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AJCP / SHP/EAHP Workshop

Myelodysplastic Syndromes
1 2
Attilio Orazi, MD, FRCPath, and Magdalena B. Czader, MD, PhD
Key Words: Myelodysplastic syndrome; Refractory cytopenia with unilineage dysplasia; Refractory anemia with ring sideroblasts;
Refractory cytopenia with multilineage dysplasia; Refractory anemia with excess blasts; MDS associated with an isolated del(5q)
chromosomal abnormality

DOI: 10.1309/AJCPRCXX4R0YHKWV
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Abstract Myelodysplastic syndromes (MDSs) are hematopoietic
Session 4 of the 2007 Workshop of the Society stem cell disorders characterized by ineffective
for Hematopathology/European Association for hematopoiesis producing marrow failure and a propensity
Haematopathology was devoted to myelodysplastic 1,2
syndromes (MDSs). Submitted cases highlighted to progress into acute myeloid leukemia (AML).
important issues and difficulties in relation to the
diagnosis and classification of MDS. Much of the
discussion focused on the correlation, or lack of it, Etiology and Pathogenesis
between morphologic examination and other diagnostic The etiology of MDSs is not known. The association of
techniques, cytogenetics in particular. The cases MDSs with increasing age suggests genetic damage caused by
included examples of isolated del(5q) chromosomal hazardous exposure or inherited susceptibility. Risk factors
abnormality, including the “classical” 5q– syndrome include exposure to benzene and other solvents, diesel fuel,
and other myeloid neoplasms. Other cytogenetic 3
smoking, and immunosuppression. Chemotherapy and radia-
abnormalities in MDSs and the role of cytogenetics tion therapy are associated with therapy-related MDS (dealt
in diagnosing MDSs were addressed. Particularly with in a separate article). The pathophysiology of MDSs is
challenging is the correct identification of fibrotic complex and involves abnormalities in the regulation of cel-
subtypes of MDSs and their separation from subsets 4
lular proliferation, maturation, and survival.
of acute myeloid leukemia with myelofibrosis such as In AML, there is widespread support for the concept that
acute panmyelosis with myelofibrosis. The its development requires at least 2 somatic gene altera-tions:
association and eventual relation of MDSs one mutation to augment the rate of cellular prolif-eration or
(hypoplastic in particular) with aplastic anemia, enhance cell survival (a class I mutation), usually
paroxysmal nocturnal hemoglobinuria, and other constitutively activating a tyrosine kinase or a RAS family
nonneoplastic disorders were illustrated. member, and another mutation impairing normal cellular
Novel cytogenetic and molecular genetic differentiation (a class II mutation), usually deregulating a
approaches are likely to revolutionize the classification hematopoietic transcription factor or a transcriptional coacti-
of MDSs. However, it is unlikely that these new vator, such as homeobox family members or the components
techniques will be capable, on their own, of adequately 4
of core binding factor. In AML, these types of somatic gene
stratifying patients for treatment purposes. At least for alterations include recurrent chromosome abnormali-ties
the foreseeable future, the diagnosis of MDS requires detected by cytogenetics and other acquired mutations such as
integration of morphologic, immunophenotypic, and TP53, NRAS, KRAS, KIT, PTPN11, CEBPA, CSF1R
genetic features in the light of patient history and (C-FMS), NF1, and BRAF point mutations and MLL partial
clinical manifestations. 5
tandem duplications.
290 Am J Clin Pathol 2009;132:290-305 © American Society for Clinical Pathology
290 DOI: 10.1309/AJCPRCXX4R0YHKWV
AJCP / SHP/EAHP Workshop

Unfortunately, our understanding of the molecular pathol- Diagnostic Workup


ogy of MDSs remains considerably more primitive than our
6 The diagnostic workup of MDSs includes morphologic
understanding of the biology of AML. Recurrent chromo-
somal gains and losses such as deletion of chromosomes 5, 7, evaluation of peripheral blood, marrow aspirate, and bone
13, and 20 and the sex chromosomes or trisomy 8 are common marrow biopsy specimens, interpreted in the context of the
in MDSs; however, the majority of them remain 1,2,16
CBC results and adequate clinical information. As pre-
pathogenetically obscure. A notable exception is the loss of viously mentioned, correlation with marrow cytogenetics is
5q31-33, which has been recently linked to a culprit gene, essential. It needs to be emphasized, however, that the
RPS14, coding for a component of the 40S ribosomal subunit
presence of a normal karyotype does not exclude a diag-nosis
7
and involved in the erythroid differentiation. The informative of an MDS. Conversely, an abnormal karyotype may indicate
reciprocal translocations, such as those that have led to a prog- an MDS within an appropriate clinical context.
nostically relevant subgrouping in AML, are rare in MDSs.
Only a few uncommon MDS-associated rearrangements have Morphologic Features
been identified and further characterized, such as those Although an MDS can be suspected from the clinical
involving 3q26 (corresponding to the zinc finger DNA bind-ing history and the peripheral blood counts, the diagnosis is
protein, MDS1-EVI1), 3q25.1 (the p53 regulator, MLF1), and usually made by morphologic inspection of the peripheral
1p36 (PRDM16, formerly MEL1, another zinc finger blood, bone marrow aspirate, and bone marrow biopsy
8

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transcription factor). Notably, all 3 of these latter genes are 1,2
specimen. The previously used French- American-British
involved in balanced translocations, which are observed in 17
fewer than 5% of patients with an MDS. The point mutations (FAB) classification was based entirely on findings iden-
detected in AML have also turned out to be uncommon in tifiable by cytologic analysis of stained smears of periph-eral
MDSs, with a notable exception of the deletions in mitochon- blood and bone marrow aspirate. The main criteria for
5,9,10 subclassification of MDSs were the percentage of blasts in the
drial DNA.
peripheral blood and bone marrow aspirates and the presence
Despite these limitations, chromosomal abnormali-ties in of dysplastic changes in at least 1 of the 3 main marrow cell
MDSs detectable by conventional karyotyping are clinically lines. A more comprehensive approach is the one used by the
1,2
important. An abnormal karyotype can prove clonality, current World Health Organization (WHO) system, which
helping in establishing a diagnosis of MDS by ruling out, eg, a stresses the importance of integrating other techniques such as
reactive pathogenesis. Karyotypic informa-tion is bone marrow biopsy histologic exami-nation, cytogenetics,
prognostically useful,
11
and, in the case of deletions of and molecular genetics, in the light of relevant clinical
information. Morphologic dysplasia is not necessarily
chromosome 5q, knowledge of the karyotype can even help in
12
synonymous with an MDS, and, in part to address the issue of
selecting a specific treatment, lenalidomide. To enhance the “false -positive” myelodysplasia, the WHO classification
detection of cytogenetic or genetic anomalies, fluorescence in system recommends that at least 10% of the cells in a lineage
situ hybridization (FISH) analysis as well as other karyotype be morphologically dysplastic to declare a dysplasia of this
based techniques (eg, spectral karyotyping) can be successfully 1,2
lineage.
used. In addition, recent evidence has shown that high-
resolution single-nucleotide polymorphism Affymetrix (Santa The currently used WHO classification of MDSs is
Clara, CA) genotyping microarrays rep-resent an effective principally based on the percentage of blasts in the bone
technique for detecting cytogenetically cryptic genomic marrow and peripheral blood and the type and degree of
13,14 dysplasia. In particular, the extent of dysplasia, unilineage
aberrations. This and other sensitive approaches may, in
vs multilineage, has an important role in the WHO subclas-
the future, allow stratification of patients for early therapeutic 17
interventions. So far, however, treat-ment of MDSs is tailored sification, a feature not considered in the FAB system. In
to the clinical manifestations that predominate in an individual addition, the presence of ring sideroblasts is assessed by
patient and that are responsible for the disease-associated iron staining. The absence of monocytosis (monocytes,
morbidity. Nevertheless, select new therapies such as drugs 9
<1,000/µL [1 × 10 /L] in the blood; no monocytosis in the
inducing DNA hypomethyla-tion such as 5-azacitidine and 5- bone marrow [<5% monocytes; normal range, 0%-4%]) is
15
aza-2′- deoxycitidine have shown promising results. In important to distinguish between MDSs and chronic
addition to the acquired intrin-sic genetic defects of myelomonocytic leukemia, a subtype of myelodysplastic/
hematopoietic stem cells, a proportion of patients with MDSs myeloproliferative neoplasm (MDS/MPN) formerly con-
exhibit T cell–mediated inhibition of hematopoiesis and, sidered to belong to the MDS category. Monocytes in the
because of that, may respond well to immunosuppression. In bone marrow are best appreciated by using nonspecific
these cases, MDSs share similar pathophysiology with esterase stains (recommended is the -naphthyl butyrate
acquired aplastic anemia (AA). 18
esterase).

© American Society for Clinical Pathology Am J Clin Pathol 2009;132:290-305 291


291 DOI: 10.1309/AJCPRCXX4R0YHKWV 291
Orazi and Czader / MyelodysplaStic Syndromes

Blasts 27
among different observers is often considerably lower.
The enumeration of blasts is important for the diagnosis The factors that are largely responsible for inconsistencies
and classification of MDSs, and, in most studies, the blast per-
in the diagnosis and classification include the variability in
1,2
centage is one of the most important prognostic indicators. It the quality of specimens, inaccurate enumeration of blasts,
is also an integral component of currently used prognostic and the erroneous inclusion in the MDS category of cases
scoring systems such as the International Prognostic Scoring with nonclonal dysplastic hematopoiesis or with other types
11 of myeloid neoplasms (eg, MDS/MPN). Therefore, the
System and the more recent WHO classification–based
19 impor-tance of a critical evaluation of morphologic features
prognostic scoring system. Blasts should be carefully enu-
in the light of other laboratory results and clinical
merated from well-prepared peripheral blood smears and bone
information can-not be overemphasized.
marrow aspirate smears. Immature cells to be included in the
The WHO Classification of the Myelodysplastic
blast count include myeloblasts—without and with a few fine
Syndromes (2008 Revision, 4th ed) has been recently pub-
azurophilic granules—monoblasts, and megakaryoblasts. 28
Promonocytes are also considered as “blast equivalents” in the lished. The updated classification, which largely overlaps
1 1
WHO classification scheme. These cells, which in the absence with the 2001 WHO scheme, distinguishes the following
of cytochemistry for esterase are morphologically difficult to MDS subtypes: (1) refractory cytopenia with unilineage
distinguish from promyelocytes and early myelo-cytes, are dysplasia with the subcategories of refractory anemia (RA),
rarely found in MDSs. Their presence suggests a diagnosis of refractory neutropenia (RN), and refractory thrombocytopenia

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chronic myelomonocytic leukemia or, in the presence of an (RT); (2) refractory anemia with ring sideroblasts (RARS);
increased blast count, AML with monocytic differentiation. (3) refractory cytopenia with multilineage dysplasia (RCMD);
(4) refractory anemia with excess of blasts (RAEB) with sub-
The blast count derived from the aspirate smears should categories RAEB-1 and RAEB-2; (5) MDS, unclassifiable; and
be carefully correlated with the estimate from the biopsy sec- (6) MDS with isolated del(5q) chromosomal abnormality. The
1,2,20-22 main features of these subtypes are described in the fol-lowing
tions. Often, in the marrow biopsy specimen, blasts
may be hard to appreciate, particularly if there is marrow paragraphs and summarized in ❚Table 1❚ .
fibrosis. In such cases, an immunohistochemical stain for
22-26 Refractory Cytopenia With Unilineage Dysplasia
CD34 anti-gen may be very helpful. However, because not
This designation encompasses the MDS cases that mani-
all blasts are CD34+, care must be taken not to use the CD34
fest with refractory cytopenia associated with dysplasia limited
result in lieu of careful morphologic assessment. Additional
to 1 cell line and includes RA and the rare cases of RN and RT.
markers can be used to facilitate the visibility of CD34– blasts
Refractory bicytopenia may be included in this category if
(eg, CD117, lysozyme, CD68). Myeloperoxidase is often weak
accompanied by unilineage dysplasia, but refrac-tory
or negative in blasts seen in MDSs. Flow cytometry may help
in assessing the frequency of marrow blasts and to confirm pancytopenia that is associated with unilineage dysplasia
their immunophenotype. In addition, aberrant antigen should be considered MDS, unclassifiable.
expression and side scatter abnormalities (owing to low The initial complaint is, in most cases, related to anemia
granularity in the granulocytic cells) have also been shown to (these cases are properly designated as RA). The anemia may
roughly correlate with the severity of the MDS. be normocytic/normochromic but is often macrocytic. Blasts
are absent in the blood or represent less than 1% of the dif-
ferential count, and they account for fewer than 5% of the
nucleated marrow cells. The marrow is usually hypercellular
Classification of MDS due to erythroid hyperplasia, and dyserythropoiesis is present,
The concept of the WHO system is that classification of but ring sideroblasts account for fewer than 15% of the eryth-
hematopoietic neoplasms should be based not only on roid cells. Fewer than 10% of the cells in the granulocytic or
morphologic findings but also on the use of clinical, megakaryocytic lineages show dysplasia. No Auer rods are
genetic, immunophenotypic, and biologic information to present. The diagnosis is frequently one of exclusion; in the
1
define sepa-rate disease entities. However, because a single absence of cytogenetic abnormality, it requires cytopenia(s) of
biologic or genetic marker that reliably identifies all or most at least 6 months’ duration and the exclusion of poten-tial
cases of MDS has not yet been discovered, bone marrow reactive causes. In cases characterized by anemia and
morphologic assessment remains the most important tool dyserythropoiesis, conditions such as megaloblastic anemia
for classifying the majority of cases of MDS. and congenital dyserythropoietic anemia must be carefully
Although concordance in the diagnosis of MDSs is gen- excluded. In general, RA can be considered as a “low-grade”
erally reported to be approximately 80%, this only applies to MDS with median survival in the range of 6 to 7 years and
cooperative clinical trials. Outside this setting, concordance only 5% to 10% of cases progressing to overt acute leukemia.
292 Am J Clin Pathol 2009;132:290-305 © American Society for Clinical Pathology
292 DOI: 10.1309/AJCPRCXX4R0YHKWV
AJCP / SHP/EAHP Workshop

❚Table 1❚
Summary of Findings in the Revised (2008) World Health Organization Classification of MDSs

Disease Blood Findings Bone Marrow Findings


*†
Refractory cytopenia with Cytopenia ; no or rare blasts (<1%); monocytes, Dysplasia (≥10%) in 1 lineage only; <5% blasts;
  unilineage dysplasia   ≤1,000/µL (1 × 10 /L)
9
  <15% ring sideroblasts
  (RA, RN, RT)
9
RARS Anemia; no blasts; monocytes, ≤1,000/µL (1 × 10 /L) Erythroid dysplasia only; <5% blasts; ≥15% ring
sideroblasts

Refractory cytopenia with Cytopenia(s); no or rare blasts (<1%) ; monocytes, Dysplasia in >10% of the cells of ≥2 myeloid lineages;
  multilineage dysplasia   9
≤1,000/µL (1 × 10 /L); no Auer rods

  <5% blasts; <15% ring sideroblasts; no Auer rods
RAEB-1 Cytopenias; <5% blasts ; monocytes, ≤1,000/µL Unilineage or multilineage dysplasia; 5%-9% blasts;
9 § §
(1 × 10 /L); no Auer rods no Auer rods
RAEB-2 Cytopenias; 5%-19% blasts; monocytes, ≤1,000/µL Unilineage or multilineage dysplasia; 10%-19% blasts;
9
(1 × 10 /L); Auer rods +/– Auer rods +/–
MDS with isolated del(5q) Anemia; usually normal or slightly increased platelets; Normal to increased megakaryocytes with hypolobated
<5% blasts; no Auer rods nuclei; <5% blasts; del (5q) is sole cytogenetic
abnormality; no Auer rods

MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB, RA with excess of blasts; RARS, RA with ring sideroblasts; RN, refractory neutropenia; RT, refractory
thrombocytopenia.
*
Bicytopenia may be occasionally observed.

Cases with unilineage dysplasia and pancytopenia are classified as MDS, unclassifiable.
‡If the marrow blast percentage is <5% but there are 2%-4% myeloblasts in the blood, the diagnostic classification is RAEB-1. If the marrow blast percentage is <5% and

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there are 1% myeloblasts in the blood, the case should be considered MDS, unclassifiable.
§
Cases with Auer rods and <5% blasts in the blood and <10% in the marrow should be classified as RAEB-2.

RN and RT are very rare and likely account for fewer than 3 9
than 1,000 × 10 /µL (1,000 × 10 /L), and the differential
1% to 2% of all MDS cases; extreme caution should be used diagnosis between RARS and a myeloproliferative disorder
in making such diagnoses. such as essential thrombocythemia becomes problematic. If the
3 9
platelet count is 450 × 10 /µL (450 × 10 /L) or greater and the
Refractory Anemia With Ring Sideroblasts
megakaryocytes have features of those described in the MPNs,
RARS is an MDS characterized by unexplained anemia, an analysis for a JAK2 mutation is indicated. Most of these
morphologic dysplasia of the erythroid lineage, and ring cases may be assigned to the provisional entity of RA with ring
sideroblasts constituting 15% or more of the erythroid precur- 30
sideroblasts and thrombocytosis, which is cur-rently
sors. There is no significant granulocytic or megakaryocytic considered within the MDS/MPN group.
dysplasia (<10%). Anemia is the principal finding. The RBCs
often exhibit a “dimorphic” pattern of normochromic and Refractory Cytopenia With Multilineage Dysplasia
hypochromic cells, but macrocytosis is frequently observed as This subcategory is an addition in the WHO classifica-
well. The criteria are similar to those described for RA, except tion of MDSs that was not recognized in the FAB system,
that in the bone marrow, ring sideroblasts account for 15% or and its identification has improved the prognostic useful-
more of the erythroid precursors. ness of the morphologic classification of MDSs.
31-38
RARS is a low-grade process. In most series, it is reported
RCMD is characterized by 1 or more cytopenias in the
to have the best prognosis and lowest rate of conver-sion to
peripheral blood and dysplastic changes in 2 or more of the
AML of all MDS subtypes. A median survival of 7 to 9 years
myeloid lineages: erythroid, granulocytic, and/or
or longer is commonly reported, and the conversion rate to
megakaryocytic. There are fewer than 1% blasts in the
acute leukemia is less than 5%. It must be remembered that
blood and fewer than 5% in the bone marrow. Auer rods are
ring sideroblasts can be found in any of the subsets of MDSs
not found. If 15% or more of the erythroid precursors are
and also in AML. Furthermore, they may be seen in
ring sideroblasts the designation of RCMD with ring
nonneoplastic diseases as well. In some cases, such as in the
sideroblasts can be made, although reportedly there is no
Pearson syndrome, ring sideroblasts result from abnor-malities
significant prognostic impact if ring sideroblasts are found.
(mutation or deletion) of mitochondrial DNA that is important
Cases that meet the criteria for RCMD but that have
29
in regulating iron metabolism. Whether some patients persistently 1% blasts in the blood should be considered
diagnosed with RARS who have no evidence of a cytogenetic MDS, unclassifiable, and those with multilineage dysplasia
abnormality may have ring sideroblasts due only to and fewer than 5% blasts in the bone marrow but 2% to 4%
mitochondrial DNA abnormalities and no clonal genomic blasts in the blood should be classi-fied as RAEB-1.
abnormalities is not clear. In rare patients, the platelet count is Patients with RCMD have a worse outcome (reported
3 9
elevated (≥450 × 10 /µL [450 × 10 /L]), sometimes to more
median survival of 17-33 months) than patients with RA.

© American Society for Clinical Pathology Am J Clin Pathol 2009;132:290-305 293


293 DOI: 10.1309/AJCPRCXX4R0YHKWV 293
Orazi and Czader / MyelodysplaStic Syndromes

Refractory Anemia With Excess of Blasts cases with persistent cytopenias lacking diagnostic morpho-
RAEB is an MDS with 5% to 19% blasts in the bone mar- logic features of MDSs (<10% dysplastic cells in any
row or blood. However, if there are fewer than 5% blasts in the lineage) but with cytogenetic abnormalities considered as
bone marrow, the finding of 2% to 4% blasts in the periph-eral presumptive evidence of an MDS.
blood is sufficient for the diagnosis of RAEB-1. Two
subcategories are recognized: RAEB-1, defined as having 5%
to 9% blasts in the bone marrow or 2% to 4% in the blood, and Prognostic Considerations
RAEB-2, when blasts are 10% or more in the marrow and/or MDSs display impressive clinical heterogeneity run-ning
5% or more in the blood. Patients with RAEB-2 have worse the gamut from an indolent disease with a near-normal life
survival and a higher rate of disease transformation to AML. expectancy to an aggressive malignancy overlapping with
RAEB is a serious disorder, regardless of whether it transforms AML. Following the original 1982 FAB classification
17
to overt acute leukemia. The median survival time is less than scheme, various additional systems have been proposed to
2 years in most series, and although 30% to 40% of patients improve prognostic predictive power in MDSs. In 1997,
develop overt acute leukemia, more will die of the 11
Greenberg et al developed the International Prognostic
complications of neutropenia, thrombocytopenia, or anemia Scoring System, based on bone marrow blast percentage,
than of acute leukemia. Median survival time for RAEB-1 is prognostically relevant cytogenetic abnormalities, and num-ber
approximately 18 months vs 10 months for RAEB-2. of cytopenias. In 2001, the FAB guidelines were revised, and

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their updated version was integrated into the WHO clas-
MDS Associated With an Isolated del(5q) 1,28
sification system, which is currently in use worldwide.
Chromosomal Abnormality
More recently, transfusion dependency has been shown to have
This subtype of MDS is characterized by anemia with or a significant effect on survival of patients with MDSs. The
without other cytopenias and a sole cytogenetic abnormality of integration of transfusion dependency within the WHO system
del(5q). Myeloblasts constitute fewer than 5% of nucleated has produced the so-called WHO classification–based
bone marrow cells and fewer than 1% of peripheral blood 19
prognostic scoring system.
leukocytes. Auer rods are not seen. An interstitial deletion of
the long arm of chromosome 5 is common in MDSs. Among
cases with isolated del(5q), it is important to distinguish a The MDS Section of the Workshop
unique clinicopathologic entity of the 5q– syndrome seen The 2007 Society for Hematopathology/European
predominantly in older women. This syndrome is character- Association for Haematopathology Workshop on Myeloid
ized by macrocytic anemia, normal or elevated platelet count, Neoplasms and Mastocytosis included a total of 16 cases in the
megakaryocytes with monolobated or hypolobated nuclei,
MDS section. This section illustrated important diagnostic
fewer than 5% blasts, and a relatively good prognosis. An
issues in relation to MDSs and included cases of the disease
approximately 10- to 15-Mb commonly deleted region at 5q31
associated with isolated del(5q) chromosomal abnormal-ity,
39
has been established. There are several other regions that are including the “classical” 5q– syndrome and other MDS entities
deleted in patients with other types of MDS and AML, but with isolated del(5q). Other issues raised by submit-ted cases
deletions between bands 5q21 and 5q32 are limited to this included cytogenetic abnormalities (other than 5q
syndrome. The critical gene(s) in this syndrome may thus be abnormalities) seen in MDSs, the role of cytogenetics on its
different from the genes associated with deletions of 5q found own in diagnosing MDSs, and problems in relation to the
in other types of MDSs or AML. Recently, a defect in ribo- differential diagnosis of MDS vs rare subtypes of AML,
somal protein function due to haploinsufficiency of RPS14 has particularly acute panmyelosis with myelofibrosis and eryth-
7,40
been implicated in the pathogenesis of the 5q– syndrome. roleukemia. The association and eventual relation of MDSs
Patients with isolated del(5q) have a very favorable response to with paroxysmal nocturnal hemoglobinuria (PNH), AA, and
the drug lenalidomide.
12 other nonneoplastic disorders were also illustrated by several
cases and addressed in the discussion. The main topics and the
MDS, Unclassifiable
cases that illustrated them are summarized herein.
This subtype encompasses cases that do not fit easily into the
other categories of MDS. Three possible situations that qualify for MDS Associated With Isolated del(5q) and the
this diagnosis include (1) cases that fit the criteria for a diagnosis Association of del(5q) With Other Conditions
of refractory cytopenia with unilineage dysplasia or RCMD but in Isolated deletions of the long arm of chromosome 5,
which a percentage of 1% blasts in the blood is found on at least 2 del(5q), are observed in 10% of MDSs. They are associated
occasions, (2) MDS with morpho-logic unilineage dysplasia with a more favorable prognosis, although the clinical course
associated with pancytopenia, and (3) varies considerably. If 1 or more additional chromosomal
294 Am J Clin Pathol 2009;132:290-305 © American Society for Clinical Pathology
294 DOI: 10.1309/AJCPRCXX4R0YHKWV
AJCP / SHP/EAHP Workshop

aberrations are present, the overall survival is significantly shorter. detected only in granulocytes, while trisomy 12 was detected only
Case 141 illustrated a classic example of 5q– syndrome with a in lymphocytes ❚Image 1C❚ . The coexistence of an MDS and
typical clinical picture and morphologic findings. chronic lymphocytic leukemia is rare. In a large series, only 1% of
The workshop included 2 cases that demonstrated the association the untreated patients diagnosed with MDS had also a B-cell
41
between the occurrence of an MDS with isolated del(5q) and lymphoid malignancy. The association is most likely merely coincidental.
neoplasms. Case 36 illustrated a patient with a long history of chronic In patients with chronic lymphocytic leukemia previously treated
lymphocytic leukemia, later given a diagnosis of an MDS with an with alkylating agents, a secondary MDS may be observed,
isolated 5q– abnormal-ity. The bone marrow morphologic findings, although its occurrence is also uncommon despite extensive use of
42
which included a multinodular/interstitial small lymphoid cell alkylating agents in this condition. Case 85 illustrated the
infiltration and predominance of monolobated megakaryocytes are association of a plasma cell dyscrasia and an MDS, the latter
shown in ❚Image 1A❚ and ❚Image 1B❚ . By FISH, the 5q– associated with isolated del(5q). The bone marrow showed the
abnormality was presence of the typical nonlobated
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B

D
A

C
❚Image 1❚ (Case 36) Coexistent chronic lymphocytic leukemia and myelodysplastic syndrome with 5q–. A, Lymphoid
aggregate in a background of hypercellular bone marrow. B, Prominent monolobated megakaryocytes. Fluorescence in situ
hybridization showing loss of long arm of chromosome 5 (C) in myeloid cells and trisomy 12 in a proportion of mononuclear
cells with round nuclei (D). Contributed by J. Sidhu.

© American Society for Clinical Pathology Am J Clin Pathol 2009;132:290-305 295


295 DOI: 10.1309/AJCPRCXX4R0YHKWV 295
Orazi and Czader / MyelodysplaStic Syndromes

megakaryocytes ❚Image 2A❚ associated with an increased by flow cytometry at 8.4% of bone marrow cells) that were
num-ber of plasma cells, which could also be appreciated by positive for CD34, CD7, CD33, HLA-DR, CD22, CD123, and
their positivity on CD138 immunostaining ❚Image 2B❚ . By CD135; had heterogeneous CD38 expression; and were nega-
flow cytometry, plasma cells expressed CD56 antigen. tive for CD19, CD10, terminal deoxynucleotidyl transferase,
Case 7, submitted by Gerald Penn, MD, illustrated the CD13, CD117, and CD56. No response to lenalidomide was
coexistence of MDS (RCMD type) and plasma cell observed in this case. In AML, a 5q deletion is usually
myeloma. Most of the cases reported previously in the lit- associated with a complex karyotype and is also associated
erature included plasma cell myeloma, in which MDS was 46
43
with poor outcomes following treatment. However, a small
diagnosed after chemotherapy. These were considered as proportion of patients with a single del(5q) aberration and no
clonally unrelated processes: the MDS was thought to be antecedent hematologic disorder seem to have the same out-
secondary to treatment with alkylating agents. The risk of 47
both diseases has been estimated to be 10% to 20% after 10 come as patients with a normal karyotype.
43,44
years. Increased risk of secondary disease has been also MDS Diagnosed by Cytogenetics Alone and Other
reported in patients who received bone marrow trans- Cytogenetic Abnormalities Seen in MDS and Their
45 Prognostic Value
plantation (usually also pretreated with chemotherapy).
Less common are cases unrelated to therapy like the 2 cases Occasionally, one is confronted with patients who have
presented in the workshop (cases 7 and 85). persistent cytopenia (usually anemia) for which no underly-ing

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In cases like these, in which no prior treatment is cause can be found but in whom there is insufficient
involved, the plasma cell tumor and MDS may arise from a morphologic evidence to support the clinical suspicion of an
common stem cell, which may be characterized by a MDS. For some of these patients, a “working diagno-sis” of
common clonal cytogenetic abnormality. In this context, idiopathic cytopenia of unknown significance may be
44 48
Nilsson et al reported a case of monoclonal gammopathy considered, although it is important to point out that this is
of uncertain significance with del(20q) demonstrated by not synonymous with a diagnosis of MDS. In such cases, it is
FISH to be present in CD34+/CD38– (hematopoietic stem necessary to explore every possible cause for the cytopenia(s)
cells), CD34+/CD38+ (progenitors), CD19+ (B cells), and and to rule out disorders such as autoimmune disorders,
CD15+ (myeloid cells), suggesting that del(20q) might arise lymphoproliferative diseases (particularly large granular
at a multipotent progenitor/stem cell level. lymphocyte proliferations and hairy cell leukemia),
A different problem was illustrated by case 61, which was hypothyroidism and other endocrinopathies, and infections.
thought to represent a pediatric high-grade MDS associ-ated Immunohistochemical studies on biopsy specimens may
with an isolated del(5q). The marrow flow cytometry ❚Image reveal an increase in the number of blasts that was not appre-
3❚ showed a pathologic population of blasts (estimated ciated previously, and they should always be performed.
2016
B
A
❚Image 2❚ (Case 85) Myelodysplastic syndrome with isolated del(5q) and plasma cell dyscrasia. A, Typical monolobated
megakaryocytes. B, Clusters of plasma cells highlighted by CD138 immunohistochemical stain. Contributed by G. Penn.
296 Am J Clin Pathol 2009;132:290-305 © American Society for Clinical Pathology
296 DOI: 10.1309/AJCPRCXX4R0YHKWV
AJCP / SHP/EAHP Workshop

Cytogenetic studies are strongly indicated in such cases, and absence of significant dysplasia, a clonal cytogenetic abnor-
FISH may show a clonal abnormality when karyotype mality of uncertain clinical significance. The current revision
studies do not. of the WHO classification states that “Cases with chromo-
If a clonal cytogenetic abnormality is found, the diag- somal abnormalities compatible with a MDS associated with
nosis of MDS becomes more likely, and indeed, if an MDS- strong presumptive clinical evidence of a MDS but in which
associated abnormality is present, a presumptive diagnosis dysplastic features are <10% of cells in one (unilineage) or
of MDS can be made. Still, such patients should be 28
more (multilineage) of the cell lineages” are classified as
followed up carefully for morphologic evidence of MDS, unclassifiable. Of note, trisomy 8, del(20q) and dele-
dysplasia before an unequivocal diagnosis can be made. tion of the Y chromosome, even though occurring frequently,
Case 158, submitted by Dong Chen, MD, is an example of are not diagnostic of an MDS in the absence of morphologic
such a case in which the marrow karyotype showed, in the features of this disease. Similarly, the t(1;21) anomaly seen in
O
r
A
1,024 1,024 1,024
c
768 768 768
a

SSC -H
SSC -H

SSC -H
512 512 512 C

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256 256 256
M
0 0 0 D
100 101 102 103 104 100 101 102 103 104 100 101 102 103 104 A
CD45 APC GPA PE CD14 TRI
b
104 104 104
A
103 103 103
0CD2PE

2CD2PE

8CD3PE
102 102 102

101 101 101


0 0
10 10 100
100 101 102 103 104 100 101 102 103 104 100 101 102 103 104
CD19 CY5 CD34 FITC CD34 FITC

B
104 104 104
CD13FITC

CD123PE
CD33PE

103 103 103


101 101 101

2 2
10 10 102

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100 100 100
100 101 102 103 104 100 101 102 103 104 100 101 102 103 104
HLA-DR PerCP CD11b PE CD65 FITC

104 104 104

103 103 103


CD133APC

CD45 APC
CD2 PE

102 102 102

101 101 101


100 100 100
100 101 102 103 104 100 101 102 103 104 100 101 102 103 104
CD135 PE CD7 FITC CD4 PE

❚Image 3❚ (Case 61) Pediatric high-grade myelodysplastic syndrome. A, Scattergrams demonstrating aberrant
blast population positive for CD34 (8.4% of bone marrow cells), CD38, and CD22. B, Blasts were positive for
CD33, CD11b, CD65, CD123, CD135, and CD7 with low-density expression of CD4. APC, allophycocyanin; CY5,
cyanin 5; FITC, fluorescein isothiocyanate; GPA, glycophorin A; PE, phycoerythrin; PerCP, peridinin chlorophyll
protein; SSC-H, side scatter height; TRI, Tri-Color. Contributed by A. Porwit.

© American Society for Clinical Pathology Am J Clin Pathol 2009;132:290-305


297 DOI: 10.1309/AJCPRCXX4R0YHKWV
❚Image 5❚ (Case 161) Refractory cytopenia with multilineage dysplasia and ring sideroblasts in a case with del(20q). A,
Prominent erythroid dysplasia and rare dysplastic granulocytic precursors. B, Iron stain highlights ring sideroblasts.
Contributed by F. Kreisel.
298 Am J Clin Pathol 2009;132:290-305 © American Society for Clinical Pathology
298 DOI: 10.1309/AJCPRCXX4R0YHKWV
AJCP / SHP/EAHP Workshop

biopsy (CD34 immunohistology is particularly helpful) than acute myeloid leukemia associated with a fibrotic bone mar-
in the aspirate, the latter being frequently suboptimal owing 22
row. Classic myeloproliferative neoplasms, such as primary
to the presence of myelofibrosis. Only rare cases of RA with myelofibrosis (chronic idiopathic myelofibrosis), can be usu-
fibrosis have been reported. These cases seem to share the ally easily distinguished by their characteristic morphologic
poor prognosis associated with the RAEB with fibrosis features (eg, large to giant megakaryocytes with cloud-like
subtype. nuclei) and by the presence of significant splenomegaly and
57,58
Often, cases of MDS-F have prominent megakaryopoi- the lack of an abrupt presentation. Patients with MDS-F
esis, which is characterized by a wide spectrum of sizes of have an unfavorable prognosis mainly attributable to compli-
megakaryocytes, ranging from micromegakaryocytes to cations related to pancytopenia and continuous transfusions,
enlarged forms. The antibodies reactive with with a life expectancy of 9.6 months, compared with 17.4
megakaryocytic antigens (eg, CD42b and CD61) can be 52
months in MDS without fibrosis.
used to facilitate the detection of the small dysplastic forms An additional diagnostic problem was demonstrated by
(micromegakaryocytes in particular) and to confirm the case 165. This case illustrates the difficulties encountered
51
increased number of mega-karyocytes. when attempting to separate RAEB-2 from acute erythroid
The differential diagnosis of MDS-F includes several leukemia. Although by the strict adherence to WHO criteria the
other myelofibrotic myeloid neoplasms. The differential diag- case can be considered RAEB-2, the acute presentation,
nosis between MDS-F and acute panmyelosis with myelofi- complex underlying karyotype, and, above all, the increased

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brosis (APMF) was illustrated by cases 75 and 191 ❚Image numbers of pronormoblasts ❚Image 8A❚ and ❚Image 8B❚ ,
6❚ and ❚Image 7❚ . Both cases were eventually considered confirmed by immunohistochemical analysis ❚Image 8C❚
examples of MDS-F, specifically as RAEB-2 with fibrosis. and flow cytometry, raised the issue of transformation to acute
Clinically, APMF usually manifests with an abrupt onset erythroid leukemia (pure erythroid subtype). The WHO cri-
with fever and bone pain and runs a very aggressive course. teria for acute erythroid leukemia can be summarized as fol-
Morphologically, the marrow shows marked fibrosis (≥2 lows: if the overall percentage of blasts is 20% or more, the
according to the Manoharan grading system), severe trilineage diagnosis is AML; if there are fewer than 20% total blasts and
dysplasia associated with numerous dwarf megakaryocytes,
the erythroid precursors are 50% or more of all cells, the dif-
and an increased number of blasts. Based on bone marrow
ferential count of nonerythroid cells should be calculated. If
biopsy, a median blast value of 22.5% (range, ~20%-25%) was
56 blasts are fewer than 20% of nonerythroid cells, the diagnosis
reported. Most of the blasts express CD34 and are nega-tive is usually RAEB-2. If blasts are 20% or more of nonerythroid
56
for megakaryocyte-associated markers. cells, the diagnosis is erythroleukemia (erythroid/myeloid-
The differential diagnosis of APMF includes, besides M6a). Even less reproducible is the separation with the pure
MDS-F, acute megakaryoblastic leukemia and other types of erythroid leukemia subtype of acute erythroblastic leukemia
❚Image 6❚ (Case 75) Features of myelodysplastic syndrome ❚Image 7❚ (Case 191) Rapid clinical progression and
with fibrosis, including significant dysmegakaryopoiesis. morphologic features compatible with acute panmyelosis
Contributed by C. Montalvo. with myelofibrosis. Contributed by R. Gupta.

© American Society for Clinical Pathology Am J Clin Pathol 2009;132:290-305 299


299 DOI: 10.1309/AJCPRCXX4R0YHKWV 299
Orazi and Czader / MyelodysplaStic Syndromes

(M6b), which was the alternative diagnostic consideration in Hypoplastic MDS (h-MDS) is more frequent in women
this case. However, since there is an extensive overlap in cyto- and occurs with an age-related frequency similar to that seen in
genetics between RAEB-2 and acute erythroblastic leukemia, it nonhypoplastic cases. Previous genotoxic exposure or therapy
is uncertain if the distinction is clinically meaningful. needs to be excluded because hypocellular marrows can also
64
be seen in cases of therapy-related MDS. Generally, h-MDS
The Association and Eventual Relation of MDSs, is associated with pronounced cytopenias, a finding that may
Particularly Hypoplastic MDSs, With PNH, AA, suggest a diagnosis of acquired AA.
and Pure Red Cell Aplasia The diagnosis may be difficult, largely because fatty bone
The marrow cellularity is normal or increased for age in marrows usually produce poor quality aspirates. A careful
90% of patients with MDS but is hypocellular in about 5% to inspection of peripheral blood smears and bone marrow touch
1,11,59-62
10% of the cases. Hypocellularity is defined as bone preparations together with a detailed analysis of adequately
marrow cellularity of less than 30% in a patient younger than representative bone marrow biopsy sections cannot be over-
63
60 years or less than 20% in patients older than 60 years. In emphasized. In this diagnostic context, megaloblastic features
MDS, rarely the cellularity falls below 10%, which is in alone have insufficient specificity to establish a diagnosis of
contrast with what is regularly seen in cases of severe AA. MDS because megaloblastic features and macrocytosis are
However, in these rare cases of MDS with markedly fatty mar- common findings in AA as well. According to the FAB criteria,
row, the distinction from AA may be at times impossible. most cases of hypoplastic MDS can be classified

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C ❚Image 8❚ (Case 165) Features overlapping between refractory
anemia with excess blasts-2 and acute myeloid leukemia,
French-American-British type M6b. A, Significant erythroid
predominance with dyserythropoiesis. B, Bone marrow biopsy
showed 100% cellularity with erythroid predominance and
granulocytic and megakaryocytic dyspoiesis. C, Erythroid
predominance confirmed by glycophorin immunostain.
Contributed by S. Sasu.
300 Am J Clin Pathol 2009;132:290-305 © American Society for Clinical Pathology
300 DOI: 10.1309/AJCPRCXX4R0YHKWV
AJCP / SHP/EAHP Workshop

60
as RA (66.7% in 1 series). The presence of 20% or more 103
U 1,023 V
myeloblasts in a hypocellular marrow rules out MDS in favor

CD15PC5
2
100

FSLin
of hypocellular AML. Dysplastic features other than dyseryth- 10
ropoiesis occur less frequently in hypoplastic MDS and/or are 101
of lower grade in comparison with normocellular to hypercel-
lular MDS. Because the patients do not have an increased pro-
portion of blasts in the aspirate or in the bone marrow biopsy 0 1,023 00 1,023
specimen, the separation from AA by morphologic criteria SS Lin SS Lin
alone may be problematic. This is further compounded by the
103 X1 X2 103 X1 X2
high proportion of cases showing a mesenchymal reaction, 2 2
10 10
especially an increase in the number of mast cells and reactive

PE

PE
AA
lymphoid follicles, features similar to those observed in bone 101 101 X3

CD16

CD55
X4
X3 X4 AA
marrow biopsies obtained from patients with AA. Despite all of
0 10 0

this, the differential diagnosis is still principally based on bone 10 1.1% 0.7%
marrow histologic and immunohistologic features. Within the 0 1 2 3 0 1
10 10 10 10 10 10 102 103
context of a markedly hypocellular bone marrow, the detection
CD66b FITC CD59 FITC
of “residual” megakaryopoiesis, particularly in association with

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dysmegakaryopoiesis, and the presence of dysgranulopoiesis ❚Image 9❚ (Case 131) A small paroxysmal nocturnal
(the latter in peripheral blood or marrow smears/touch hemoglobinuria clone (1% granulocytes negative for CD55,
preparations) support the diagnosis of h-MDS. If reticulin CD59, CD16, and CD66b) in a patient with refractory
fibrosis is detected, this would also favor h-MDS. anemia with multilineage dysplasia. FITC, fluorescein
Immunohistochemical analysis can help in distinguish-ing isothiocyanate; FS, forward scatter; Lin, linear; PC5,
h-MDS from acquired AA, the former disorder being
phycoerythrin–cyanin 5; PE, phycoerythrin; SS, side
characterized by higher CD34 expression as compared with the
scatter. Contributed by O. Pozdnyakova.
60-62
latter. Flow cytometry has shown similar findings in
65
relation to CD34+ cells. Finally, bone marrow cellular-ity
does not appear to be an important prognostic factor in MDSs
because patients with h-MDS have been shown to have a study of patients with PNH has shown that in this condition,
prognosis similar to that of patients with MDS with cytogenetically abnormal clones are not necessarily malignant
71
normocellular or hypercellular marrows. The distinction from and may not be predictive of evolution to leukemia.
AA, however, is significant because the risk of progression to Distinctively uncommon is the association between
acute leukemia is much greater in h-MDS than in the former MDS and pure red cell aplasia, as shown by case 124,
66 submitted by Gang Yue, MD. The incidence of this
disease. Cytogenetic studies may be of particular value in
this group as abnormalities of chromosomes 5 and/or 7 are 72
association is prob-ably underestimated. Pure red cell
frequently observed in hypocellular MDSs. The presence of aplasia may rarely be simulated by the presence of a 5q–
other cytogenetic abnormalities (eg, trisomy 8) may not be abnormality, which should always be excluded. Although
discriminatory because it can also be observed in AA. an immunologic basis (simi-lar to hypoplastic MDS) had
From a pathogenetic standpoint, however, it is important been hypothesized, the precise pathogenetic mechanism is
to stress that AA and MDSs have a number of overlapping unknown. Therapy with steroids does not help, and patients
67,68
features, such as the appearance of a clone of PNH cells are often candidates for immuno-suppressive treatment.
and evidence of T cell–mediated myelosuppression that may
respond to immunosuppressive therapy, suggesting that, at least Other Reactive Conditions
in a proportion of cases, they share a common Morphologic myelodysplasia does not necessarily trans-
69,70
pathophysiologic mechanism. Case 131 represented an late into a diagnosis of MDS. Vitamin B 12 and folic acid defi-
example of an MDS, a case of RCMD, associated with a PNH ciencies lead to megaloblastic changes and often severe dys-
clone ❚Image 9❚ . It is important to remember, however, that erythropoiesis, and such deficiencies must always be excluded
abnormal morphologic bone marrow features reminiscent of before making a diagnosis of MDS, particularly RA. Heavy
MDS are not uncommon in PNH marrows, and some of the metal intoxication, particularly arsenic poisoning, and copper
cases of MDS with associated PNH clones may not repre-sent deficiency can induce marked and sometimes truly bizarre
an MDS. The presence of a karyotype abnormality may help in morphologic abnormalities in the erythroid and granulocytic
establishing the diagnosis of MDS in this context. However, 73,74
series. A number of drugs and medications, ranging from
caution should be used here, too. A relatively large alcohol to growth factors, can also induce myelodysplastic

© American Society for Clinical Pathology Am J Clin Pathol 2009;132:290-305 301


301 DOI: 10.1309/AJCPRCXX4R0YHKWV 301
Orazi and Czader / MyelodysplaStic Syndromes

features. Congenital dyserythropoietic anemia may be diffi-cult HIV infection. Chronic parvovirus, Epstein-Barr virus, and
75 cytomegalovirus infections have been associated with cytope-
to distinguish from RA. In each case with morphologic
dysplasia, it is important to consider other possibilities. nias and an array of dysplastic features in immunocompro-
In general clinical practice, it is important to remember mised and nonimmunocompromised patients.
that anemia associated with a high mean corpuscular volume Hemophagocytosis can rarely produce marrow changes
and a low reticulocyte count may be seen in patients with that resemble those seen in MDS. Case 115 was an example
hypothyroidism or liver failure. In most of these cases, the of hemophagocytic lymphohistiocytosis (HLH) in a patient
anemia is macrocytic but not megaloblastic, and the only with a history of a low-grade MDS. Although the morpho-
feature similar to MDS is usually the presence of macrocy- logic findings were considered compatible with HLH
tosis. Among the conditions associated with anemia and with
❚Image 10❚ , the diagnosis of MDS was not well
other cytopenias most commonly seen in clinical practice, it is
substantiated. The distinction between HLH and MDS can
worthwhile mentioning autoimmune diseases (these can also
be difficult owing to overlapping symptoms of
cause myelofibrosis, an occurrence termed autoim-mune
pancytopenia. Clinically, HLH can be mistaken, especially
myelofibrosis) and other hematopoietic neoplasms, eg,
in pediatric patients, for acute leukemia or an aggressive
lymphomas, and nonhematopoietic malignancies causing
paraneoplastic myelodysplasia. All of these can, to a certain
MDS. Bone marrow changes morphologically mimicking
77-79
extent, mimic the presentation of MDSs. MDSs in patients with HLH have also been reported.

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1
Viral disorders, particularly HIV infection, may be asso- From the New York Presbyterian Hospital, Weill Cornell
2
ciated with myelodysplastic features. In HIV infection, like in Medical Center, New York, NY; and Department of Pathology
MDS, cytopenias are common and the marrow is often hyper- and Laboratory Medicine/Clarian Pathology Laboratory,
Indiana University School of Medicine, Indianapolis.
cellular. Dyserythropoiesis is the most frequently reported
myelodysplastic change and has been described in up to 70% Address reprint requests to Dr Orazi: New York Presbyterian
of patients with HIV infection, but dysmegakaryopoiesis and Hospital, Weill Cornell Medical Center, 525 E 68th St, Starr
dysgranulopoiesis have also been described. These cases may Pavilion ST-702-B, New York, NY 10065.
also show some fibrosis. However, the presence of cellular
debris in association with an increased number of plasma cells
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© American Society for Clinical Pathology Am J Clin Pathol 2009;132:290-305 305
305 DOI: 10.1309/AJCPRCXX4R0YHKWV 305

Sindroma Mielodisplasia

Abstrak

Sesi 4 dari 2007 Workshop of the society for Hematopathology/Euroean Association for

Haematopathology telah berperan dalm sindroma mielodisplasia (MDS). Kasus yang diberikan

menggaris bawahi pada isu penting dan kesulitan dalam hubungan terhadap diagnosis dan klasifikasi

MDS. Banyak dari diskusi berfokus pada korelasi, atau kurang dari itu, antara pemeriksaan morfologi

dan teknik diagnostik lainnya, sebagiannya adalah cytogenetic. Kasus meliputi contoh dari kelainan

kromosom del(5q) yang di isolasi, meliputi “clasical” 5q-syndrome dan neoplasma myeloid lainnya.

Ditujukan juga tentang kelainan cytogenetic lainnya pada MDS dan peran dari cytogenetics dalam

mendiagnosis MDS. Khususnya tantagan dalam identifikasi secara benar dari subtipe fibrotik dari MDS

dan pemisahan mereka dari subset leukimia myeloid akut dengan myelofibrosis seperti pada

panmyelosis akut degan myelofibrosis. Hubungan dan relasi kejadian pada MDS (hipoplassia pada

sebagain) dengan anemia aplastik, paroxysmal nocturnal hemoglobinuria dan kelainan non neoplastik

lainnya.

Penangnan cytogenetic dan molekular genetik terbaru tampaknya merevolusi klasifikasi dari

MDS. Namun, tampaknya bahwa teknik terbaru ini dapat cocok, untuk tujuan pengobatan. Minimal
untuk alasan masa depan, diagnosis MDS membutuhkan integrasi dari morfologi, imunofenotipe, dan

gambaran genetik pada riwayat pasien dan manifestasi klinis.

Sindroma mielodisplasia merupakan kelainan hematopoietic stem cell di karakteristikkan oleh

ketidakefektifan hematopoiesis yang menyebabkan kegagalan bone marrow dan dapat menyebabkan

akut mieloid leukimia (AML).

Etiologi dan Patogenesis

Etiologi MDS tidak diketahui. Hubungan dari MDS dengan peningkatan usia menunjukkan

kerusakan genetik yang diseabkan oleh paparan berbahaya atau kerentanan yang diturunkan. Faktor

risiko diantaranya adalah papran terhadap benzen dan larutan lainnya, bahan bakar diesel, merokok, dan

imunosupresi. Terapi kemoterapi dan radiasi dihubungkan dengan MDS yang dihubungkan dengan

terapi (terdapat pada artikel terpisah). Patofisiologi MDS merupakan hal yang rumit dan melibatkan

kelainan dalam regulasi dari proliferasi, pematangan, dan survival selular.

Pada AML, terdapat dukungan penyebaran untuk konsep bahwa perkembangan ini

membutuhkan minimal gangguan 2 gen somatik: satu mutasi terhadap kecepatan augmentasi proliferasi

selular atau survival sel (mutasi kelas I), biasanya secara konstitutif mengaktivasi tyrosine kinase atau

anggota keluarga RAS, dan mutasi lainnya yang menggangu diferensiasi selular normal (mutasi kelas

II), biasanya deregulasi faktor hematopoeitic transkripsi ata transkripsional koaktivator, seperti anggota

famili homeobox atau komponen dari core binding factor. Pada AML, gangguan somatik jenis tipe ini

meliputi kelainan kromosom rekuren yang dideteksi oleh sitogenetik dan mutasi yang didapat lainnya

seperti TP53, NRAS, KRAS, KIT, PTPN11, CEBPA, CSF1R (C-FMS), NF1, dan BRAF poin mutasi dan

MLL duplikasi sebagian tandem.

Sayangnya, pemahaman kami tentang patologi molekular dari MDS masih lebih primitif

dibandingkan pemahaman kami tentang biologi dari AML. Kehilangan rekuren kromosomal seperti

delesi dari kromosom 5,7, 13 , dan 20 dan kromosom sex atau trisomi 8 sering ditemukan pada MDS;

namun, mayoritas dari mereka masih tidak jelas patogenesisnya. Pengecualian yang ditemukan adalah

kehilangan dari 5q31-33, yang baru-baru ini dihubungkan dengna culprit gene, RPS14, yang

mengenkoding untuk komponen dari 40S ribosomal subunit dan dilibatkan dalam diferensiasi eritroid.
Translokasi reciprocal yang informatif, membuat prognostik relevan mmebuat subgrup pada AML, dan

jarang pada MDS. Hanya beberapa penyusunan ulang dihubungkan dengan MDS yang terjadi ridak

sering yang telah diidentifikasi dan karakteristik lebih lanjut, seperti yang melibatkan 3q26 (yang

bertanggung jawab terhadap zinc finger DNA binding protein, MDS1-EV11), 3q25.1 (regulator p53,

MLF1) dan 1p36 (PDM16, membentuk MEL1, faktor transkripsi zinc finger lainnya). Semua 3 dari

gene terakhir ini di libatkan dalam keseimbangan translokasi, yang di observasi pada kurang dari 5%

pasien dengan MDS. Poin mutasi di deteksi di AML telah berubah menjadi yang jrang pada MDS,

dengan penegcualian delesi dalam mitokondria DNA.

Walaupun keterbatasan ini, kelainan kromosom dalam MDS dapat dideteksi oleh karyotyping

konvensional yang penting secara klinis. Kelainan karyotype dapat membuktikan clonalitas, membantu

menegakkan diagnosis MDS dengan melakukan, seperti reaktif patogenesis. Informasi karyotypic

merupakan prognostik yang berguna, dan, dalam kasus delesi kromosom 5q, pengetahuan tentang

karyotype dapat membantuk dalam memiliki pengobatan psesifik, lenalidomide. untuk mempermudah

deteksi anomali cytogenetic atau genetik, analisis fluorescence in situ hybridization (FISH) dan juga

teknik dasar karyotype ainnya (seperti, spectral karyotyping) dapat berhasil digunakan. Bukti terbaru

menunjukan bahwa resolusi tinggi single-nukleotida polimorfisme Affmetrix (Santa Clara, CA)

genotyping microarrays merupakan teknik yang efektif utnuk mendeteksi cytogenetically cryptic

genomic aberaations. Ini dan penanganan sensitif lainnya dapat memberikan stratifikasi pasien untuk

intervensi pengobatan awal . sejauh ini, namun, pengobatan MDS di arahkan terhadap manifestasi klinis

yang predominan pada individu pasiem dan yang bertanggung jawab trhadap morbiditas yang

dihubungkan dengan penyakit. Pemilihan terapi baru seperti obat yang menginduksi hipometilasi DNA

seperti 5-azacitidine dan 5-aza-2’-deoxycitidine teah menunjukkan hasil yang menjanjikan. Pada defek

genetik intrinsik yang didapat tentang hematopoietic stem cell, proporsi dari pasien dengan MDS

menunjukkkan inhibisi yang dimediasi sel T dalam hal hematopoiesis dan, karena itu, dapat merespon

baik terhadap imunosupresi. Pada kasus ini, MDS berbagi patofisiologi yang serupa dengan acquired

aplastic anemia (AA).

Penegakkan Diagnosis
Penegakkan diagnosis MDS meliputi evaluasi morfologi dari darah perifer, aspirasi marrow, dan

biopsi spesimen bone marrow, di interpretasikan dalam konteks hasil CBC dan informasi klinis yang

adekuat. Seperti yang sebelumnya telah disebutkan, korelasi dengan marrow cytogenetik merupakan hal

yang esensial. Diperlukan untuk penekanan bahwa adnaya karyotype normal tidak mengekslusikan

diagnosis dari MDS. Karyotupe abnormal dapat menunjukkan MDS dalam konteks klinis yang pantas.

Gambaran Morfologi

Walalupun MDS dapat di duga dari riwayat klinis dan hitung darah perifer , diagnosis biasanya

dibuat dengan inspeksi morologi darah perifer, aspirasi bone marrow, dan biopsi spesimen bone

marrow. Klasifikasi French-American-Britisg (FAB) yang sebelumnya digunakan berdasarkan pada

temuan identifikasi keseluruhan dengan analisis cytologic dari pewarnaan smears dari darah perifer dan

aspirasi bone marrow. Kriteria uatama untuk subklasifikasi MDS adalah persentase dari blas pada darah

perifer dan aspirasi bone marrow dan adanya perubahan displastik setidaknya 1 dari 3 sel marrow

utama. Penagangan yang lebih komprehensif merupakan satu-satunya yang digunakan oleh sistem

World Health Organization (WHO) , yang menekankan pentingnya integrasi teknik lainnya seperti

biopsi bone marrow pemeriksaan histologis, cytogenetik, dan molekular genetik, dalam informasi klinis

relevan lainnya. Morfologi displasia tidak sinonim dengan MDS, dan merupakan bagian dari yang

dialamatkan dalam isu “false positif” myelodisplasia, sistem klasifikasi WHO merekomendasikan

bahwa setidaknya 10% sel dalam lineage secara morfologi yang mengalami displastik disebut seagai

displasia dari lineage ini.

Klasifikasi yang digunakan WHO sekarang ini tentang MDS secara prinsip berdasarkan pada

persentase blast dalam bone marrow dan darah perifer dan jenis dan derajat dari displasia. Perluasan

displasia, unilineage vs multilineage, memiliki peran penting dalam subklasifikasi WHO, gambaran

tidak terdapar pada sistem FAB. Adanya ring sedroblast yang dinilai dengan pewarnaan besi. Tidak

munculnya monocytosis (monosit, <1000/µL[1x109/L] dalam darah; tidak ada monositosis dalam bone

marrow [<5% monosit; kisaran normal, 0%-4%]) merupakan hal yang penting untuk membedakan

antara MDS dengan kronik myelomonocytic leukimia, subtipe dari myelodysplastic/myeloproliferative

neoplasma (MDS/MON) yang sebelumnya dimasukkkan kedalam kategori MDS. Monosiit dalam bone
marrow paling baling di apresiasikan dengan menggunakan pewarnaan nonspesific esterase (yang

direkomendasikan adalah α-naphthyl butyrate esterase).

Blasts

Enumerasi blast merupakan hal yang penting untuk mendiagnosis dan klasifikasi MDS, dan

pada pbanyak penelitian, persentase blast merupakan salah satu hal yang paling penting sebagai

indikator prognosis. Ini juga merupakan konponen penting dari sistem skoring prognostik yang

digunakan saat ini seerti pada International Prognostic Scoring System dan sistem skroring prognostik

terbaru yang berdasarkan pada klasifikasi WHO. Blast sebaiknya di enumerasi secara hati-hati dari

smear darah perifer yang telah dipersiapkan dengan baik. Sel imatur di libatkan dalam jumlah blast

meliputi myeloblast-tanpa dan dengan beberapa azurofilik graul-monoblast, dan megakaryoblast.

Promonoctes juga di katakan sebagai “blast equivalents” pada skema klasifikasi WHO. Sel ini , yang

tidak ada pada cytochemistry untuk esterase secara morfologi sulit untuk dibedakan dari promyelocytes

dan early myelocytes jarang ditemuukan pada MDS. Keadaanya menunjukkan diagnosis kronik

myelomonocytic leukimia atau, ada pada peningkatan jumlah blast, AML degan diferensiasi monosit.

Jumlah blast berasal dari smear yang di aspirasi harus secara hati-hati di korelasikan dengan

jumlah dari biopsi. Sering terjadi, pada spesimen bone marow, blast sulit untuk di apresiasi, khusunya

jika terdapat marrow yang fibrosis. Dalam kasus seperti ini, pewarnaan immunohistokimia untuk CD34

anti-gen dapat sangat membantu. Namun, karena tidak semua blast adalah CD34 +, perawatan harus

tidak menggunakan hasil CD34 dalam penilaian morfologi secara hati-hato. Penanda tambahan yang

dapat digunakan untuk memfasilitasi vivibilitas dari CD34-blast (seperti, CD117, lysozyme, CD68).

Myeloperoksidase sering lemaj atau negatif dalam blast yang terlihat dalam MDS. Aliran cytometry

dapat membantu dalam menilai frekuensi dari marrow blast dan untuk mengkonfirmasi immunofenotipe

mereka. Ekspresi abeerant antigen dan kelainan side scatter( granulitas rendah dalam sel granulocytic)

menunjukan secara kasar korelasi dengan keparahan dari MDS.

Klasifikasi MDS

Konsep dari sistem WHO adalah klasifikasi hematopoietic neoplasma harus berdasarkan tidak

hanya pada temuan morfologis tetapi juga pada penggunaan klinis, genetik, immunofenotipe, dan
informasi biologi untuk mendefinisikan pemisahan penyakit. Namun, penanda biologi atau genetik yang

tunggal yang dapat mengidentifikasi semua atau kebanyakan kasus MDS masih belum ditemukan,

penilaian morfologi bone marrow masih merupakan alat yang paling penting untuk mengklasifikasikan

mayoritas kasus dari MDS.

Walaupun kecocokan dalam diagnosis MDS secara umum dilaporkan mencapai 80%, ini hanya

di aplikasikan pada uji klinis yang kooperatif. Diluar kondisi ini, kecocokan pada observer berbeda

sering rendah. Faktor yang bertanggung jawab untuk inkonsistensi dalam mendiagnosis dan klasifikasi

meliputi variabilitas dalam kualitas spesimen, enumerasi blast yang tidak akurat, dan erroenus inklusi

dalam kategori MDS dari kasus dengan nonclonal dysplastic hematopoeisis atau dengna jenis lain dari

myeloid neoplasms (seperti MDS/MPN). Pentingnya evaluasi kritis dari gambaran morfologi dalam

hasil laboratorium lainnya dan infomrasi klinis tidak dapat di tekankan secara berlebih.

Klasifikasi WHO dari sindroma myelodisplastic (2008 Revisi, edisi ke 4) yang baru

dipublikasikan. Klasifikasi yang di update, yang secara besar overlap dengan skema EHO 2001,

perbedaan subtipe MDS sebagai berikut : (1) refractory cytopenia dengan unilineade dysplasia dengan

subkategori dari refractory anemia (RA), refractory neutropenia (R), dan refractory thrombocytopenia

(RT); (2) refractory anemia dengan ring sideroblast (RARS); (3) refractory cytopenia dengan

multilineage dysplasia (RCMD); (4) refractory anemia dengan kelebihan blast (RAEB) dengan

subkategori RAEB-1 dan RAEB-2; (5) MDS, tidak dapat diklasifikasikan; dan gambaran utama dari

subtipe ini dijeaskan dalam paragraf berikut ini dan dirangkum dalam Tabel 1.

Refraktory Cytopenia Dengan Unilineage Dysplasia

Penunjukkan ini meliputi kasus MDS yang bermanifestasi dengan refractory cytopenia yang

dihubungkan dengan dysplasia tang terbatas pada 1 sel line dan meliputi RA dan kasus langka RN dan

RT. Refractory bicytopenia dapat dimasukkan kedalam kategori ini jika ditemani dengan unilineage

displasia, tetapi refraktori pancytopenia yang dihubungkan dengna unilinegae displasia harus

dipertimbangkan sebagai MDS, yang tidak dapat diklasifikasikan.

Keluhan awal, pada banyak kasus, dihubungkan dengan anemia (kasus ini dirancannng dengan

baik sebagai RA). Anemia dapat normositik/normokromik tetapi sering dalam makrositik. Blast tidak
ada pada darah atau muncul kurang dari 1% dari jumlah diferensial, dan mereka kurang dari 5% sel

marrow bernukleas. Marrow biasanya hiperselullar karena eritroid hiperplasia, dan diseritropoiesies,

tetapi ring sideroblast berjumlah kurang dari 15% dari sel eritroid. Kurang dari 10% sel dalam

granulosit atau megakariosit lieages menunjukkan displasia. Tidak ada Auer rods yang ada. Pada kasus

yang dikarakteristikkan oleh anemia dan dyserytphropoiesis, kondisi seerti anemia megaloblastik dan

anemia kongenital dyserythropoieses harus secara hati-hati disingkirkan. Secara umum, RA dapat

dikatakan sebagai “low grade” mielodisplasia dengan medial suvival dalam kisaran 6 sampai 7 tahun

dan hanya 5% sampai 10% kasus yang menjadi akut leukimia RN dan RT sangat langka dan lebih

sedikit dari 1% sampai 2% dari semua kasus MDS; perhatian ekstreme harus dilakukan dalam membuat

diagnosis.

Refractory Anemia Dengan Ring Sideroblast

RARS merupakan MDS yang dikarakteristikkan oleh adanaya anemia yag tidak dapat

dijelaskan, morfologi displasia dari erythroid lineage, dan ring sideroblast yang mencapai 15% atau

lebih erythroid precursor. Tidak terdapat signifikan grannulosit atau megakaryosit dysplasia 9,10%).

Anemia merupaan temuan utama, RBC sring menunjukkan pola “dimorfik” pada sel normokromik dan

hipokromik, tetapi makrositosis sering ditemukan. Kriteria serupa dengan RA, kecuali dalam bone

marrow, jumlah ring sideroblast untuk 15% atau lebih dari prekursor erythroid.

RARS merupakan proses dengan grade yang rendah. Dalam banyak seria, dilaporkan memiliki

prognosis yang terbaik dan angka terendah dalam hal konversi menjadi AML dari semua subtipe MDS.

Median survival dari 7 sampai 9 tahun atau lebih lama sering dilaporkan, dan angka konversi menjadi

akut leukimia kurang dari 5%. Harus diingat bahwa ring sideroblast dapat ditemukan dalam subset

MDS apapun dan juga dalam AML. Lebih lanjut, mereka dapat terlihat dalam peyakit nonneoplastik.

Pada beberapa kasus, seperti pada sindroma Pearson, ring sideroblast hasil dari kelainan (mutasi atau

delesi) dari DNA mitokondrial yang penting dalam meregulasi metabolisme besi. Apakah beberapa

pasien didiagnosis dengan RARS yang tidak memilki bukti dari kelaianan cytogenetic mungkin

memiliki sideroblast karena hanya kelainan DNA mitokondrial dan tidak ada kelainan klonal genomic

tidak jelas. Pada pasien langka, jumlah platelet meningkat ( ≥450 x10 3/µL[450 x109/L]). Terkadang leih
dari 1000 x103/µL (1000x109/L), dan diagnosis banding antara RARS dan kelainan myeloproliferative

seperti essensil trombositopenia menjadi sebuah masalah. Jika jumlah platelet adaah 450 x 103/µL (450

x109/L) atau lebih dan megakaryocyte memiliki gambaran yang dijelaskan daam MP, sebuah analisis untuk mutasi JAK2 di

indikasikan. Banyak dari kasus ini ditemukan dengan ring sideroblast dan trombositosis, yang dimasukkan kedalam

kelompok MDS/MPN.

Tabel 1 Rigkasan daam Klasifikasi MDS meurut WHO (2008)


Penyakit Temuan Darah Bone Marrow
Refractory cytopenia Cytopenia, tidak ada Displasia ( ≥10%) dalam
dengan unilinage orrare blast (<1%); hanya 1 lineage; <5%
dysplasia (RA,RN,RT) monosit, ≤1000/µL blast; <15% ring
(1x109) sideroblast
RARS Anemia; tidak ada blast; Hanya Eritroid displasia;
monosit, ≤1000/µL (1 <5% blast; ≥15% ring
x109/L) sideroblast
Refractory cytopenia Cytopenia ; tidak ada rare Displasia dalam >10%
degan multilineage blast (<1%), monosit, dari sel 2 myeloid
dysplasia ≤1000/µL (1x109/L); lineages; <5% blast;
tidak ada Auer rods <15% ring sideroblast;
tidak ada Auer rods
RAEB-1 Cytopenia; <5% blast, Unilineage atau
monosit, ≤1000/µL multilineage dysplasia;
(1x109/L); tidak ada Auer 5%-9% blast; tidak ada
rods Auer rods
RAEB-2 Cytopenia; 5%-19% Unilineage atau
blast; monosit ≤1000/µL multilinegae dysplasia;
(1x109/L); Auer rods 10%-19% blast; Auer
rods +/-
MDS dengan del(5q) Anemia; platelet biasanya Megakaryocyte Normal
yang di isolasi noral atau agak sampai meningkat dengan
meningkat; <5% blast; hypolobated nuclei; <5%
tidak ada Auer rods blast; del(5q) merupakan
kelainan sole cytogenetic;
tidak ada Auer rods

Refractory Cytopeina Dengan Multiliniage Dysplasia

Subkategori ini merupakan tambahan dalam klasifikasi WHO MDS yang tidak dikenal dalam

sistem FAB, dan identifikasi ini telah memperbaiki kegunaan prognosis dari klasifikasi morfologi dari
MDS. RCMD di karakteristikkan oleh 1 atau lebih dari cytopenia dalam darah perifer dan perubahan

displasia dalam 2 atau lebih myeloid lineages; erythroid, granulocytic, dan/atau megakaryocytic.

Kurang dari 1% blasat dalam darah dan kurang dari 5% dalam bone marrow. Auer rods tidak

ditemukan. Jika 15% atau lbeih prekursor eritroid adalah ring sideroblast penunjukkan RCMD dnan

ring sideroblast dapat dibuat, walaupun dilaporkan tidak terdapat dampak prognosis yang signifikan jika

ring sideroblast ditemukan. Kasus yang memenuhi kriteria untuk RCMD tetapi persisten 1% blast

dalam darah harus dipertimbangkan sebagai MDS,yang tidak dapat diklasifikasikan, dan dengan

multilineage dysplasia dan kurang dari 5% blast dalam bone marrow tetapi 2% sampai 4% blast dalam

darah sebaiknya di klasifikasikan sebagai RAEB-1. Pasien dengan RCMD memiliki hasil yang lebih

buruk (median survival dari 17-33 bulan) dibandingkan pasien dengan RA.

Refractory Anemia dengan Kelebihan Blast

RAEB merupakan MDS dengan 5% sampai 19% blast dalam bone marrow atau darah. Namun,

jika kurang dari 5% blast dalam bone marrow, temuan dari 2% sampai 4% blast dalam darah perifer

cukup untuk mendiagnosis RAEB-1. Dua subkategori di kenal; RAEB-1, didefinisikan sebagai yang

memiliki 5% sampai 9% blast dalam bone marrow atau 2% sampai 4% dalam darah, dan RAEB-2, saat

blast mencapai 10% atau lebih dalam marrow dan/atau 5% atau lebih dalam darah. Pasien dengan

RAEB-2 memiliki survival yang lebih buruk dan angka transformasi penkit menjadi AML yang lebih

tinggi.RAEB merupakan penyakit yang serius, terlepas dari apakah itu bertransformasi menjadi akut

leukimia. Median waktu survival kurang dari 2 tahun pada kebanyak series, dan walaupun 30% sampai

40% pasien menjadi akut leukimia, lebih banyak yang akan meninggal akibat komplikasi dari

neutropeni, trombositopeni, atau anemia dibandingkan leukimia akut, Median waktu survival untuk

RAEB-1 diperkirakan 18 bulan vs 10 bulan untuk RAEB-2.

MDS dihubungkan dengan Isolated del(5q)

Kelainan kromosomal

Jenis subtipe MDS dikarakteristikkan oleh anemia dengan atau tanpa cytopenia lainnya dan

kelainan sole cytogenetic del(5q). Myeloblast kurang dari 5% sel bone marrow yang ternukleasi dan

kurang dari 1% leukositosis darah perifer. Auer rods tidak ditemukan. Delesi interstisial dari long arm
kromosom 5 sering ditemukan ada MDS. Pada kasus dengan isolasi del(5q), penting untuk

membedakan entitas clinicopathology yang unik dari 5q-syndrome yang terlihat lebih utama pada

wanita yang lebih tua. Sindroma ini dikarakteristikkan oleh anemia makrositik, normal atau jumlah

platelet yang meningkat, megakariosit dengan monolobated atau hipolobated nuclei, kurang dari 5%

blast, dan prognosis relatif baik. Diperkiarkan 10 sampai 15 Mb umunnya dihapud di egio pada 5q31.

Terdapat sejumlah regio lainnya yang di hapus pada pasien dengan jenis lainnya MDS dan AML, tetapi

delesi antara bands 5q21 dan 5q32 terbatas terhadap sindroma ini. Gen kritis dalam sindorma ini

berbeda dari gen yang dihubungkan dengan delesi 5q yang ditemukan pada jenis MDS lainnya atau

AML. Defek dalam fungsi protein ribosomal karena haploinsufisiensi dari RPS14 telah berdampak

dalam patogenesis dari 5q-sindrome. Pasien dengan del(5q) memiliki respon yang menyenangkan

terhadap obat lenalidomide,

MDS, yang tidak dapat diklasifikasikan

Subtipe meliputi kasus yang tidak cocok dengan mudah kedalam kategori lainnya dari MDS.

Tiga situasi kemungkinan yang mengkualifikasi untuk diagnosis diantaranya (1) kasus yang cocok

dengan kriteria untuk diagnosis dari refractory cytopenia dengan unilineage dysplasia atau RCMD tetai

dalam persentase 1% blast dalam darah ditemukan minmal 2 kali, (2) MDS dengan morfologi

unilineage displasia dihubungkan dengan pansitopenia, dan (3) kasus dengan persisten cytopenia

kekurangan gambaran diagnostik MDS (<10% sel displasia dalam lineage apapun) tetapi dengan

kelainan cytogenetic yang dipertimbangkan sebagai bukti dari MDS.

Pertimbangan Prognosis

MDS menunjukkan heterogenitas klinis yang impresif memberikan prognosis penyakit dari

penyakit yang sangat parah hingga yang biasa-biasa saja. Setelah skema klasifikasi FAB 1982, sejumlah

sistem tambahan telah diajukan pada perbaikan kekuatan prediktif prognosis dalam MDS. Pada tahun

1997, Greenberg dkk mengembangkan International Prognostic Scoring System, berdasarkan pada

persentase blast bone marrow, yang secara prognostic relevan terhadap kelainan cytogenetic, dan

jumlah dari cytoperias. Pda 2011, pedoman FAB di revisi, dan versi terbaru di integrasikan dengan
sistem klasifikasi WHO, yang sekarang ini digunakan di dunia. Yang paling terbaru, transfusi

dependensi dalam sistem WHO telah menciptakan sistem skoring prognostik berdasarkan klasifikasi

WHO.

Seksi MDS pada Workhsop

2007 Society for Hematopathologyy/European Association for Haematopathology Workshop

ada Myeloid Neoplasma dan Mastocytosis meliputi total dari 16 kasus dalam seksi MDS. Seksi ini

menunjukkan pentingnya isu diagnosis dalam hubungan terhadap MDS dan meliputi kasus dari

penyakit yang dihubungkan dengan kelainan kromosomal del(5q) yang di isolasi meliputi “clasical” 5q-

syndrome dan entitas MDS lainnya dengan del(5q) yang di isolasi. Isu lainnya muncul dari kasus yang

di kirimkan di antaranya kelainan cytogenetic (kelainan lain 5q) yang terlihat pada MDS, peran

cytogenetik dalam mendiagnosis MDS, dan masalah yang berhubungan dengan diagnosis banding dari

MDS vs subtipe langka AML, khususnya akut panmyelosis dengan myelofibrosis dan erythroleukemia.

Hubungan dan relasi kejadian MDS dengan paroxysmal nocturnal hemoglobinuria (PNH), AA, dan

kelainan non neoplastik lainya juga di dilustrasikan oleh sejumlah kasus dan di alamatkan dalam diskusi

ini. Topik utama dan kasus yang mengilustrasikan mereka di rangkum di sini.

MDS yang dihubungkan dengan Isolat del (5q) dan hubungan del(5q) dengan kondisi lainnya

Delesi yang di isolasi dari long arm kromosom 5, del(5q), ditemukan pada 10% MDS. Mereka

dihubungkan dengan prognosis yang lebih baik, walalupun perjalanan penyakit bervariasi. Jika 1 atau

lebih kromosomal tambahan muncul, survival secara keseluruhan lebih singkat secara signifikan. Kasus

141 meng ilustrasikan contoh klasik dari 5q-syndrome dengan gambaran klinis tipikal dan temuan

morfologi yang tipikal.

Workshop memasukkan 2 kasus yang menunjukkan hubungan antara tingkat terjadinya MDS

dengan isolat del(5q) dan lymphoid neoplasma. Kasus 36 mengilustrasikan pasien dengan riwayat

panjang dari kronik lymphocytic leukimia, diagnosis terkair dari MDS dengan kelainan 5q yang di

isolasi. Temuan morfologi bone marrow , yang meliputi sel infiltrasi multinodular/interstisial lymphoid

yang kecil dan lebih utama dari monolobated megakaryoctes ditunjukkan pada gambar 1A dan gambar

1B. oleh FISH, kelainan 5q hanya di deteksi pada granulosit, sedangkan trisomy 12 di deteksi hanya
pada limfosit. Gambar 1C. koeksistensi MDS dan kronik lymphocityc leukimia adalah jarang. Dalam

serial yang besar, hanya 1% pasien yang tidak diobati di diagnosis dengan MDS juga memiliki

keganasan B-cel. Hubungan ini bisanya koinsidental. Pada pasien dengan kronik lymphocytic leukimia

yang sebelumnya diobati dengan agen ankylating, MDS sekunder dapat ditemukan, walalupun

kejadiannya juga tidak sering walaupun penggunaan yang luas dari agen ankylating dalam kondisi ini.

Kasus 85 mengilustrasikan hubungan plasma sel dysxrasia dan MDS, hubungan terakhir dengan isolat

del(5q). bone marrow menunjukkan adanya tipikal nonlobated megakariosit (Gambar 2A). dihubungkan

dengan peningkatan jumlash sel plasma , yang daat di apresiasian oleh positivitas mereka pada CD138

immunostaining(Gambar 2B). melalui aliran sitometri, sel plasma mengekspresika antigen CD56.

Kasus 7, di kiriman oleh Gerald Penn, MD, mengilustrasikan koeksistensi MDS (jenis RCMD)

dan sel plasma myeoloma. Banya dari kasus yang dilaporkan sebelumnya dalam literatur memasukkan

sel plasma myeloma, pada MDS yang didiagnosis setelag kemoterapi. Ini dipilih sebagai proses yang

tidak berhubungan; MDS diperkirakan dapat terjadi secara sekunder terhadap pengobatan dengan agen

alkylating. Risiko dari kedua penyakit di estimasikan 10% sampai 20% setelah 10 tahun. Peningkatan

risiko dari penyakit sekunder telah dilaporkan pada pasien yang mendapatkan transplanasi bone marrow

(biasanya juga pentrasi dengan kemoterapi). Yang jarang adalah kasus yang tidak berhubungan dengan

terapi seperti kasus 2 yang terdapat pada workshop (kasus 7 dan 85)

Pada kasus seperti ini, yang tidak ada pengobatan sebelumnya di masukkan, plasma sel tumor

dan MDS mungkin muncul dari stem sel umum, yang dikarakteristikkan oleh kelainan clonal

cytogenetic yang umum. Dalam konteks ini, Nilisson dkk melaporkan kasus monoklonal gammopathy

dari signifikansi yang belum dipahami dengan del(20q) yang ditunjukkan oleh FISH yang terdapat pada

CD34+/CD38-(hematopoietic stem cells), CD34+/CD38+ (progenitor), CD19+ (Sel B), dan CD15+ (sel

myeloid), menunjukkan bahwa del(20q) dapat muncul pada tingkat multipoten progenitor/stem sel.

Masalah berbeda di ilustrasika oleh kasus 61, yang terdapat pada anak dengan MDS derajat

tinggi yang dihubungkan dengan isolat del(5q). aliran cytometry marrow (gambar 3) menunjukkan

populasi patologis dari blast (dihitung dengan aliran citometer pada 8.4% sel bone marrow) yang positif

terhadap CD34, CD7, CD33, HLA-DR, CD22, CD123, dan CD135; yang memiliki ekspresi CD38 yang
heterogen; dan negatif untuk CD19, CD10, terminal deoxyucleotidyl transferase, CD13, CD117, dan

CD56. Tidak ada respon terhadap lenalidomide yang ditemukan pada kasus ini. Pada AML, sebuah

delesi 5q biasanya dihubungkan dengan kompleks karyotye dan juga dihubungkan dengan hasil yang

buruk setelah pengobatan. Namun, porporsi kecil dari pasien dengan aberasi tunggal del(5q) dan tidak

ada ada kelainan hematologi cendetung memiliki hasil yang sama dengan pasien karyotipe yang

normal.

Gambar 1. (kasus 36) koeksistensi kronik lymphocytic leukimia dan myelodyspalastic syndrome

dengan 5q- A. agregrasi lymphoid pada latar belakang hiperselular bone marrow. B. monolobated

megakariosit yang menonjol. Fluorescence in situ hibridisasi menunjukkan kehilanag lengan panjang

dari kromosom 5 (C) dalam sel myeloid dan trisomi 12 dalam proporsi dari sel mononuklear dengan

nuclei yang bulat (D), di kontribusikan oleh J, Sindhu.

MDS di diagnosis dengan Cytogenetik tunggal dan kelaianan Cytogenetic lainnya yang terlihat

pada MDS dan nilai prognosis mereka

Terkadang, satu di konfrontasikan dengan pasien yang memilik persisten cytopenia (biasanya

anemia) untuk yang tidak ada penyebab yang mendasari yang ditemukan tetapi pada orang yang tidak

cukup bukti morfologisnya untuk mendukung kecurigaan klinsi dari MDS. Untuk beberapa pasien ini,

“diagnosis kerja” dari idiopatik cytopenia dapat didiagnosis, walaupun penting untuk poin bahwa hal ini

tidak sinonim dengan diagnosis dengan MDS. Pada beberapa kasus, penting untuk mengeksplorasi

setiap kemungkinan penyebab cytopenia dan menyingirkan diagnosis seperti kelainan autoimun,

penyakit lymphoproliferatif (khususnya granular besar lymphocyte proliferasi dan hairy cell leukimia),

hypothyroidisme dan endokrinopati lainnya, dan infeksi.

Pemeriksaan imunohistokimia pada spesimen biopsi dapat memperlihatkan peningkatan jumlah

blast yang tidak muncul sebelumnya, dan ini sebaiknya dilakukan. Pemeriksaan cytogenetic sangat kuat

di indikasikan pada kasus seperti ini, dan FISH dapat menujukkan kelainan clonal saat pemeriksaan

karyotype tidak dapat.


Jika kelainan ctogenetic clonal ditemukan, diagnosis dari MDS menjadi lebih mudah, dan

memang, jika MDS dihubungka dengan kelainan ini, diagnosis MDS dapat ditegakkan. Pada pasin ini

sebaiknya di follow up secara hati-hato untuk bukti morfologi dari displasia sebelum diagnosis

unequivocal dapat dibuat.

Kasus 158, yang dikirim oleh Dong Chen, MD, merupakan contoh dari kasus ini yang marroe

karyotype menunjukkannya, dalam ketidakadaan displasia yang signifikan, kelainan cytogenetik clonal

dari signifikansi klinis yang tidak dipahami, revisi yang ada tentang klasifikasi WHO berpendapat

bahwa “kasus dengan kelainan kromosomal cocok dengan MDS yang dihubungkan dengan bukti klnis

yang kuat dari MDS tetai pada gambaran displasia <10% sel dalam satu (unilineage) atau lebih

(multiliniae) dari lineage sel yang diklasifikasikan untuk MDS, yang tidak dapat diklasifikasikan.

Trisomy 8, del(20q) dan delesi dari kromosom Y, walaupun sering terjadi , bukan lah diagnosis MDS

dalam kondisi tidak adanya gambaran morfologi dari penyakit ini, serupa, anomali t(1;21) terlihat

dalam kasus 158 yang tidak secara spesifik karakteristik dari MDS, dan mengapa ini muncul dikatakan

sebagai yang tidak cocok untuk menegakkan diagnosis MDS.

Kasus 192 merupakan contoh dari RCMD (Gambar4) yang diubungkan dengan t(6;9)(p23;q34).

AML dengan t(6;9)(p23;q34) (DEK-NUP214) pada dewasa dan anak-anak secara umum memiliki

prognosis yang buruk, serupa dengan AML lainnya dengan kelaianan cytogenetic. Sehingga, adanya

t(6;9) meningkatkan kekhawatiran prognosis dalam kasus ini, yang secara morfologis dapat konsisten

dengan MDS derajat ringan (tidak dihubungkan dengan peningkatan jumlah blast). Sehingga, kasus

t(6;9) dengan blast kurang dari 20% sebaiknya di monitor ketat untuk perkembangan dari bukti yang

lebih definitif dari AML. Kasus 162 dikarakteristikkan oleh adanay temuan morfologis yang serupa

dengan RCMD dengan ring sideroblast dalam hubungan dengan isolat del(20q). kelainan cytogenetic

ini, sering terlihat pada kasus dengan unilinegae displasia (RA), dihubungkan dengan penyakit dan

perubahan displasia yang miimal dan sering bermanifest dengan anemia dan trombositopenia. Adanya

multilineage displasia (gambar 5) pada kedaaa adanya del(20q), seperti yang terlihat pada kasus ini,

masih belum jelas secara signifikan.


Gambar 2. (kasus 85) sindroma myelodisplasia dengan isolat del(5q) dan sel plasma displasia. A.

monolobated tipikal megakariosit. B. kumpulan sel plasma yang diterangi dengan CD138 pewarnan

imunohistokimia. Kontribusi dari G.penn

Gambar 3. (kasus 61) pediatrik dengan sindroma myelodisplasia derajat tingi. A. Scattergrams

mnunjukan adanya populasi blast yang positif terhadap CD34 (8.4% sel bone marrow), CD38, dan

CD22, B. Blast positif terhadap CD33, CD11b, CD65, CD123, CD135, dn CD7 dengan ekspresi CD4

densitas rendah. APC, aalphycocyanin; CY5, cyanin 5; FITC, fluorescein isothiocyanate; GPA,

glycophorin A; PE, phycoerythrin; PerCP, peridinin chlorophyll protein; SSC-H, sisi scatter height, TRI,

Tri-color. Kontribusi oleh A.Porwit.

MDS dengan Fibrosis, APMF, dan Fibrotik AML lainnya

Sekitar 5% sampai 10% kasus MDS secara signifikan meningkatkan serabut marrow reticulin

atau bahkan fibrosis kolagen pada diagnosis, dan mereka memberi istilah MDS dengan fibrosis (MDS-

F). MDS-F juga dikarakteristikkan oleh pansitopenia yang berat. Organomegali minima atau tidak ada.

Secara keseluruhan pasien dengan MDS-F dilaporkan memiliki waktu survival yang lebih singkat

dibandingkan dengan pasien tanpa gambaran ini.

Untuk kualifikasi kasus MDS-F, skor fibrosis reticulin yang diwarnai silver 2 atau lebih pada

dasar dari system yang diajukan peh Manoharan dkk harus didapatkan. Hingga 50% MDS yang

dihubungkan dengan terapi memiliki marrow fibrosis, marrow sering menunjukkan trilineage displasia

dengan dismegakaryopoeises yang menonjol. Pada kebanyakan kasus, peningkatan jumlah dari blast

telihat; sehingga, kebanyakan kasus gagal dalam RAEB subgrup, blast lebih mudah di dokumentasikan

pada marrow

Gmbar 4. (kasus 192) eritroid dan granulosit displasia pada refraktori anemia dengan multilineage

displasia dan 1(6;9)(p23;q34). Di kontribusi oleh G.Bhagat

Gambar 5 (Kasus 161) refraktori cytopenia dengan multilineage displasia dan ring sideroblastoma pada

kasus dengan del(20q).A. displasia erythroid yang menonjol dan prekursor displasia granulosit yang

jarang. B, pewarnaan besi akan menampakkan ring sideroblast

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