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M yelodysplastic Syndrome Associated with Bone Marrow Fibrosis Leuk Lymphoma Downloaded from informahealthcare.com by University of British Columbia on 12/10/14 For personal use only.

GIORGIO LAMBERTENGHI-DELILIERS, CLAUD10 ANNALORO, ALESSANDRO ORIANI AND DAVIDE SOLIGO Istituto di Scienze Mediche, University of Milan, Fondazione Matarelli, Milan, Italy (Received 6 March 1992)

Bone marrow biopsy (BMB) in myelodysplastic syndrome (MDS) frequently reveals a slight alteration in the reticulin stroma which does not have any clinical significance. However, in a minority of cases, full-blown bone marrow fibrosis (BMF) can be found. Primary MDS patients with BMF show distinct clinico-pathological features and an unfavourable prognosis mainly attributable to complications deriving from pancytopenia and continuous transfusions, while leukemic transformation occurs only rarely. Since BMF may characterize other hematological disorders, primary MDS with BMF should be included in the differential diagnosis particularly with malignant myelofibrosis (MM) and idiopathic myelofibrosis (IMF). Secondary MDS with BMF represent a variety of preleukemic conditions in subjects treated for previous neoplasias. Unlike the primary forms, they do not form a clearcut clinico-pathological entity. KEY WORDS:

myelodysplastic syndrome

bone marrow fibrosis

INTRODUCTION

alteration in the reticular stroma is observed, the FAB diagnosis is usually termed refractory anemia with excess of blasts (RAEB) or refractory anemia (RA) and it has been suggested that, in these patients, there is a slightly higher prabability of leukemic transformation3. However the majority of reports have not shown any significant correlation between fibrosis and prognosis'V6, although a number of studies do not even consider histological parameters in their statistical Only one recent study has shown a negative correlation between fibrosis and prognosis'". In a minority of MDS cases, reticular stroma change is manifested as full-blown bone marrow fibrosis (BMF), which may be present at the time of diagnosis of MDS or subsequently revealed by means of serial BMBs during follow up. On the other hand, it is well known that the presence of severe BMF, comparable with that found in myelofibrosis, may complicate the course of a number of hematologic and non-hematologic diseases' '.

In about 50% of patients with myelodysplastic syndrome (MDS), bone marrow biopsy (BMB) reveals variable but mostly a slight alteration in the reticular stroma'. According to the majority of authors, the presence of mild fibrosis does not lead to any substantial change in the clinicopathological or prognostic features of MDS. In such cases, the well established relationship between fibrosis and megakaryocytic hyperplasia with dysmegakaryocytopoiesis has been questioned by a recent morphometric and immunohistochemical study2. It has also been observed that fibrosis is accompanied by an increase in bone marrow cellularity3, while thickening of the reticular stroma, during the course of MDS, with bone marrow hypocellularity is a rare When an Address for correspondence: Professor Giorgio LambertenghiDeliliers, Istituto di Scienze Mediche, Via Francesco Sforza, 35, 20122, Milano, Italy. 51

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NOSOGRAPHIC CHARACTERIZATION OF MDS WITH BMF

heterogeneous: in addition to four typical cases of MDS with BMF, it also included three cases in which the discovery of BMF was simultaneous with the diagnosis of leukemic transformation, at least two of these patients exhibited a megakaryocytic phenotype. It is possible that, as previously discussed, these cases might have been MM transformations of MDS. The frequency of BMF is less than 10% in primary MDS and probably higher in the secondary forms. Nevertheless, although therapy-related MDS with BMF resembles the primary form in many aspects it can be differentiated on the basis of a number of important characteristics, which will be discussed later. Distribution by sex does not differ from that of other types of MDS. While there is general consensus that MDS with BMF can be accepted as a distinct variety, there are significant differences of opinion concerning the clinico-pathological features described in this entity.

Although it is likely that the majority of MDS cases with BMF have been missed in the analyses of large series, reports of single cases have been published in the literature even prior to the establishment of the FAB classification. The available data suggest that the association between MDS and BMF may be the result of different physiopathological mechanisms. This is supported by objective differences in the histological pictures, the presence of primary MDS together with MDS secondary to anti-neoplastic radio-chemotherapy, and by the fact that BMF may be observed at the onset of the disease or at variable time periods after diagnosis. One misleading factor is the difference in terminology used in the descriptions of individual cases published at different times. In 1977, Yeung” described a patient with sideroblastic anemia evolving into malignant myelofibrosis (MM). The interpretation of this and other similar cases13 can sometimes PRIMARY MDS WITH BMF be questioned, considering the fact that MM has only more recently been definitely recognized as a Pathological features nosographic entity14*’’. The evolution of MDS into MM would now be considered as the leukemic In the majority of cases, BMF is discovered at the transformation of an MDS with a predominant time of MDS diagnosis. It is less frequently observed megakaryocytic phenotype. The frequent association later in the course of the disease and, in these cases, with sideroblastic anemia is not surprising, since this fibrosis generally appears within six month^'^'^ 7*22. cytological subtype was easily diagnosed well before There are no morphological or clinical differences the proposal of the FAB classification. More rarely, between MDS with BMF at diagnosis, and those cases cases of sideroblastic anemia developing histologic in which BMF appears later on. These findings pictures similar to those of idiopathic myelofibrosis suggest that, in a considerable number of patients, a sub- or pre-clinical BMF-free myelodysplastic phase (IMF) have also been r e p ~ r t e d ’ ~ . ’ ~ . precedes the appearance of fibrosis, contradicting the ’ ~ a group of eight In 1982, Sultan et ~ 1 . collected cases of “acute myelodysplasia with fibrosis”: four of hypothesis recently proposed by Shibata and Takathat cases of MDS with BMF are preceded primary nature and four in patients previously treated with anti-neoplastic radio-chemotherapy. At diag- by a myeloproliferative phase. BMF does not seem to be indicative of a specific nosis, these patients were characterized by bone marrow dysplasia of the three hemopoietic series, MDS FAB subtype, although the predominance of BMF and an increase in aggregated blasts but, one form or another is not rare in individual A survey of the literature suggests a without full-blown leukemic infiltration. Although some authors have expressed a different opinion 9, prevalence of RA and RAEB, although all of the Sultan et al. cases appear to be distinct from MM and authors report difficulties in aspirating a diagnostic recall the various reports published over the last ten bone marrow sample. In MDS with BMF, there is a years in which BMF seems to identify a particular high degree of bone marrow cellularity, which decreases only in the advanced stages of the disease. subtype of MDS. Apart from a single report in which the degree of Furthermore, there is an association with megafibrosis was not clearly indicated2’, there are about karyocytic hyperplasia, dysmegakaryocytopoiesis 60 well-documented cases of MDS with BMF, the and a prevalence of megakaryocytic precursors majority of them grouped in small series18,19*21-23.which do not show a tendency towards aggregaThis close association has led some Furthermore, one of these series” is nosographically

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MDS WITH BONE MARROW FIBROSIS

authors to hypothesize that an additional alteration of the megakaryocytic series might exist; however, there is no unequivocal evidence for this2’sZ9. An increase in the number of blast cells has also been observed, although there is little information about the pattern of blastic infiltration, which was rarely considered, particularly before Tricot’s observation3’ of the abnormal localization of immature precursors (ALIP). Even taking these limitations into account, the literature shows that in MDS there is a fair correlation with BMF between the presence of blast aggregates and the cytologic diagnosis of RAEB, and between the diagnosis of RA and a diffuse distribution of immature precursors without a tendency towards aggregation. The diagnosis of MDS with BMF is based on the simultaneous finding of dysplasia of the three hemopoietic series and the presence of increased degrees of fibrosis according to traditional evaluation scales32.It is generally easy to differentiate MDS with BMF from myeloproliferative syndromes in general, and idiopathic myelofibrosis (IMF) in particular. In the latter there are no signs of dysmyelopoiesis or a significant arrest in hematopoietic maturation; furthermore, megakaryocytes tend to aggregate and all of the maturation stages are present’ Nevertheless, according to some23*27*33 there are intermediate pictures between MDS and IMF or MDS cases which are difficult to differentiate from IMF even after ferrokinetic investigations. It is not usually difficult to differentiate MDS with BMF from MM (whether primary, or the result of the leukemic transformation of a pre-existent MDS); against a diagnosis of MM are the signs of erythroblastic and granulocytic dysplasia, and the smaller number of blasts even when they are present in aggregates of various sizes. Furthermore, particularly in cases of secondary MDS with BMF, there is always the possibility of noting the transition to a distinct leukemic phase. Cytogenetic analysis has not yet helped our understanding of the mechanisms underlying the pathogenesis of MDS with BMF. While this type of analysis was not performed in many of the published cases, the presence of BMF usually makes it difficult to aspirate adequate bone marrow samples so that examinations have generally been carried out only on peripheral blood. No particularly frequent cytogenetic abnormalities have emerged; the least sporadic anomalies are monosomy 7 and the deletion of the long arm of chromosome 5, both of which are also frequently encountered in MDS without BMF22.23.27-29.34

’.

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Clinical features In MDS with BMF, the symptoms attributable to MDS are usually accompanied by only modest organomegaly unlike in cases of IMF. In the larger series, profound peripheral pancytopenia is the main characteristic finding, the most frequently reported being thrombocytopenia in contrast with an expansion of the bone marrow megakaryocytic series’8v20-22*26. Thrombocytosis is rarely However, even when initial cell counts are not very low, peripheral pancytopenia may develop in the short term 19.36 There is considerable controversy concerning the prognostic significance of BMF in MDS. Pagliuca et al. l 9 reported good survival in their ten patients; however, nine of these belonged to the FAB subgroup without an excess of blasts and, although the prognostic significance of the FAB classification is still controversial, it is generally accepted that the forms without an excess of blasts have a significantly better life expectancy. Consequently, the survival of Pagliuca’s patients must be considered less favourable. Watts et al.3s have reported a surprisingly good response to steroid therapy in three cases of MDS with BMF but the degree of fibrosis in these patients seems to have been less than that found in the typical cases, and one of the patients had an apparently short follow-up and another showed concomitant bronchial neoplasia. Del Potro3’ reported relatively benign clinical and hematological data in a single patient, but the patient died with a cerebral hemorrhage shortly after diagnosis. The majority of authors agree that the definition “MDS with BMF” identifies a group of MDS patients with an unfavourable p r o g n ~ s i s ’ ~ * ~ ’.- M ~ ~aschek *’~ et a/.” report a greater risk of leukemic transformation; however, as previously mentioned, this study probably includes patients with variable degrees of marrow fibrosis, only some of whom can be considered as typical cases of MDS with BMF. On the other hand, leukemic transformation occurs only exceptionally in well-documented cases of primary MDS with BMF23*28,more frequent is the report of a transition from a form without excess of blasts to one with excess of The poor prognosis of MDS with BMF is mainly attributable to complications deriving from pancytopenia and continuous transfusions. Compared to other diseases characterized by bone marrow failure, death is more frequently due to hemorrhagic than to infective causes22*30*34. This links up with the

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al.

4. Yoshida, Y.,Oguma, S., Uchino, H. and Maekawa, T. (1989). Refractory myelodysplastic anemias with hypocellular bone marrow. J. Clin. Pathol., 41, 763-7. 5. Nand, S.and Godwin, J. E. (1988).Hypoplastic myelodysplastic syndrome. Cancer, 62, 958-64. 6. Coiffier, B., Adeleine, P., Gentilhomme, O., Felman, P., Treille-Ritouet, D. and Bryon, P. A. (1987).Myelodysplastic syndromes. A multiparametric study of prognostic factors in 336 patients. Cancer, 60,3029-32. 7. Jacobs, R. H., Cornbleet, M. A., Vardiman, J. W., Larson, R. A., Le Beau, M. M. and Rowley, J. D. (1986).Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes. Blood, 67, 1765-72. 8. Garcia, S., Sanz, M. A., Amigo, V., Colomina, P., Carrera, SECONDARY MDS WITH BMF M. D., Lorenzo, J. I. and Sam, G. F. (1988).Prognostic factors in chronic myelodysplastic syndromes: a multivariate analysis in 107 cases. Am. J. Hematol., 27, 163-8. There are significant differences between the primary Sanz, G. F., Sang M. A., Vallespi, T., Canizo, M. C., and secondary forms of MDS showing BMF. First of 9. Torrabadella, M., Garcia, S., Irriguible D. and San Miguel, all, the frequency of BMF is probably greater in the J. F. (1989).Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic secondary forms3’. syndromes: a multivariate analysis of prognostic factors in 370 As far as morphology is concerned, despite the patients. Blood, 74, 395-408. presence of some dysplasia and fibrosis, bone marrow 10. Cassano, E.,Giordano, M., Riccardi, A., Cocci, A. and Cazzola, M. (1990).Myelodysplastic syndromes: a multiparametric study cellularity is low and megakaryocytic dysplasia is less of prognostic factors and a proposed scoring system. evident or even absent”*’’. There are no significant Haematologica, 75, 141-5. hematological or clinical differences at the onset but, 11. Hasselbach, H. (1990).Idiopathic myelofibrosis: a clinical study of 80 patients. Am. J. Hematol., 34, 291-300. although prognosis remains poor in both types, 12. Yeung, K. Y.and Trowbridge, A. A. (1977).Idiopathic acquired mortality in secondary MDS is mainly attributable to sideroblastic anemia terminating in acute myelofibrosis. leukemic transformation, as observed by Sultan et Cancer, 39, 359-65. 13. Butler, W. M., Taylor, H. G. and Viswanathan U. (1982). a1.‘* in three of their four cases. Idiopathic acquired sideroblastic anemia terminating in acute Secondary MDS with BMF can be considered as a myelosclerosis. Cancer, 49, 2497-9. particular variety of the different “pre-leukemic” 14. Bearman, R. M., Pangalis, G. A. and Rappaport, H. (1979). Acute (“malignant”) myelosclerosis. Cancer, 43,279-93. conditions and it is well known that these may precede 15. Bain, B. J., Catovsky, D., O’Brien, M., Prentice, H. G., Lawlor, the onset of leukemia in subjects treated with E., Kumaran, T. O., McCann, S. R., Matutes, E. and Galton, radiochemotherapy for previous neoplasias. In these D. A. G. (1981).Megakaryoblastic leukemia presenting as acute myelofibrosis. A study of four cases with the platelet-peroxidase cases, fibrosis can be attributed to the iatrogenic bone Blood, 58, 20613. marrow damage and to causes related to the course 16. reaction. Heilmeyer, L. (1966).Disturbance in Heme Synthesis. C. C. of the preceding neoplasia, rather than to primary Thomas, Springfield IL: p. 132. activation of megakaryocytes. Similar to other 17. Lukowicz, D. F.,Myers, T. J., Grasso, J. A. and Albala, M. M. (1982).Sideroblastic anemia terminating in myelofibrosis. Am. secondary pre-leukemic forms, and unlike primary J. Hematol., 13,253-7. forms of MDS with BMF, its regular evolution into 18. Sultan, C., Sigaux, F., Imbert, M. and Reyes, F. (1981).Acute myelodysplasia with myelofibrosis: a report of eight cases. Br. acute leukemia suggests that secondary MDS with J. Haematol, 49, 11-16. 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above-mentioned hypothesis of additional specific megakaryocytic anomalies in the pathogenesis of MDS with BMF. The rare cases of MDS with BMF who are candidates for allogeneic bone marrow transplantation have a less favourable prognosis than patients without BMF, probably due to the greater risk of early complications and a lack of engraftment34.

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MDS WITH BONE MARROW FIBROSIS

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cation, bone marrow histology and immunohistochemical assessment. Am. J. Clin. Pathol. (manuscript in preparation).

Myelodysplastic syndrome associated with bone marrow fibrosis.

Bone marrow biopsy (BMB) in myelodysplastic syndrome (MDS) frequently reveals a slight alteration in the reticulin stroma which does not have any clin...
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