Page 1130 - Hematology_ Basic Principles and Practice ( PDFDrive )

996 Part VII Hematologic Malignancies

applicability to children. A number of classification systems for hemophagocytosis, abnormal nuclei, and giant forms), or erythroid
children and adults have now been proposed. Taken together, it may lineages (megaloblastoid maturation, nuclear budding and multinu-
be useful to think about childhood MDS as primary or secondary in cleated forms, and ringed sideroblasts) can be multiple and varied.
nature, with secondary MDS arising either from a known inherited Similar dysplastic changes can occur in the peripheral blood for each
BM failure syndrome, prior acquired aplastic anemia, or as a compli- of these lineages. Although dysplastic changes in the BM are a
cation from prior chemotherapy or radiation therapy. A diagnosis of common feature of MDS, it is important to remember that dysplasia,
primary MDS would then apply to all other cases. unto itself, is not diagnostic of MDS because dysplastic features are
Historically, one of the most commonly used classification systems associated with other conditions and can be found in normal BM
was the French-American-British (FAB) system, originally proposed donors. 54
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in 1982. This classification system recognized five forms of MDS Flow cytometric analysis can serve as a useful addition to histo-
in adults: refractory anemia (RA), refractory anemia with ringed pathology and to quantitate the number of blasts based on aberrant
sideroblasts (RARS), refractory anemia with excess of blasts (RAEB), cell surface antigen expression. It is also helpful in detecting popula-
refractory anemia with excess of blasts in transformation (RAEB-T), tions of PNH-like cells 55,56 . However, although beneficial, flow
and CMML. Using this system, whereas RAEB and RAEB-T were cytometric findings are not generally diagnostic of MDS.
commonly reported in children, RA and RARS were thought to be Cytogenetic abnormalities are seen in approximately half of
rare in children. However, a population-based study in the United children diagnosed with de novo MDS. Karyotypic abnormalities
Kingdom showed 25% of childhood MDS cases to be RA or RARS, most commonly seen are −7, 7q−, and +8. Abnormalities in chro-
suggesting inaccurate diagnosis or reporting of these subtypes in other mosomes 6, 9, 11, 12, and 13 are rare in children. Specific abnormali-
pediatric studies. CMML has only rarely been reported in children. ties seen in adults, including −5, 5q−, and −Y, are very rarely seen in
Additional subtypes of MDS are now recognized that do not fit children.
well into the FAB system, including hypoplastic MDS, therapy-
related MDS, refractory cytopenias with trilineage dysplasia, MDS
associated with myelofibrosis, and MDS associated with inherited Differential Diagnosis
disorders (congenital neutropenias, Shwachman-Diamond syndrome,
FA), Down syndrome, neurofibromatosis type 1, and mitochondrial Although the history, physical examination, evaluation of the BM
cytopathies. 46,47 Therefore the World Health Organization (WHO) and peripheral blood, and cytogenetic analysis often make the diag-
proposed changes to the FAB criteria to account for many of these nosis of MDS, other diseases should be considered. Congenital dis-
subtypes. 48,49 Importantly, whereas adults commonly present with RA orders such as Down syndrome, FA, Shwachman-Diamond syndrome,
without cytopenias in the myeloid or platelet lineages, this is very Diamond-Blackfan anemia, congenital dyserythropoietic anemias,
rare in children since they more often have cytopenias in more than and hereditary sideroblastic anemia should be considered. The dif-
one cell line. Therefore children with low-grade MDS are classified ferential should also include AML with a low blast count, mitochon-
as having refractory cytopenia as opposed to RA. Thus in 2008 the drial cytopathies such as Pearson syndrome, rheumatic diseases
WHO classification of pediatric MDS included the provisional cat- including juvenile idiopathic arthritis, and myeloproliferative
egory of RCC based on persistent cytopenia with less than 5% blasts disorders. Specifically, PNH, although rare in children, should be
50
in the bone marrow and less than 2% blasts in the peripheral blood. considered. Deficiencies of vitamin B 12 and folate can cause megalo-
Under this classification, it is recommended that children with refrac- blastic changes that resemble the dysplastic changes seen in MDS.
tory cytopenia with multilineage dysplasia (RCMD) be classified as Other nutritional deficiencies, including copper, iron, thiamine,
RCC until it is clarified whether the number of lineages involved is riboflavin, and pyridoxine, should be considered. Infections caused
an important prognostic discriminator in childhood MDS. Under by human immunodeficiency virus, parvovirus, Epstein-Barr virus,
the 2016 revision of the WHO classification of myeloid and neo- cytomegalovirus, and human herpes virus 6 can cause changes that
plasms and acute leukemia, RCC remains a provisional entry. 51 resemble MDS. Finally, the differential diagnosis should include
toxins (insecticides, chemotherapy agents, and arsenic), as well as
cytokine exposure and radiation.
Clinical Manifestations Hypoplastic MDS (RCC) can be difficult to distinguish from
severe aplastic anemia and inherited bone marrow failure syndromes,
Signs and symptoms of MDS are nonspecific and are usually attribut- especially when no chromosomal aberrations are detected. One
able to pancytopenia (fever, infections, pallor, fatigue, bruising, and interesting area of research that may help in differentiating between
petechiae). Lymphadenopathy, hepatomegaly, and splenomegaly are these diagnoses is the use of cytokine-based programs. In one pre-
uncommon presenting signs in children with MDS. liminary study, thrombopoietin and IL-17 levels were useful in dif-
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ferentiating hypoplastic MDS from aplastic anemia. When the
diagnosis is unclear, prospective monitoring and serial BM examina-
Laboratory Manifestations tions may serve as useful aids in making an accurate diagnosis.
Commonly accepted minimal diagnostic criteria for pediatric MDS
include the absence of common de novo AML karyotypic abnormali- Therapy
ties and at least two of the following: (1) sustained, unexplained
anemia; neutropenia or thrombocytopenia; dysplastic morphology in Although MDS is a heterogeneous, clonal disease of hematopoietic
the erythroid; granulocytic or megakaryocytic lineages (at least stem cells (HSCs) that can manifest different clinical courses, it is
bilineage), and (2) an acquired, sustained clonal cytogenetic abnor- not readily curable by conventional chemotherapy and requires
mality and 5% or more blasts in the BM. 8,52 Almost half of all children allogeneic hematopoietic cell transplantation (HCT) for cure in most
with MDS in one series presented with refractory cytopenia, most cases. Some children with RCC and RCMD who do not have life-
notably neutropenia and thrombocytopenia. 53 threatening neutropenia and who do not require transfusions may
Morphologically, the BM may be hypocellular, normocellular, or only require close observation (see box on Treatment Overview for
hypercellular. A diagnosis of MDS is made based on the presence of Children With MDS). Although children with this disease may
dysplastic changes in at least two cell lineages. The dysplastic changes eventually develop progressive disease requiring HCT, they may have
53
in the granulocytes (hypogranulation, nuclear hyposegmentation, long periods when minimal treatment is required. The use of AML-
megaloblastoid maturation, and a left shift with an increased number like chemotherapy for patients with RCMD with excess blasts
of myeloblasts), megakaryocytes (micromegakaryocytes, abnormal (RCMD-EB) is controversial but may serve to “debulk” patients with
megakaryocyte nuclei), monocytes (increase in BM monocytes, a high percentage of blasts before HCT. 6,58,59 However, this potential
abnormal granulation with persistence of azurophilic granules, benefit may be offset by toxicities associated with AML-like