryocytes . 29 Recent studies have revealed that c-sis encodes one chain of human PDGF, suggesting that this oncogene may be responsible for the clonal stem cell defect leading to unregulated fibrosis and extramedullary hematopoiesis characteristic of idiopathic myelofibrosis . 3 o ,3 t Classification This review is primarily about idiopathic myelofibrosis . Myelofibrosis of secondary causes is discussed for clarification or differential diagnosis . Experimentally-produced myelofibrosis in animals is not included . A classification of myelofibrosis is shown . (Table 1) Clinical Features
Idiopathic myelofibrosis is primarily a disease of individuals beyond the age of 50 years, and of about equal sex distribution . It has been described in children and rarely can be familial .32 .33 Often the illness is insidious in onset and diagnosed only following an investigation of splenomegaly accidentally discovered . The incidence of idiopathic myelofibrosis is uncom-
REVIEWS
99
Table 1 Classification of myelofibrosis Primary Idiopathic myelofibrosis (agnogenic myeloid metaplasia) Secondary Other myeloproliferative disorders Chronic myelogenous leukemia Infiltrative disorders Metastatic carcinoma Malignant lymphomas Marrow toxins Benzene Ionizing radiation Immunological Systemic lupus erythematosis Infectious Tuberculosis Acute Myelofibrosis Acute megakaroblastic leukemia Experimental myelofibrosis
mon, usually stated as only 1/3 as frequent as chronic myelogenous leukemia . The cardinal physical finding is splenomegaly, which develops in all patients . The size of the spleen is massive in about 10% of patients and can be among the largest spleen found in any disorder, including kala-azar, Gaucher's disease, and tropical splenomegaly . The vascular consequences of the `big spleen' syndrome with its large mass of myeloid metaplasia gives rise to the very serious complications of bleeding gastric and esophageal varices and ascites . Ascites can also result from peritoneal myeloid metaplasia . 34 Other physical findings seen in idiopathic myelofibrosis include hepatomegaly in about 2/3 of patients, lower extremity bone tenderness and a dermatitis consisting of raised, tender plaques which resemble Sweet's syndrome ." As this disease progresses patients almost always show evidence of weight loss . Skin and mucous membrane purpura reflect the abnormal coagulation status and frequently peripheral edema occurs . Cutaneous papulonodules due to skin extramedullary hematopoiesis are quite distinctive and initially may be confused with nodules of malignant lymphoma . 36 The Budd-Chiari syndrome has been described in idiopathic myelofibrosis but is seen less frequently than in polycythemia vera . 37 Laboratory Findings
Bony changes are characteristically seen in patients with myelofibrosis . Radiologically apparent sclerosis occurs in at least 1/2 of these patients . Bones most frequently involved include the proximal portion of the long bones and the axial skeleton . Osteolytic lesions occur rarely ." When routine radiologic studies show dense bones and splenomegaly the most likely diagnosis is myelofibrosis . 39 Hematologic abnormalities are almost always found in myelofibrosis . The most distinctive finding is anemia, which is invariably present except in very early cases . The distinctive abnormalities in the blood film are teardrop poikilocytes and nucleated red cells
100
IDIOPATHIC MYELOFIBROSIS: HISTORICAL REVIEW, DIAGNOSIS AND MANAGEMENT
(Fig . 1) . Anemia worsens as the disease progresses . Initially the primary cause of anemia is ineffective erythropoiesis . Later in the course of the disease the causes of the anemia become complex 40 and include splenic trapping with hemolysis, hemodilution secondary to plasma volume expansion, bleeding related to varices or ulcer disease, folate deficiency and rarely autoimmune hemolytic anemia and acquired hemoglobin H disease ." -" The reticulocyte count is often elevated in anemic patients with myelofibrosis, reflecting ineffective erythropoiesis or hemolysis, or both . The elevation varies but it is usually modest . Moderate elevation of the neutrophil count is often seen in the early stage of idiopathic myelofibrosis . Neutropenia occurs in 15-25% of patients . Hyposegmentation (acquired Pelger-Huet anomaly) is commonly found . Small numbers of basophils and immature white cells, including 1-5% blast cells can commonly be found in the blood film at the time of diagnosis . In the later stages of this disease a fullblown leukoerythroblastosis picture is frequently present. Terminally, leukopenia is common and increasing number of blast cells may superficially be confused with conversion to acute leukemia . However, in most of these cases the marrow picture remains that of fibrosis . The leukocyte alkaline phosphatase scores are usually high, but low scores have been described in 25% of patients with idiopathic myelofibrosis . 45 When transition to acute myelogenous leukemia occurs (5-10%), the change may be very rapid with massive increase in peripheral blood immaturity . Increased platelet counts are found in about 50% of patients with myelofibrosis when these patients are seen early in the course of the disease . Abnormal appearing platelets are frequently observed, particularly giant platelets . With increasing splenomegaly, thrombocytopenia often ensues and often causes hemorrhagic problems . Qualitative platelet defects add to the troublesome nature of this problem . Latent DIC may cause great hemorrhagic difficulty, particularly at the time of splenectomy . 25 Bone marrow aspiration almost always results in
a `dry tap' ; however, the marrow biopsy always reveals fibrosis and often osteosclerosis . The amount of marrow fibrosis correlates directly with the degree of osteosclerosis . 2 The fibrosis in the marrow may be extensive at the time of diagnosis, or it may be spotty, associated with areas of hypercellularity . Megakaryocytic hyperplasia is characteristic of the marrow in idiopathic myelofibrosis . (Fig . 2) Increased numbers of plasma cells are not usually found in the marrow of idiopathic myelofibrosis, but an increase of serum `M' components has been commented on . 2 A recent review confirms a remarkably high incidence of monclonal gammopathies in idiopathic myelofibrosis . Overt plasma cell dyscrasias have been reported ." Splenic sampling by needle aspiration and/or biopsy is no longer attempted because of the high risk of hemorrhage . The pathology of surgically removed spleens show the distinctive features of extramedullary hematopoiesis . This occurs only in the red pulp . Trilineage myeloid tissue is always found, although one lineage usually predominates . These pathological findings are clearly different from the total replacement of normal splenic architecture as seen in chronic myelogenous leukemia . The degree of splenic hematopoiesis does not correlate with the degree of marrow fibrosis, consistent with the prevailing opinion that splenic hematopoiesis is a separate and autonomous process from marrow fibrosis ."
Fig . 1 Blood film showing characteristic teardrop erythrocytes in a patient with myelofibrosis . Wright Giemsa stain . 500 x magnification .
Fig . 2 Marrow biopsy from a patient with myelofribrosis, showing megakaryocytic hyperplasia with atypical and dwarf forms. H & E stain . 100 x magnification .
Differential Diagnosis
It is usually not difficult to distinguish idiopathic myelofibrosis from other myeloproliferative disorders . Occasionally there may be a problem distinguishing idiopathic myelofibrosis from chronic myelogenous leukemia when the latter is associated with marrow fibrosis. But even in this situation the findings of normal red cell morphology, a low leukocyte alkaline phosphatase score and the detection of the Philadelphia chromosome will almost always pinpoint the correct diagnosis of chronic myelogenous leukemia . Post-polycythemic myelofibrosis can pre-
BLOOD REVIEWS
sent difficulty in the differential diagnosis if the preexisting polycythemia vera is not known to the physician . Rarely, confusion can occur in the early diagnostic stage of essential thrombocythemia . A summary of the clinical and laboratory comparisons of these different myeloproliferative disorders is presented . (Table 2) Rarely, a myelodysplastic disorder may present with striking myelofibrosis and increased marrow megakaryocytes . In this unusual situation, the features of myelodysplasia such as pancytopenia, absence of impressive splenomegaly and additional marrow findings of dyshematopoiesis usually permit a distinction from idiopathic myelofibrosis ." 'Acute myelofibrosis' or `malignant myelosclerosis' is really a variant of acute leukemia, now called acute megakaryoblastic leukemia and should offer no confusion with the entirely different clinical and pathological findings seen in idiopathic myelofibrosis .t"9 Management The natural history of idiopathic myelofibrosis is quite variable . Many patients are diagnosed in an asymptomatic state and are clinically fine for years without any intervention . In this author's observations, patients with idiopathic myelofibrosis tend to fair better than those patients with post-polycythemic myelofibrosis. Anemia When intervention becomes necessary it most often is for the treatment of anemia . Symptoms are often overt when the hemoglobin level falls below 8 gm/dl . Treatment of symptomatic anemia depends on the major cause . When it is due primarily to folate or pyridoxine or iron deficiency, improvement of the anemia is usually gratifying following the administration of the appropriate drug . When there is evidence of overt hemolysis, prednisone may be quite helpful . In the normocytic and normochromic anemia Table 2
101
not due to the above stated causes, a therapeutic trial with androgen therapy should be instituted . About 30-40% of these anemic patients will respond to this hormonal treatment . The mechanism of action is uncertain but perhaps it is related to stimulation of endogenous erythropoietin . Effective androgen drugs include Danazol, 200 mg three times daily, orally, or testosterone enanthate, 400 mg intramuscularly, weekly . Recently biosynthetic (recombinant) erythropoietin has become available for the treatment of anemic and azotemic patients on dialysis . Its therapeutic effect has been amazing . This happy result has not been the experience with the use of erythropoietin in anemias of other causes . There are no peer-reviewed published reports of the usefulness of erythropoietin in idiopathic myelofibrosis per se . This author is aware of anecdotal information which indicate no dramatic improvement in the anemia of myelofibrosis and related myeloproliferative syndromes with the usual dose employed for azotemic patients . Further studies utilizing very large doses of the hormone are forthcoming . As the clinical status of patients with myelofibrosis deteriorates, the anemia worsens and transfusional dependency ensues . In this author's experience a significant proportion of these patients maintain a reasonably good quality of life for 1-2 years with only the judicious use of red cell transfusions . In the author's opinion it is useful if family members or friends can serve as directed donors . Splenectomy, when indicated as discussed below, is the most definitive way of ameliorating the severe anemia of idiopathic myelofibrosis . Chemotherapy
Hydroxyurea and busulfan are helpful in the management of symptomatic patients with idiopathic myelofibrosis . Leukocytosis is reduced with the use of these drugs accompanied by a gratifying reduction of the constitutional symptoms of weight loss and sweating.
Differential characteristics of the chronic myeloproliferative syndromes
Observation
CML
Idiopathic myelofibrosis
Polycythemia vera
Essential thrombocythemia
Hemoglobin level White count /gl Differential white count
Usually J Usually >50,000 Myelocytes and younger stages on presentation
I Usually
I . M . Weinstein S UMMA R Y. Idiopathic myelofibrosis is reviewed from several aspects . The historical development of knowledge about this disorder is discussed, from early descriptions of extramedullary hematopoiesis associated with numerous etiologies, a debate over pathogenetic mechanisms, followed by newer evidence which placed this disorder with the myeloproliferative disorders . Evidence is presented showing that idiopathic myelofibrosis is an acquired clonal disorder in terms of the hematopoietic abnormalities, but that the marrow fibrosis is a result of non-clonal disordered fibrogenesis . The clinical, laboratory and pathologic features of idiopathic myelofibrosis are discussed . The features which distinguish this disorder from the other myeloproliferative disorders, particularly chronic myelogenous leukemia are emphasized . The natural history is described together with an evaluation of accepted and experimental therapy .
Idiopathic myelofibrosis is defined as a chronic myeloproliferative disorder, characterized by marrow fibrosis, splenomegaly, peripheral blood leukoerythroblastosis and red cell poikilocytes (teardrops) . This disorder has been described under at least 37 different names, primarily that aspect of the syndrome that most impressed the authors ." The most commonly used alternative name for this disorder is agnogenic myeloid metaplasia . 3 In this review only the term idiopathic myelofibrosis will be used . Historical Review In 1879, 13 years before Vaquez described polycythemia vera,a Heuck described `two cases of leukemia with peculiar blood and bone marrow findings' .' This is the first acceptable report of this disorder . Heuck noted osteofibrosis of the bone marrow and extramed1 . M. Weinstein, MD, Clinical Professor of Medicine, Department of Medicine, Division of Hematology-Oncology, UCLA School of Medicine ; Attending Physician and Member, Board of Governors, Cedars-Sinai Medical Center, Los Angeles, California 90024-1678, USA . Correspondence to : 1 . M . Weinstein, MD, 8635 W . Third Street, Suite 1165, Los Angeles, California 90048, USA . Blood Rervwr (1991) 5, 9s-Ie4 !© 1991 W nginan Group UK Ltd
ullary hematopoiesis of the liver and spleen . Beginning with the turn of the 20th century other authors published case reports of patients with splenomegaly, osteosclerosis and 'leukemic' blood pictures .' , ' From 1905-1930 most published reports on this subject depicted patients with massive splenomegaly, myeloid metaplasia and osteosclerosis, often in association with tuberculosis and cancer .' , ' There was confusion in these early attempts to distinguish secondary myeloid metaplasia from the idiopathic variety ; a dilemma that still exists today . It was generally held that the development of extramedullary hematopoiesis in the liver and spleen was compensatory to bone marrow fibrosis . In the 1930's and 1940's more careful studies were reported, attempting to codify this ill-defined clinical pathological syndrome into a single entity . Several authors emphasized the co-existence of myeloid metaplasia and infection or metastatic cancer . Others emphasized a similarity of the extramedullary blood formation to the normal embryological 9-, t In 1950, Block and Jacobsen published an state . important paper arguing that idiopathic myeloid metaplasia was an entity of unknown origin, closely related to polycythemia vera but fundamentally
BLOOD different from chronic myelogenous leukemia ." In 1951, Damashek introduced the concept of the 'myeloproliferative syndrome', speculating that chronic myelogenous leukemia, polycythemia vera and agnogenic myeloid metaplasia were all closely related neoplastic marrow disorders with a common propensity to transform into acute leukemia ." In the ensuing decade, this concept became widely accepted Despite the elegant publication by Ward and Block' on the natural history of agnogenic myeloid metaplasia in which they presented clinical, pathological and embryological data refuting the neoplastic nature of the disorder, by 1970 most authorities agreed that idiopathic myelofibrosis was a neoplastic disorder . In 1975, studies on patients who had idiopathic myelofibrosis and G6PD heterozygosity were shown to have only one type of G6PD in their red cells, white cells and platelets ." In the same year, Silverstein's timely monograph presented all the known pertinent historical, clinical and laboratory features of this disorder up to that time . The report clearly established that idiopathic myelofibrosis was a chronic myeloproliferative syndrome ." Etiology and Pathogenesis In the past decade, investigators have confirmed the clonal nature of this disorder in the hematopoietic cells, but the fibroblastic proliferation in the marrow appears to be a secondary phenomenon .26,2 . The type of collagen primarily involved in myelofibrosis (Type 111) has been reported ." Of great significance is the evidence that the increased collagen content of the marrow in idiopathic myelofibrosis is the result of release of growth factors, primarily derived from platelets and megakaryocytes . 29 Recent studies have revealed that c-sis encodes one chain of human PDGF, suggesting that this oncogene may be responsible for the clonal stem cell defect leading to unregulated fibrosis and extramedullary hematopoiesis characteristic of idiopathic myelofibrosis . 3 o ,3 t Classification This review is primarily about idiopathic myelofibrosis . Myelofibrosis of secondary causes is discussed for clarification or differential diagnosis . Experimentally-produced myelofibrosis in animals is not included . A classification of myelofibrosis is shown . (Table 1) Clinical Features
Idiopathic myelofibrosis is primarily a disease of individuals beyond the age of 50 years, and of about equal sex distribution . It has been described in children and rarely can be familial .32 .33 Often the illness is insidious in onset and diagnosed only following an investigation of splenomegaly accidentally discovered . The incidence of idiopathic myelofibrosis is uncom-
REVIEWS
99
Table 1 Classification of myelofibrosis Primary Idiopathic myelofibrosis (agnogenic myeloid metaplasia) Secondary Other myeloproliferative disorders Chronic myelogenous leukemia Infiltrative disorders Metastatic carcinoma Malignant lymphomas Marrow toxins Benzene Ionizing radiation Immunological Systemic lupus erythematosis Infectious Tuberculosis Acute Myelofibrosis Acute megakaroblastic leukemia Experimental myelofibrosis
mon, usually stated as only 1/3 as frequent as chronic myelogenous leukemia . The cardinal physical finding is splenomegaly, which develops in all patients . The size of the spleen is massive in about 10% of patients and can be among the largest spleen found in any disorder, including kala-azar, Gaucher's disease, and tropical splenomegaly . The vascular consequences of the `big spleen' syndrome with its large mass of myeloid metaplasia gives rise to the very serious complications of bleeding gastric and esophageal varices and ascites . Ascites can also result from peritoneal myeloid metaplasia . 34 Other physical findings seen in idiopathic myelofibrosis include hepatomegaly in about 2/3 of patients, lower extremity bone tenderness and a dermatitis consisting of raised, tender plaques which resemble Sweet's syndrome ." As this disease progresses patients almost always show evidence of weight loss . Skin and mucous membrane purpura reflect the abnormal coagulation status and frequently peripheral edema occurs . Cutaneous papulonodules due to skin extramedullary hematopoiesis are quite distinctive and initially may be confused with nodules of malignant lymphoma . 36 The Budd-Chiari syndrome has been described in idiopathic myelofibrosis but is seen less frequently than in polycythemia vera . 37 Laboratory Findings
Bony changes are characteristically seen in patients with myelofibrosis . Radiologically apparent sclerosis occurs in at least 1/2 of these patients . Bones most frequently involved include the proximal portion of the long bones and the axial skeleton . Osteolytic lesions occur rarely ." When routine radiologic studies show dense bones and splenomegaly the most likely diagnosis is myelofibrosis . 39 Hematologic abnormalities are almost always found in myelofibrosis . The most distinctive finding is anemia, which is invariably present except in very early cases . The distinctive abnormalities in the blood film are teardrop poikilocytes and nucleated red cells
100
IDIOPATHIC MYELOFIBROSIS: HISTORICAL REVIEW, DIAGNOSIS AND MANAGEMENT
(Fig . 1) . Anemia worsens as the disease progresses . Initially the primary cause of anemia is ineffective erythropoiesis . Later in the course of the disease the causes of the anemia become complex 40 and include splenic trapping with hemolysis, hemodilution secondary to plasma volume expansion, bleeding related to varices or ulcer disease, folate deficiency and rarely autoimmune hemolytic anemia and acquired hemoglobin H disease ." -" The reticulocyte count is often elevated in anemic patients with myelofibrosis, reflecting ineffective erythropoiesis or hemolysis, or both . The elevation varies but it is usually modest . Moderate elevation of the neutrophil count is often seen in the early stage of idiopathic myelofibrosis . Neutropenia occurs in 15-25% of patients . Hyposegmentation (acquired Pelger-Huet anomaly) is commonly found . Small numbers of basophils and immature white cells, including 1-5% blast cells can commonly be found in the blood film at the time of diagnosis . In the later stages of this disease a fullblown leukoerythroblastosis picture is frequently present. Terminally, leukopenia is common and increasing number of blast cells may superficially be confused with conversion to acute leukemia . However, in most of these cases the marrow picture remains that of fibrosis . The leukocyte alkaline phosphatase scores are usually high, but low scores have been described in 25% of patients with idiopathic myelofibrosis . 45 When transition to acute myelogenous leukemia occurs (5-10%), the change may be very rapid with massive increase in peripheral blood immaturity . Increased platelet counts are found in about 50% of patients with myelofibrosis when these patients are seen early in the course of the disease . Abnormal appearing platelets are frequently observed, particularly giant platelets . With increasing splenomegaly, thrombocytopenia often ensues and often causes hemorrhagic problems . Qualitative platelet defects add to the troublesome nature of this problem . Latent DIC may cause great hemorrhagic difficulty, particularly at the time of splenectomy . 25 Bone marrow aspiration almost always results in
a `dry tap' ; however, the marrow biopsy always reveals fibrosis and often osteosclerosis . The amount of marrow fibrosis correlates directly with the degree of osteosclerosis . 2 The fibrosis in the marrow may be extensive at the time of diagnosis, or it may be spotty, associated with areas of hypercellularity . Megakaryocytic hyperplasia is characteristic of the marrow in idiopathic myelofibrosis . (Fig . 2) Increased numbers of plasma cells are not usually found in the marrow of idiopathic myelofibrosis, but an increase of serum `M' components has been commented on . 2 A recent review confirms a remarkably high incidence of monclonal gammopathies in idiopathic myelofibrosis . Overt plasma cell dyscrasias have been reported ." Splenic sampling by needle aspiration and/or biopsy is no longer attempted because of the high risk of hemorrhage . The pathology of surgically removed spleens show the distinctive features of extramedullary hematopoiesis . This occurs only in the red pulp . Trilineage myeloid tissue is always found, although one lineage usually predominates . These pathological findings are clearly different from the total replacement of normal splenic architecture as seen in chronic myelogenous leukemia . The degree of splenic hematopoiesis does not correlate with the degree of marrow fibrosis, consistent with the prevailing opinion that splenic hematopoiesis is a separate and autonomous process from marrow fibrosis ."
Fig . 1 Blood film showing characteristic teardrop erythrocytes in a patient with myelofibrosis . Wright Giemsa stain . 500 x magnification .
Fig . 2 Marrow biopsy from a patient with myelofribrosis, showing megakaryocytic hyperplasia with atypical and dwarf forms. H & E stain . 100 x magnification .
Differential Diagnosis
It is usually not difficult to distinguish idiopathic myelofibrosis from other myeloproliferative disorders . Occasionally there may be a problem distinguishing idiopathic myelofibrosis from chronic myelogenous leukemia when the latter is associated with marrow fibrosis. But even in this situation the findings of normal red cell morphology, a low leukocyte alkaline phosphatase score and the detection of the Philadelphia chromosome will almost always pinpoint the correct diagnosis of chronic myelogenous leukemia . Post-polycythemic myelofibrosis can pre-
BLOOD REVIEWS
sent difficulty in the differential diagnosis if the preexisting polycythemia vera is not known to the physician . Rarely, confusion can occur in the early diagnostic stage of essential thrombocythemia . A summary of the clinical and laboratory comparisons of these different myeloproliferative disorders is presented . (Table 2) Rarely, a myelodysplastic disorder may present with striking myelofibrosis and increased marrow megakaryocytes . In this unusual situation, the features of myelodysplasia such as pancytopenia, absence of impressive splenomegaly and additional marrow findings of dyshematopoiesis usually permit a distinction from idiopathic myelofibrosis ." 'Acute myelofibrosis' or `malignant myelosclerosis' is really a variant of acute leukemia, now called acute megakaryoblastic leukemia and should offer no confusion with the entirely different clinical and pathological findings seen in idiopathic myelofibrosis .t"9 Management The natural history of idiopathic myelofibrosis is quite variable . Many patients are diagnosed in an asymptomatic state and are clinically fine for years without any intervention . In this author's observations, patients with idiopathic myelofibrosis tend to fair better than those patients with post-polycythemic myelofibrosis. Anemia When intervention becomes necessary it most often is for the treatment of anemia . Symptoms are often overt when the hemoglobin level falls below 8 gm/dl . Treatment of symptomatic anemia depends on the major cause . When it is due primarily to folate or pyridoxine or iron deficiency, improvement of the anemia is usually gratifying following the administration of the appropriate drug . When there is evidence of overt hemolysis, prednisone may be quite helpful . In the normocytic and normochromic anemia Table 2
101
not due to the above stated causes, a therapeutic trial with androgen therapy should be instituted . About 30-40% of these anemic patients will respond to this hormonal treatment . The mechanism of action is uncertain but perhaps it is related to stimulation of endogenous erythropoietin . Effective androgen drugs include Danazol, 200 mg three times daily, orally, or testosterone enanthate, 400 mg intramuscularly, weekly . Recently biosynthetic (recombinant) erythropoietin has become available for the treatment of anemic and azotemic patients on dialysis . Its therapeutic effect has been amazing . This happy result has not been the experience with the use of erythropoietin in anemias of other causes . There are no peer-reviewed published reports of the usefulness of erythropoietin in idiopathic myelofibrosis per se . This author is aware of anecdotal information which indicate no dramatic improvement in the anemia of myelofibrosis and related myeloproliferative syndromes with the usual dose employed for azotemic patients . Further studies utilizing very large doses of the hormone are forthcoming . As the clinical status of patients with myelofibrosis deteriorates, the anemia worsens and transfusional dependency ensues . In this author's experience a significant proportion of these patients maintain a reasonably good quality of life for 1-2 years with only the judicious use of red cell transfusions . In the author's opinion it is useful if family members or friends can serve as directed donors . Splenectomy, when indicated as discussed below, is the most definitive way of ameliorating the severe anemia of idiopathic myelofibrosis . Chemotherapy
Hydroxyurea and busulfan are helpful in the management of symptomatic patients with idiopathic myelofibrosis . Leukocytosis is reduced with the use of these drugs accompanied by a gratifying reduction of the constitutional symptoms of weight loss and sweating.
Differential characteristics of the chronic myeloproliferative syndromes
Observation
CML
Idiopathic myelofibrosis
Polycythemia vera
Essential thrombocythemia
Hemoglobin level White count /gl Differential white count
Usually J Usually >50,000 Myelocytes and younger stages on presentation
I Usually
