Case 2 -
Refractory cytopenia with multilineage dysplasia (RCMD)
Sa Wang, UT MD Anderson Cancer Ctr, Houston, TX
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The classification of bone marrow neoplasms manifesting with erythroid predominance has been fraught
with controversy since their original description.
For myeloid neoplasms with ≥50% marrow erythroid elements that are not therapy-related or AML
with recurrent cytogenetic abnormalities, the blast count plays a critical role in further
classification. The WHO recommendation is to first enumerate myeloblasts as a proportion of total cells:
if they are 20% or more, most of these cases will be classified as AML with myelodysplasia-related
changes (AML-MRC) either due to a prior history of MDS, high-risk karyotype, or significant morphologic
dysplasia (as discussed above). If myeloblasts are less than 20% of total cells, the recommendation is
to count the myeloblasts as a proportion of the non-erythroid elements: if 20% or more, the diagnosis is
AEL (acute erythoid leukemia) (a subtype of AML-NOS), and if less than 20%, the case is classified as
MDS. The classification algorithm is illustrated in Figure 1.
84 year old woman, with a history of an artificial heart
valve, noticed significant fatigue and paleness around May 2009. Upon evaluation she was found to be
pancytopenic. She received red cell transfusion, and bone marrow (BM) biopsy and aspirate was performed:
CBC at the time of BM biopsy:
WBC: 2.3 with 70% neutrophils; 28% lymphocytes and 2% monocytes;
Hb: 6.8; Hct 23.2%; MCV 92;
Bone Marrow: 80% cellularity; trilineage dyspoiesis; 1% blasts; 63%
erythroid; 12% lymphocytes/plasma cells; and 25% all other myeloid series.
Chromosomal analysis: 46, XX
Refractory cytopenia with multilineage dysplasia (RCMD);
Interim history: She received 5-azacitidine from 09/28/09 to 07/21/10 with
an initially significant improvement in transfusion dependency. In August 2011, her counts deteriorated.
The patient is now referred back here for an assessment of the situation and treatment recommendations.
CBC at this visit: WBC 0.6 with 12.5% neutrophils; 82.5% lymphocytes; 5%
eosinophils; Hb 7.1, Hct 24.1%; MCV 94; Platelet 19
Bone Marrow: Cellularity: 70%; Trilineage dyspoiesis; Blasts: 8%;
Erythroid precursors: 72%; other maturing myeloid elements: 9%.
CD34: 10% positive cells
E-Cadherin: many erythroid precursors
Chromosomal Analysis: 61-58,XX,+1,+2,+6,+7,+9,+16,+16,-21[cp2]]/ 46,
FISH for chromosome 8, trisomy 8: 4%, tetrasomy 8: 2%
RAEB with erythroid hyperplasia (≥50%) versus AEL share very similar morphological features.
Erythroid lineage often demonstrates variable degree of dysplasia, such as nuclear irregularity,
binucleation, nuclear fragmentation, vacuolization of cytoplasm, and coarse basophilic stippling of the
cytoplasm. Ring sideroblasts are a frequent finding in RAEB-E and AEL, but appear to have no clinical or
Myeloblasts can be distinguished from pronormoblasts by their smaller size, more scant cytoplasm that
is pale and far less basophilic than that of pronormoblasts, and more irregularly dispersed nuclear
chromatin. Myeloblasts should always be counted separately from pronormoblasts; the latter are usually
counted together with all erythroid elements and a separate enumeration of pronormoblasts is only
required for a diagnosis of pure erythroid leukemia (PEL).
A high-quality bone marrow aspirate (or well-prepared touch imprints) must be examined to assess
dysplasia and quantify blasts and erythroid elements. A 500-cell count of the bone marrow aspirate
should be performed in all myeloid neoplasms with erythroid predominance to ensure an accurate count,
particularly since small differences in the percentages of blasts or erythroids may profoundly affect the
The bone marrow biopsy is also an essential component of the workup of myeloid neoplasms with
erythroid proliferation, particularly in cases where the aspirate may be compromised or hemodilute due to
marrow fibrosis. Myeloblasts are usually CD34+ and CD117+ and thus can be identified and their numbers
estimated in the biopsy (Figure 2E), although this should not substitute for a blast count on the
aspirate or touch preparation. Early erythroid elements in both benign conditions and in myeloid
neoplasms may variably express CD117, but are CD34 negative. Glycophorin can help to highlight erythroid
elements; E-cadherin is the most sensitive and specific marker of benign and neoplastic pronormoblasts
and effectively stains PEL cases.
In addition to the count of myeloblasts, other subtle morphological differences are observed between
AEL and RAEB-E. In AEL, the maturing myeloid elements are often markedly decreased, and the BM cellular
component is mainly of erythrocytes with maturation; myeloblasts and some lymphocytes. In contrast,
RAEB-E BM often contains more maturing myeloid elements.
The border between a high-grade MDS with erythroid predominance versus AEL is rather blurred, and it
can be particularly challenging in cases of AEL arising from MDS. A slight difference in blast counting
may render two different diagnoses, and may subject patients to different clinical management: MDS or
AML. To identify more subjective criteria, and clinicopatholoic features that help us to correctly make
diagnosis are crucial.
The 2008 WHO classification has emphasized the incorporation of clinical presentation, cytogenetic
and/or molecular genetic findings into myeloid neoplasm classification. However, the relative
contribution of each of these parameters to the final diagnosis varies depending on the particular
disease entity, and a multiparameter approach is required. In myeloid neoplasms with a prominent
erythroid proliferation, cytogenetic changes, rather than blast counts have been found to be more
critical in predicting outcomes of patients. AEL and RAEB-E may form a continuum analogous to
therapy-related myeloid neoplasms, in which clinical outcomes are generally similar irrespective of blast
count, but are strongly influenced by the karyotype risk group.