Leukemia Research Vol. 16, No. 1, pp. 51-54, 1992.
0145-2126/9:2 $5.00 + .00 Pergamon Press plc
Printed in Great Britain.
MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKEMIAS (AML) WITH MYELOFIBROSIS MICH~LE IMBERT, DOYEN NGUYEN AND CLAUDE SULTAN Laboratory of Hematology-Immunology, Henri Mondor Hospital, 94010 Creteil Cedex, France Abstract--Acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) enter rarely in the differential diagnosis of myelofibrosis (MF). MF of marked intensity, resulting in either "dry taps" or non-representative smears, is encountered in approximately 10% of cases. MF may be observed in any type of AML, most frequently in acute megakaryoblastic leukemia (M7). Apart from some typical cases of MDS, MF is associated with cases of acute myelodysplasia with myelofibrosis (and a major megakaryocytic component). This syndrome has been described under various headings: acute or malignant myelosclerosis, and acute MF. It should be distinguished from M7 and from myeioproliferative syndromes. Key words: Myelodysplastic syndromes, acute myeloid leukemias, myelofibrosis, megakaryoblastic leukemias, acute myelofibrosis, malignant myelosclerosis.
INTRODUCTION
is reticulin fibrosis, which may be of marked intensity in approximately 15% of cases. The extent of the fibrosis can be such that bone marrow aspiration results in either "dry taps" or extremely scanty and non-representative aspirates. In such instances, the exact subclassification of the acute leukemia or myelodysplastic syndrome may not be possible. In our experience, diagnostic difficulties due to poor aspirates are encountered in approximately 10% of cases.
THE LABORATORYevaluation of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) relies on adequate bone marrow aspirates, which usually can be collected without difficulty unless coexisting myelofibrosis (MF) is present. The resulting bone marrow smears are usually normocellular or hypercellular. The main criterion for distinguishing A M L from MDS [1, 2] is the percentage of blasts in the bone marrow. Currently, MDS can be subclassilied into five categories based on the following features: the percentage of blasts, the presence of ring sideroblasts, and the presence of a monocytic component [1]. Similarly, morphological examination of bone marrow smears, in conjunction with other parameters (such as cytochemistry and immunology) leads to the classification of AML into eight subgroups. These subgroups are defined according to their lineage differentiation and degree of maturation [2-4]. According to previous reports [5-9], the incidence of myelofibrosis at the time of diagnosis in AML or MDS varies from 30 to 72%. Some authors have postulated that the fibrosis represents a reactive response [10, 11]. In nearly all instances, the process
ACUTE MYELOID LEUKEMIAS WITH MYELOFIBROSIS Peripheral pancytopenia, with a few circulating blasts, is the typical presentation in patients with AML-MF. Bone marrow aspirates are scanty to nil, with scattered naked, smudged nuclei and a few hematopoietic precursors. On bone marrow biopsies, there is severe fibrosis and extensive infiltration by immature cells. Precise subclassification of the leukemic cells can be difficult. Occasionally, the disease can be classified on the basis of morphology and cytochemical stains alone. In most instances, however, confirmation of the myeloid origin of the leukemic cells requires a large panel of monoclonal antibodies on bone marrow biopsy frozen sections. Myelofibrosis can be observed in any type of acute leukemia. It is most frequently associated with acute megakaryoblastic leukemia (M7). De-novo M7 is a rare disease, especially in adults [12-14]. Although
Abbreviations: AML, acute myeloid leukemia; MDS,
myelodysplastic syndromes; MF, myelofibrosis; M7, acute megakaryocytic leukemia; AMMF, acute myelodysplasia with myelofibrosis (and a major megakaryoeytic component). 51
52
M. IMaERTet al.
the diagnosis may be suspected from the morphological appearance of the blasts, it must be confirmed by either of the following: (1) the demonstration of platelet peroxidase by ultracytochemistry [15]; or, (2) the presence of glycoprotein III (CD 61), glycoprotein IIb/IIa (CD 41) or glycoprotein Ib (CD 42) [16]. The prognosis of M7 is poor. Complete remissions are uncommon and, if achieved, are usually of short duration. MYELODYSPLASTIC SYNDROMES WITH MYELOFIBROSIS Myelofibrosis occurs rarely in MDS, both in the primary (idiopathic) type and in secondary MDS. It is probably more frequent in secondary MDS. Of great interest is a poorly understood syndrome which at this point in time is best described as "acute myelodysplasia with myelofibrosis (and a major megakaryocytic component)" (AMMF). The affected patients are usually older than 50 years of age, and present with signs and symptoms of acute onset bone marrow insufficiency, such as fatigue, infections and bleeding. There is no associated organomegaly. The peripheral blood demonstrates neutropenia, thrombocytopenia, and a normochromic, normocytic anemia with reticulocytopenia. There is usually mild anisopoikilocytosis with a few schizocytes and/or tear-drop cells. Occasional circulating blasts can be detected, along with a few intermediate myeloid precursors and some nucleated red cells. The bone marrow aspirates, when adequate, demonstrate dysplastic features in all cell lines, such as micromegakaryocytes, pseudo Pelger-Hiiet anomaly, hypogranulation, abnormal erythroid precursors, and occasionally ring sideroblasts. Definitive diagnosis relies mainly on the bone marrow biopsy, in which the following features are observed: (a) Intense myelofibrosis, occasionally destructive. In a few cases, this may be accompanied by focal deposits of coarse collagen fibers (evidence of progression towards myelosclerosis) and/or focal increased osteoblastic activity along bony trabeculae. (b) Megakaryocytic hyperplasia, with abundant abnormal megakaryocytes. (c) A moderate excess of blasts, however without forming sheets or large clusters. The percentage of blasts estimated from the biopsies is usually in the range of 10-20%. (d) The presence of residual maturing erythroid and myeloid precursors. There is a spectrum of morphologic appearances, depending on the intensity of the fibrosis, the relative number of maturing myeloid precursors, and the
relative preponderance of megakaryocytes. Two distinct morphologic variants are common, however, and will be described in more detail. The more frequent presentation is characterized by a "nondestructive" myelofibrosis, and a hyperceUular marrow in which dwarf megakaryocytes with scant cytoplasm, hypolobated nuclei and coarsely stippled chromatin predominate. The nuclei of some megakaryocytes may be fragmented. The dysplastic features present in the erythroid and myeloid series are similar to those observed in other idiopathic MDS such as refractory anemia with excess blasts. Blasts are moderately increased (in the range of 10-20%) and display a polymorphic appearance. In some cases, the morphology is suggestive of a myeloid origin. As discussed above, confirmation by additional cytochemical stains and immunophenotyping studies is often difficult, since few blasts are present in the marrow aspirates and peripheral blood. This entity was previously described by our group [17] as "acute myelodysplasia with myelofibrosis". Very similar, if not identical cases, have been reported under various names such as acute myelofibrosis [18, 19] and acute myelosclerosis [20]. Similar cases have also been described under the term "acute megakaryoblastic leukemia" [21]. It may be important to separate this entity from AML of subtype M7 ("acute megakaryoblastic leukemia"), however. The criteria for the diagnosis of M7 have been previously published [3]. We believe that the diagnosis of M7 should be reserved for leukemias composed of a homogeneous megakaryoblastic population, which can be identified by appropriate immunological and/or ultrastructural studies. In contrast, the cellular proliferation in AMMF is not of purely megakaryocytic lineage but involves all three cell lines (i.e. a "panmyelosis") with a preponderance of more mature elements. The polymorphic appearance of the blasts further suggests that they are of more than one lineage. The second variant is rare and represents one extreme of the morphological spectrum of AMMF. It is characterized by a destructive myelofibrosis, with focal deposition of coarse collagen fibers. Scattered within the fibrotic stroma are abundant dystrophic megakaryocytes, with scant, poorly defined cytoplasm, and elongated hyperchromatic nuclei. Some of the megakaryocytes are located within dilated sinuses. Erythroid and myeloid precursors are decreased. Occasional small clusters of blasts can be identified. Bone marrow aspiration results in "dry taps", precluding adequate assessment of the dysplastic process and the nature of the blasts. This type of presentation has been often referred to as "malignant myelosclerosis" [22].
Myelodysplasticsyndromesand acute myeioidleukemiaswith myelofibrosis Irrespective of the bone marrow morphology, the clinical course is grim and often evolves into acute leukemia [17]. The leukemic cell population can be of myeloid origin [23], "mixed" (with myeloid, erythroid and/or megakaryoblastic components), or "undifferentiated" [17, 24]. In rare cases, the leukemic infiltration may be found in the spleen [18, 21]. No satisfactory remission rate has been attained, despite various chemotherapy protocols [17, 19]. The survival is less than a year. Bone marrow transplantation, a possible therapeutic alternative, has rarely been applied to this group of patients in view of their advanced age. The overall incidence of A M M F is low (approximately 2-3% from our files of A M L and MDS). There has been great confusion as to where to best classify this entity. Some authors have previously interpreted it as the acute form of myeloproliferative syndromes [22], while others have considered it to be an acute leukemia (particularly M7) [21]. We feel that A M M F is best classified as an MDS, with which it shares the two cardinal features of peripheral pancytopenia and a hypercellular dysplastic marrow. It also appears that A M M F and "malignant myelosclerosis" are not separate disorders, but represent two morphologic manifestations of the same clinicopathological entity. In fact, the two types of histology may coexist and merge into each other on a single bone marrow biopsy specimen. A M M F is a diagnosis to be considered in the differential of any case presenting with pancytopenia and myelofibrosis. We have shown, in a previous study [25], that about 20% of such cases have A M M F as the underlying pathology.
REFERENCES 1. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1982) French-American-British (FAB) cooperative group. Proposals for the classification of myelodysplastic syndromes. Br. J. Haemat. 51, 189. 2. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the FrenchAmerican-British cooperative group. Ann. Int. Med. 103, 620. 3. Bennett J.M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1985) Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the FrenchAmerican-British cooperative group. Ann. Int. Med. 103, 460. 4. Bennett J. M., Catovsky, D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1991) French-American-British (FAB) cooperative group. Proposal for the recognition of minimally differ-
53
entiated acute myeloid leukaemia (AML-MO). Br. J. Haemat. 78, 325.
5. Kundel D. W., Brecher G., Bodey G. P. & Brittin G. M. (1964) Reticulin fibrosis and bone marrow infarction in acute leukemia. Implications for prognosis. Blood 23, 526. 6. Manoharan A., Horsley R. & Pitney W. R. (1979) The reticulin control of bone marrow in acute leukaemia in adults. Br. J. Haemat. 43, 185. 7. Islam A., Catovsky D., Goldman J. M. & Galton D. A. G. (1984) Bone marrow fibre content in acute myeloid leukaemia before and after treatment. J. clin. Pathol. 37, 1259. 8. Tricot G., De Wolf-Peeters C., Hendrickx B. & Verwilghen R. L. (1984) Bone marrow histology in myeiodysplastic syndromes. I. Histological findings in myelodysplastic syndromes and comparison with bone marrow smears. Br. J. Haemat. 57, 423. 9. Delacretaz F., Schmidt P. M., Piguet D., Bachmann F. & Costa J. (1987) Histopathoiogy of myelodysplastic syndromes. The FAB classification (Proposals) applied to bone marrow biopsy. A m . J. clin. Pathol. 87, 180. 10. Clare N., Elson D. & Manhoff L. (1982) Cytogenetic studies of peripheral myeloblasts and bone marrow fibroblasts in acute myelofibrosis. A m . J. clin. Pathol. 77, 762. 11. Van Slyck E. J., Weiss L. & Dully M. (1970) Chromosomal evidence for the secondary role of fibroblastic proliferation in acute myelofibrosis. Blood 36, 729. 12. Cairney A. E., McKenna R., Arthur D. C., Nesbit M. E. Jr & Woods N. G. (1986) Acute megakaryoblastic leukaemia in children. Br. J. Haemat. 63, 541. 13. Noel P. & Li C. Y. (1990) M7 acute leukemia in the adult: a 10 year experience at Mayo Clinic. Blood 76, 304a. 14. Schaison G., Daniel M. T., Berger R. & Baruchel A. (1990) De novo acute megakaryoblastic leukemia (AMKL) in children. Blood 76, 316a. 15. Breton-Gorius J. & Guichard J. (1976) Amrlioration des techniques permettant de rrvrler la peroxydase plaquettaire. Nouv. Rev. Fr. Hemat. 16, 381. 16. San Miguel J. F., Gonzalez M., Canizo M. C., Ojeda E., Orfao A., Caballero M. D., Moro M. J., Fisac P. & Lopez Borrasca A. (1988) Leukemias with megakaryoblastic involvement: clinical, hematologic, and immunological characteristics. Blood 72, 402. 17. Sultan C., Sigaux F., Imbert M. & Reyes F. (1981) Acute myelodysplasia with myelofibrosis: a report of eight cases. Br. J. Haemat. 49, 11. 18. Fabich D. R. & Raich P. C. (1977) Acute myelofibrosis. A report of three cases. A m . J. clin. Pathol. 67, 334. 19. Hruban R. H., Kuhadja F. P. & Mann R. B. (1987) Acute myelofibrosis. Immunohistochemical study of four cases and comparison with acute megakaryocytic leukemia. Am. J. clin. Pathol. 88, 578. 20. Bearman R. M., Pangalis G. A. & Rappaport H. (1979) Acute ("malignant") myelosclerosis. Cancer 43, 279. 21. Den Ottolander G. J., Te Velde J., Brederoo P., Geraedts J. P. M., Slee H. T., Willemzee R., Zwann F. E., Haak H. L., Muller H. P. & Bieger R. (1979) Megakaryoblastic leukaemia (acute myelofibrosis): a report of three cases. Br. J. Haemat. 42, 9. 22. Lewis S. M. & Szur M. B. (1963) Malignant myelosclerosis. Br. Med. J. ii, 472.
54
M. IMBERTet al.
23. Weisenburger D. D. (1980) Acute myelofibrosis terminating as acute myeloblastic leukemia. Am. J. clin. Pathol. 73, 128. 24. Schreeder M. T., Prchal J. T., Parmley R. T., Carroll A. J., Gewirtz A. M. & Hoffman R. (1985) An acute myeloproliferative disorder characterized by myelofibrosis and blast cells that express phenotype proper-
ties associated with multiple hematopoietic lineages. Am. J. din. Pathol. 83, 114.
25. Imbert M., Scoazec J. Y., Mary J. Y., Jouault H., Rochant H. & Sultan C. (1989) Adult patients presenting with pancytopenia: a reappraisal of underlying pathology and diagnostic procedure in 213 cases. Hemat. Pathol. 3, 159.
0145-2126/9:2 $5.00 + .00 Pergamon Press plc
Printed in Great Britain.
MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKEMIAS (AML) WITH MYELOFIBROSIS MICH~LE IMBERT, DOYEN NGUYEN AND CLAUDE SULTAN Laboratory of Hematology-Immunology, Henri Mondor Hospital, 94010 Creteil Cedex, France Abstract--Acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) enter rarely in the differential diagnosis of myelofibrosis (MF). MF of marked intensity, resulting in either "dry taps" or non-representative smears, is encountered in approximately 10% of cases. MF may be observed in any type of AML, most frequently in acute megakaryoblastic leukemia (M7). Apart from some typical cases of MDS, MF is associated with cases of acute myelodysplasia with myelofibrosis (and a major megakaryocytic component). This syndrome has been described under various headings: acute or malignant myelosclerosis, and acute MF. It should be distinguished from M7 and from myeioproliferative syndromes. Key words: Myelodysplastic syndromes, acute myeloid leukemias, myelofibrosis, megakaryoblastic leukemias, acute myelofibrosis, malignant myelosclerosis.
INTRODUCTION
is reticulin fibrosis, which may be of marked intensity in approximately 15% of cases. The extent of the fibrosis can be such that bone marrow aspiration results in either "dry taps" or extremely scanty and non-representative aspirates. In such instances, the exact subclassification of the acute leukemia or myelodysplastic syndrome may not be possible. In our experience, diagnostic difficulties due to poor aspirates are encountered in approximately 10% of cases.
THE LABORATORYevaluation of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) relies on adequate bone marrow aspirates, which usually can be collected without difficulty unless coexisting myelofibrosis (MF) is present. The resulting bone marrow smears are usually normocellular or hypercellular. The main criterion for distinguishing A M L from MDS [1, 2] is the percentage of blasts in the bone marrow. Currently, MDS can be subclassilied into five categories based on the following features: the percentage of blasts, the presence of ring sideroblasts, and the presence of a monocytic component [1]. Similarly, morphological examination of bone marrow smears, in conjunction with other parameters (such as cytochemistry and immunology) leads to the classification of AML into eight subgroups. These subgroups are defined according to their lineage differentiation and degree of maturation [2-4]. According to previous reports [5-9], the incidence of myelofibrosis at the time of diagnosis in AML or MDS varies from 30 to 72%. Some authors have postulated that the fibrosis represents a reactive response [10, 11]. In nearly all instances, the process
ACUTE MYELOID LEUKEMIAS WITH MYELOFIBROSIS Peripheral pancytopenia, with a few circulating blasts, is the typical presentation in patients with AML-MF. Bone marrow aspirates are scanty to nil, with scattered naked, smudged nuclei and a few hematopoietic precursors. On bone marrow biopsies, there is severe fibrosis and extensive infiltration by immature cells. Precise subclassification of the leukemic cells can be difficult. Occasionally, the disease can be classified on the basis of morphology and cytochemical stains alone. In most instances, however, confirmation of the myeloid origin of the leukemic cells requires a large panel of monoclonal antibodies on bone marrow biopsy frozen sections. Myelofibrosis can be observed in any type of acute leukemia. It is most frequently associated with acute megakaryoblastic leukemia (M7). De-novo M7 is a rare disease, especially in adults [12-14]. Although
Abbreviations: AML, acute myeloid leukemia; MDS,
myelodysplastic syndromes; MF, myelofibrosis; M7, acute megakaryocytic leukemia; AMMF, acute myelodysplasia with myelofibrosis (and a major megakaryoeytic component). 51
52
M. IMaERTet al.
the diagnosis may be suspected from the morphological appearance of the blasts, it must be confirmed by either of the following: (1) the demonstration of platelet peroxidase by ultracytochemistry [15]; or, (2) the presence of glycoprotein III (CD 61), glycoprotein IIb/IIa (CD 41) or glycoprotein Ib (CD 42) [16]. The prognosis of M7 is poor. Complete remissions are uncommon and, if achieved, are usually of short duration. MYELODYSPLASTIC SYNDROMES WITH MYELOFIBROSIS Myelofibrosis occurs rarely in MDS, both in the primary (idiopathic) type and in secondary MDS. It is probably more frequent in secondary MDS. Of great interest is a poorly understood syndrome which at this point in time is best described as "acute myelodysplasia with myelofibrosis (and a major megakaryocytic component)" (AMMF). The affected patients are usually older than 50 years of age, and present with signs and symptoms of acute onset bone marrow insufficiency, such as fatigue, infections and bleeding. There is no associated organomegaly. The peripheral blood demonstrates neutropenia, thrombocytopenia, and a normochromic, normocytic anemia with reticulocytopenia. There is usually mild anisopoikilocytosis with a few schizocytes and/or tear-drop cells. Occasional circulating blasts can be detected, along with a few intermediate myeloid precursors and some nucleated red cells. The bone marrow aspirates, when adequate, demonstrate dysplastic features in all cell lines, such as micromegakaryocytes, pseudo Pelger-Hiiet anomaly, hypogranulation, abnormal erythroid precursors, and occasionally ring sideroblasts. Definitive diagnosis relies mainly on the bone marrow biopsy, in which the following features are observed: (a) Intense myelofibrosis, occasionally destructive. In a few cases, this may be accompanied by focal deposits of coarse collagen fibers (evidence of progression towards myelosclerosis) and/or focal increased osteoblastic activity along bony trabeculae. (b) Megakaryocytic hyperplasia, with abundant abnormal megakaryocytes. (c) A moderate excess of blasts, however without forming sheets or large clusters. The percentage of blasts estimated from the biopsies is usually in the range of 10-20%. (d) The presence of residual maturing erythroid and myeloid precursors. There is a spectrum of morphologic appearances, depending on the intensity of the fibrosis, the relative number of maturing myeloid precursors, and the
relative preponderance of megakaryocytes. Two distinct morphologic variants are common, however, and will be described in more detail. The more frequent presentation is characterized by a "nondestructive" myelofibrosis, and a hyperceUular marrow in which dwarf megakaryocytes with scant cytoplasm, hypolobated nuclei and coarsely stippled chromatin predominate. The nuclei of some megakaryocytes may be fragmented. The dysplastic features present in the erythroid and myeloid series are similar to those observed in other idiopathic MDS such as refractory anemia with excess blasts. Blasts are moderately increased (in the range of 10-20%) and display a polymorphic appearance. In some cases, the morphology is suggestive of a myeloid origin. As discussed above, confirmation by additional cytochemical stains and immunophenotyping studies is often difficult, since few blasts are present in the marrow aspirates and peripheral blood. This entity was previously described by our group [17] as "acute myelodysplasia with myelofibrosis". Very similar, if not identical cases, have been reported under various names such as acute myelofibrosis [18, 19] and acute myelosclerosis [20]. Similar cases have also been described under the term "acute megakaryoblastic leukemia" [21]. It may be important to separate this entity from AML of subtype M7 ("acute megakaryoblastic leukemia"), however. The criteria for the diagnosis of M7 have been previously published [3]. We believe that the diagnosis of M7 should be reserved for leukemias composed of a homogeneous megakaryoblastic population, which can be identified by appropriate immunological and/or ultrastructural studies. In contrast, the cellular proliferation in AMMF is not of purely megakaryocytic lineage but involves all three cell lines (i.e. a "panmyelosis") with a preponderance of more mature elements. The polymorphic appearance of the blasts further suggests that they are of more than one lineage. The second variant is rare and represents one extreme of the morphological spectrum of AMMF. It is characterized by a destructive myelofibrosis, with focal deposition of coarse collagen fibers. Scattered within the fibrotic stroma are abundant dystrophic megakaryocytes, with scant, poorly defined cytoplasm, and elongated hyperchromatic nuclei. Some of the megakaryocytes are located within dilated sinuses. Erythroid and myeloid precursors are decreased. Occasional small clusters of blasts can be identified. Bone marrow aspiration results in "dry taps", precluding adequate assessment of the dysplastic process and the nature of the blasts. This type of presentation has been often referred to as "malignant myelosclerosis" [22].
Myelodysplasticsyndromesand acute myeioidleukemiaswith myelofibrosis Irrespective of the bone marrow morphology, the clinical course is grim and often evolves into acute leukemia [17]. The leukemic cell population can be of myeloid origin [23], "mixed" (with myeloid, erythroid and/or megakaryoblastic components), or "undifferentiated" [17, 24]. In rare cases, the leukemic infiltration may be found in the spleen [18, 21]. No satisfactory remission rate has been attained, despite various chemotherapy protocols [17, 19]. The survival is less than a year. Bone marrow transplantation, a possible therapeutic alternative, has rarely been applied to this group of patients in view of their advanced age. The overall incidence of A M M F is low (approximately 2-3% from our files of A M L and MDS). There has been great confusion as to where to best classify this entity. Some authors have previously interpreted it as the acute form of myeloproliferative syndromes [22], while others have considered it to be an acute leukemia (particularly M7) [21]. We feel that A M M F is best classified as an MDS, with which it shares the two cardinal features of peripheral pancytopenia and a hypercellular dysplastic marrow. It also appears that A M M F and "malignant myelosclerosis" are not separate disorders, but represent two morphologic manifestations of the same clinicopathological entity. In fact, the two types of histology may coexist and merge into each other on a single bone marrow biopsy specimen. A M M F is a diagnosis to be considered in the differential of any case presenting with pancytopenia and myelofibrosis. We have shown, in a previous study [25], that about 20% of such cases have A M M F as the underlying pathology.
REFERENCES 1. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1982) French-American-British (FAB) cooperative group. Proposals for the classification of myelodysplastic syndromes. Br. J. Haemat. 51, 189. 2. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the FrenchAmerican-British cooperative group. Ann. Int. Med. 103, 620. 3. Bennett J.M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1985) Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the FrenchAmerican-British cooperative group. Ann. Int. Med. 103, 460. 4. Bennett J. M., Catovsky, D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1991) French-American-British (FAB) cooperative group. Proposal for the recognition of minimally differ-
53
entiated acute myeloid leukaemia (AML-MO). Br. J. Haemat. 78, 325.
5. Kundel D. W., Brecher G., Bodey G. P. & Brittin G. M. (1964) Reticulin fibrosis and bone marrow infarction in acute leukemia. Implications for prognosis. Blood 23, 526. 6. Manoharan A., Horsley R. & Pitney W. R. (1979) The reticulin control of bone marrow in acute leukaemia in adults. Br. J. Haemat. 43, 185. 7. Islam A., Catovsky D., Goldman J. M. & Galton D. A. G. (1984) Bone marrow fibre content in acute myeloid leukaemia before and after treatment. J. clin. Pathol. 37, 1259. 8. Tricot G., De Wolf-Peeters C., Hendrickx B. & Verwilghen R. L. (1984) Bone marrow histology in myeiodysplastic syndromes. I. Histological findings in myelodysplastic syndromes and comparison with bone marrow smears. Br. J. Haemat. 57, 423. 9. Delacretaz F., Schmidt P. M., Piguet D., Bachmann F. & Costa J. (1987) Histopathoiogy of myelodysplastic syndromes. The FAB classification (Proposals) applied to bone marrow biopsy. A m . J. clin. Pathol. 87, 180. 10. Clare N., Elson D. & Manhoff L. (1982) Cytogenetic studies of peripheral myeloblasts and bone marrow fibroblasts in acute myelofibrosis. A m . J. clin. Pathol. 77, 762. 11. Van Slyck E. J., Weiss L. & Dully M. (1970) Chromosomal evidence for the secondary role of fibroblastic proliferation in acute myelofibrosis. Blood 36, 729. 12. Cairney A. E., McKenna R., Arthur D. C., Nesbit M. E. Jr & Woods N. G. (1986) Acute megakaryoblastic leukaemia in children. Br. J. Haemat. 63, 541. 13. Noel P. & Li C. Y. (1990) M7 acute leukemia in the adult: a 10 year experience at Mayo Clinic. Blood 76, 304a. 14. Schaison G., Daniel M. T., Berger R. & Baruchel A. (1990) De novo acute megakaryoblastic leukemia (AMKL) in children. Blood 76, 316a. 15. Breton-Gorius J. & Guichard J. (1976) Amrlioration des techniques permettant de rrvrler la peroxydase plaquettaire. Nouv. Rev. Fr. Hemat. 16, 381. 16. San Miguel J. F., Gonzalez M., Canizo M. C., Ojeda E., Orfao A., Caballero M. D., Moro M. J., Fisac P. & Lopez Borrasca A. (1988) Leukemias with megakaryoblastic involvement: clinical, hematologic, and immunological characteristics. Blood 72, 402. 17. Sultan C., Sigaux F., Imbert M. & Reyes F. (1981) Acute myelodysplasia with myelofibrosis: a report of eight cases. Br. J. Haemat. 49, 11. 18. Fabich D. R. & Raich P. C. (1977) Acute myelofibrosis. A report of three cases. A m . J. clin. Pathol. 67, 334. 19. Hruban R. H., Kuhadja F. P. & Mann R. B. (1987) Acute myelofibrosis. Immunohistochemical study of four cases and comparison with acute megakaryocytic leukemia. Am. J. clin. Pathol. 88, 578. 20. Bearman R. M., Pangalis G. A. & Rappaport H. (1979) Acute ("malignant") myelosclerosis. Cancer 43, 279. 21. Den Ottolander G. J., Te Velde J., Brederoo P., Geraedts J. P. M., Slee H. T., Willemzee R., Zwann F. E., Haak H. L., Muller H. P. & Bieger R. (1979) Megakaryoblastic leukaemia (acute myelofibrosis): a report of three cases. Br. J. Haemat. 42, 9. 22. Lewis S. M. & Szur M. B. (1963) Malignant myelosclerosis. Br. Med. J. ii, 472.
54
M. IMBERTet al.
23. Weisenburger D. D. (1980) Acute myelofibrosis terminating as acute myeloblastic leukemia. Am. J. clin. Pathol. 73, 128. 24. Schreeder M. T., Prchal J. T., Parmley R. T., Carroll A. J., Gewirtz A. M. & Hoffman R. (1985) An acute myeloproliferative disorder characterized by myelofibrosis and blast cells that express phenotype proper-
ties associated with multiple hematopoietic lineages. Am. J. din. Pathol. 83, 114.
25. Imbert M., Scoazec J. Y., Mary J. Y., Jouault H., Rochant H. & Sultan C. (1989) Adult patients presenting with pancytopenia: a reappraisal of underlying pathology and diagnostic procedure in 213 cases. Hemat. Pathol. 3, 159.
