Clinical Presentation Bart Scott, H. Joachim Deeg

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Contents

1.1 Symptoms upon Presentation . . . 1

1.2 Past Medical History . . . 1

1.3 Family History . . . 1

1.4 Physical Examination . . . 1

1.5 Laboratory Studies . . . 2

1.5.1 Blood . . . 2

1.5.2 Bone Marrow . . . 3

1.5.3 Chromosome Analysis . . . 4

1.5.4 Differential Diagnosis . . . 4

References . . . 4

1.1 Symptoms upon Presentation

In keeping with the broad spectrum of disorders covered by the term myelodysplastic syndrome (MDS), the clinical presentation of patients varies widely (Greenberg 2000). The patients' symptoms are a direct result of cytopenias and cell function abnormalities.

Most patients present with fatigue, a lack of energy, some with shortness of breath and dyspnea upon exer- tion, related to anemia. As their overall performance lev- el declines, they may not be able to accomplish their jobs or tasks any longer. Other patients are noted incidentally to have a low hematocrit (or other cytopenias) on the occasion of a ªroutineº check-up. Some patients will no- tice petechiae or bruises, most frequently over the lower legs, and again others will complain of recurrent infec-

tions (10%; most of bacterial etiology) or may be noted by their dentist to have a root abscess that does not heal.

1.2 Past Medical History

The preceding medical history is generally not reveal- ing. However, some patients will report that years ago they were told that they had ªanemia,º and occasional patients may have had a low platelet count ªall their lifeº (see Chapter 2, Differential Diagnosis). In addition, some patients give a history of autoimmune/inflamma- tory disorders, including vasculitis, polyneuropathy, a lupus-like syndrome, thyroiditis, arthritis and serositis (Hamblin 2002).

1.3 Family History

The family history is generally not contributory. Famil- ial cases of MDS appear to be rare.

1.4 Physical Examination

Physical examination may be rather unremarkable.

However, if patients are severely anemic they will be pale and show tachycardia. There may be petechiae, particularly in dependent parts, and bruises. Lymphad- enopathy is an unusual finding, and clinically recogniz- able splenomegaly is infrequent. If serositis is a feature, there may be corresponding pulmonary (pleural), cardi- ac (pericardial), abdominal (peritoneal) and joint (syn- ovial) findings.

Clinical Presentation

Bart Scott, H. Joachim Deeg

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1.5 Laboratory Studies 1.5.1Blood

A low hematocrit/hemoglobin is the most frequent ab- normality, and in about 30% of patients is the only cytopenia. The anemia is typically macrocytic, and the mean cellular volume (MCV) may be >110 fl, particularly in patients who turn out to have a ª5q± syndromeº;

B12 and folate deficiencies must be excluded. The reti- culocyte count is typically low. There may be anisocyto- sis, poikilocytosis, acanthocytosis. Nucleated red blood cells may be seen, as well as basophilia and Howell-Jolly bodies.

About two thirds of patients are neutropenia. Gran- ulocytes tend to be hypogranular and hyposegmented with abnormal chromatin condensation. Cells with Pel- ger-Hut morphology may be present. The relative and absolute monocyte count may be elevated. Defects in adhesion, migration, phagocytosis and bacterial killing have been described. Cells respond poorly to hemopoietic growth factors. The peroxidase reaction may be negative. Natural killer cells (NK) function may also be abnormal.

In patients with chronic myelomonocytic leukemia (CMML) (now generally classified under myeloprolifer- ative disorders) the monocyte count is elevated (³1´10⁹/liter). Patients with the proliferative variant have WBC >12´ 10⁹/liter. Hepatosplenomegaly may be present.

Thrombocytopenia of various degrees is also present in about two thirds of patients; in maybe 5% of patients it is the only peripheral blood cytopenia. Cases of an Evans-like syndrome (with thrombocytopenia and hemolytic anemia) have been observed. Platelet function is often abnormal, as reflected in prolonged bleed- ing time and impaired aggregation. In patients with a 5q± syndrome, platelet counts are typically high (Fig.

1.1).

A proportion of patients show evidence of hemoly- sis, and in some series, as many as 20% of patients have been reported to have a PIG-A mutation, a positive Ham test, abnormal or lacking expression of PIG-A anchored surface proteins, and increased sensitivity to comple- ment-mediated lysis, consistent with (paroxysmal nocturnal hemoglobinuria) PNH (see Chapter 2). The proportion of patients with a documented PNH clone has been much lower in most series. Recent data from a Ja- panese study, on the other hand, suggest an even higher 2 Chapter 1 ´ Clinical Presentation

Fig. 1.1 a±c. Illustration of morphologic findings in a patient with 5q± syndrome (courtesy of D. Myerson, M.D., Ph.D., Fred Hutchinson Cancer Research Center, Seattle, WA). a Peripheral blood smear showing Pelger-Hut appearance of granulocytes. b Bone marrow with typical megakaryocyte changes. c Megakaryocyte abnormalities (higher magnification)

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frequency of PNH positivity if sufficiently sensitive flow studies are applied (Ishiyama et al. 2003). Abnormalities in iron metabolism have been described, including iron absorption, and ferritin levels may be elevated.

There are also reports of disturbed hemoglobin chain synthesis, an increase in fetal hemoglobin, Hgb H inclusions, abnormal erythrocyte enzymes and surface antigens.

Erythropoietin levels in peripheral blood are generally high (except in patients with renal failure), although they may be low (<200 units), even in patients with marked anemia, in about 15±20% of patients (Hell- strom-Lindberg 1995).

1.5.2Bone Marrow

Bone marrow findings are described in detail in Chap- ters 2 and 5. Aspirates and biopsies typically reveal a hy- percellular marrow. However, the marrow may be nor- mocellular, and in as many as 20% of cases may be hy- pocellular (considering a 30±40% cellularity as the lower limit of normal), leading to potential difficulties with the differential diagnosis from aplastic anemia. It is also important to consider that there is a decline of overall marrow cellularity with age, and a lower cut-off for normal at 20% has been suggested for patients in their 70s and older (Hartsock et al. 1965). Generally, however, a limit of 40% is used. Since the marrow pattern may be quite heterogeneous (for reasons that are not well understood), multiple biopsies or a magnetic resonance imaging (MRI) scan may be required to be confident about the assessment.

Microscopic examination of the marrow may reveal single- or multi-lineage dysplasia. There may be marked dyserythropoiesis including multinuclear fragments and bizarre nuclear shapes, mitosis, asynchrony between cytoplasm and chromatin, basophilia of cytoplasm, or Ho- well-Jolly bodies. Erythroid precursors may show prominent megaloblastic changes. Frequently ring sideroblasts are present (five or more siderotic granules are considered pathologic; if at least one third of the nuclear circumference is covered, the term ringed sideroblast is applied). To qualify as refractory anemia with ring sideroblasts (RARS) more than 15% ringed sideroblasts must be present. If more than 50% erythroid precursors are present (with more than 30% of the myeloid lineage being blasts), the criteria for erythroleukemia are met.

Nuclear-cytoplasmatic asynchrony is also observed in

early myeloid cells, with granular cytoplasm, a reticu- lated nucleus, prominent nucleolus and perinuclear Gol- gi zone. The proportion of type I myeloblasts determines the morphologic subtype of MDS. Morphologic abnormalities in megakaryocytes include micromegakaryo- cytes, mononuclear forms, multiple small nuclei con- nected by strands of nuclear material, dysmorphic features and hypogranularity. In patients with a 5q± syndrome megakaryocytic abnormalities (usually small with single eccentric nuclei) may be prominent.

Multiparameter flow cytometry of marrow cells may show a broad array of immunophenotypic aberrancies, apparently on all cell lineages, but best characterized in myeloid and monocytoid cells (reviewed in Benesch et al. 2004; Stetler-Stevenson et al. 2001). Immunopheno- typic abnormalities may include the expression of new surface receptors, adhesion molecules or apopto- sis-related surface markers. In addition, lineage infide- lity, asynchronous antigen expression, differences in antigen density and homogeneity of expression may also be observed (Terstappen et al. 1992). These abnormalities may affect only subpopulations of cells that co- exist with normal precursors or normal maturing cells.

The proportion of CD34⁺cells may be significantly increased in refractory anemia with excess blasts in transformation (RAEBt) compared with normal cells, whereas CD66⁺⁺⁺ cells may be significantly decreased in patients with RAEB compared with patients with refractory anemia (RA) or normal marrow. CD33 intensity tends to be higher in diseases with more immature cells.

One study used hierarchical clustering to assess for similarities and differences between patient groups (Maynadie et al. 2002). Eight clusters were identified based on intensity relationships between CD16, CD34, CD36, CD38, CD17 and HLA-DR on blasts. The eight groups exhibited differences in International Prognostic Scoring System (IPSS) scores, cytogenetic risk factors, and percentage of blasts. Clustering mean intensities for the granulocytes showed increased mean intensity expression of CD38, CD13, CD33 in patients with more advanced MDS stages (RAEB, RAEBT), as might be ex- pected from a shift to the left reflecting increases in myeloblasts and immature myeloid cells.

CD34⁺cells in peripheral blood are decreased in RA patients but increased in RAEB and RAEBT patients as compared with normal. Patients with lower grades of MDS are more like normal in expression of CD114 on the CD34⁺cells than patients with more advanced stages of disease (based on the French-American-British Clas-

a 1.5 ´ Laboratory Studies 3

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sification (FAB) classification). One report suggests that patients with CD90 expression on CD34⁺cells are more likely to progress to leukemic transformation (Inaba et al. 1998).

Markers reflecting immaturity of myeloid cells such as CD7 and CD117 tend to be more frequently expressed in advanced stages of MDS and acute myeloid leukemia transformed from MDS (tAML) (Ogata et al. 2002).

Markers for maturity of myeloid cells (CD10 and CD15) appear to be more prevalent in early stages of MDS. Expression of CD7 on marrow cells, as detected in advanced stages of MDS, was found to be indepen- dently associated with a transformation-free survival (Ogata et al. 2002).

A recently developed numerical scoring system based on phenotypic and scatter characteristics of MDS marrow cells suggests a strong correlation with IPSS scores and, in an initial analysis, was significantly correlated with post-transplant outcomes (Wells et al.

2003).

1.5.3Chromosome Analysis

Chromosome abnormalities are described in detail in Chapter 6.

Approximately 40±50% of patients with de novo, and as many as 90% of patients with secondary/treatment-related MDS show clonal cytogenetic abnormalities. The frequency may be even higher when molecular tools are used.

It is important that a sample of marrow be sent for cytogenetic analysis in all patients suspected of having a diagnosis of MDS. Characteristic cytogenetic changes can confirm the diagnosis of MDS, and it also offers critical information regarding prognosis (IPSS). It is also becoming apparent that cytogenetic changes may affect treatment decisions.

1.5.4Differential Diagnosis

The differential diagnosis is discussed in detail in Chap- ter 2. It is important to emphasize that in many in- stances MDS is a diagnosis of exclusion. Therefore, if there is any doubt about the diagnosis, the patient should be re-evaluated after an observation period of 2±3 months to substantiate (or exclude) the diagnosis of MDS.

References

Benesch M, Deeg HJ, Wells D, Loken M (2004) Flow cytometry for diagnosis and assessment of prognosis in patients with myelodysplastic syndromes. Hematology 9:171±177

Greenberg PL (2000) Myelodysplastic syndrome. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (eds) Hematology: basic principles and practice. Churchill Livingstone, New York, pp 1106±1129

Hamblin TJ (2002) Immunology of the myelodysplastic syndromes. In:

Bennett JM (ed) The myelodysplastic syndromes: pathobiology and clinical management. Marcel Dekker, Inc., New York, pp 65±87

Hartsock RJ, Smith EB, Petty CS (1965) Normal variations with aging of the amount of hematopoietic tissue in bone marrow from the anterior iliac crest: a study made from 177 cases of sudden death examined by necropsy. Am J Clin Pathol 43:326±331

Hellstrom-Lindberg E (1995) Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br J Haematol 89:67±71

Inaba T, Shimazaki C, Sumikuma T, Shimura K, Takahashi R, Hirai H, Ashihara E, Sudo Y, Murakami S, Haruyama H, Fujita N, Yoshimura M, Nakagawa M (1998) Flow cytometric analysis of Thy-1 expression in myelodysplastic syndrome. Int J Hematol 68:403±410 Ishiyama K, Chuhjo T, Wang H, Yachie A, Omine M, Nakao S (2003) Poly-

clonal hematopoiesis maintained in patients with bone marrow failure harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells. Blood 102:1211±1216

Maynadie M, Picard F, Husson B, Chatelain B, Cornet Y, Le Roux G, Cam- pos L, Dromelet A, Lepelley P, Jouault H, Imbert M, Rosenwadj M, Verge V, Bissieres P, Raphael M, Bene MC, Feuillard J, The Groupe d'Etude Immunologique des Leucemies (2002) Immunopheno- typic clustering of myelodysplastic syndromes. Blood 100:2349±

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Ogata K, Nakamura K, Yokose N, Tamura H, Tachibana M, Taniguchi O, Iwakiri R, Hayashi T, Sakamaki H, Murai Y, Tohyama K, Tomoyasu S, Nonaka Y, Mori M, Dan K, Yoshida Y (2002) Clinical significance of phenotypic features of blasts in patients with myelodysplastic syndrome. Blood 100:3887±3896

Stetler-Stevenson M, Arthur DC, Jabbour N, Xie XY, Molldrem J, Barrett AJ, Venzon D, Rick ME (2001) Diagnostic utility of flow cytometric immunophenotyping in myelodysplastic syndrome. Blood 98:979±987

Terstappen LW, Safford M, Konemann S, Loken MR, Zurlutter K, Buch- ner T, Hiddemann W, Wormann B (1992) Flow cytometric charac- terization of acute myeloid leukemia. Part II. Phenotypic hetero- geneity at diagnosis. Leukemia 6:70±80

Wells DA, Benesch M, Loken MR, Vallejo C, Myerson D, Leisenring WM, Deeg HJ (2003) Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome corre- lates with the IPSS and with outcome after hemopoietic stem cell transplantation. Blood 102:394±403

4 Chapter 1 ´ Clinical Presentation