Myelodysplastic and Myelodysplastic/Myeloproliferative Neoplasms

• Myeloproliferative diseases, in general, are disorders in which proliferation of hematopoietic cells outpaces apoptosis, and cellular elements in the blood are increased while the morphology of hematopoiesis is near normal.

• Myelodysplastic diseases or syndromes are disorders in which apoptosis predominates, hematopoiesis is ineffective, and cytopenias occur.

• The myelodysplastic/myeloproliferative disorders show features of both, with variable increases in cells, as well as cytopenias and morphologic dysplasia.

Types of Abnormal Cellular Maturation

• Dyserythropoiesis : Nuclear fragmentation or karyorrhexis,

multinuclearity, nuclear budding or bridging,basophilic stippling, and ring sideroblasts.

• Erythrocytic abnormalities in the blood film include presence of oval macrocytes, anisochromia, basophilic stippling, dacryocytes, and reticulocytopenia.

• Dysgranulopoiesis: hypogranulation,nuclear hyposegmentation with increased

chromatin condensation, occasionally abnormal large azurophilic granules.

Dysmegakaryocytopoiesis: large megakaryocytes with unsegmented nuclei,

micromegakaryocytes, and megakaryocytes with two or more small, unconnected nuclei .Megakaryocytes may be decreased in number.

In the blood film, giant hypogranular platelets are frequent, and micromegakaryocytes are seen rarely.

Pseudo–Pelger-Huët neutrophil

A dysplastic megakaryocyte showing unconnected nuclear lobes

Myelodysplastic/Myeloproliferative Neoplasms

• Chronic Myelomonocytic Leukemia

• Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

• Juvenile Myelomonocytic Leukemia

• Myelodysplastic/Myeloproliferative Disease, Unclassifiable

Chronic Myelomonocytic Leukemia

• CMML is a clonal stem cell disorder in which the predominant feature is persistent monocytosis (>1 × 109/L for longer than 3 months) for which other causes have been excluded.

• Blast percentages typically are <5% in the blood and <10% in the marrow, and such cases are referred to as CMML-1. The subcategory CMML-2 refers to cases with 5%–19% blasts in the blood, with 10%–19% in the marrow, or with the presence of Auer rods.

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3. کند% می تجاوز

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از ائوزینوفیلها تعداد گردد μl/1500هرگاه با CMMLزیرگروه WHOبیشتر همراه. کند می پیشنهاد ائوزینوفیلی

: ایمونوفنوتیپ نظر و CD13,CD33از مثبت CD14,CD64,CD68مثبت متغییر صورت بهاست.

در سیتوژنتیک ناهنجاریهای 7,-8موارد% +40-20ناهنجاریهای برخی 12Pو باشد، میبیماران به t(5,17)یا t(5,12)از مناسب درمانی وپاسخ ائوزینوفیل افزایش با همراه

. دارند کینازی تیروزین های بازدارنده

بیماران در بقا متوسط و 30-20میزان باشد می سمت 30-15ماه به پیشرفت درصدAML. دارند

Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

Criteria for diagnosis of aCML : Leukocytosis (WBC ≤13 × 109/L) due to increased neutrophils and

precursors with prominent dysgranulopoiesis Prominent dysgranulopoiesis No Ph chromosome or ′ BCR/ABL-1 fusion gene No rearrangement of PDGFRA or PDGFRB Neutrophil precursors (promyelocytes, myelocytes, metamyelocytes)

≥10% of WBCs Minimal absolute basophilia; basophils usually <2% of leukocytes No or minimal absolute monocytosis; monocytes <10% of WBCs Hypercellular marrow with granulocytic proliferation and

granulocytic dysplasia, with or without dysplasia of erythroid and megakaryocytic lineages

Less than 20% blasts in blood or marrow

• Atypical CML. Top panels: Peripheral blood smear from a patient with atypical CML showed a leukocytosis with anemia and marked thrombocytopenia. Granulocytes are left-shifted, with dysplastic hypolobulated nuclei and a dysplastic nRBC is present (arrow).

• Bottom panels: Biopsy at low- and high-magnification (left and right, respectively) showing atypical granulocytic hyperplasia without sheets of blasts.

Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a clonal disorder of predominantly granulocytic and monocytic lineages, with dysplasia in these and frequently other lineages, occurring in children or young adolescents

The occurrence is 1.3 cases per million children younger than 14 years, and most affected children are younger than 3 years of age, with a 2 : 1 male predominance.

JMML is frequent in children with neurofibromatosis type 1.

• In all, 25% of patients show monosomy 7, 35% exhibit mutations of PTPN11 (encoding SHP2), and 20% each have mutations in NRAS, KRAS2, and NF1.

• Patients with normal karyotype often have markedly increased hemoglobin F.

• Blood shows leukocytosis, thrombocytopenia, and often anemia.

• The marrow is hyperplastic with granulocytic hyperplasia, variable erythroid cellularity, and often decreased megakaryocytes.

Criteria for diagnosis of JMML

Peripheral blood monocytosis >1 × 109/L Absence of Ph chromosome or ′ BCR/ABL-1 Blasts and promonocytes less than 20% of blood and marrow Plus two of the following:

o Hemoglobin F increased for ageo Immature granulocytes in the bloodo WBCs >10 × 109/Lo Clonal chromosomal abnormality (may be monosomy 7)o GM-CSF hypersensitivity of myeloid progenitors in vitro

• This peripheral blood smear from a child with JMML shows dysplastic monocytosis, left-shifted leukocytosis with a small blast, and thrombocytopenia.

Myelodysplastic/Myeloproliferative Disease,Unclassifiable

• This category of the WHO classification is used for those cases with features of myelodysplastic disease, but with the addition of prominent myeloproliferative features.

Refractory Anemia with Ring Sideroblasts Associated With Marked Thrombocytosis

Refractory Anemia with Ring Sideroblasts Associated With Marked Thrombocytosis

This disorder is included in the WHO classification under the category of MDS/MPD, unclassified.

It is characterized by features of myelodysplastic neoplasm and refractory anemia with ring sideroblasts.

Peripheral thrombocytosis ≥450 × 106/L, and increased, large atypical BM megakaryocytes.

A majority of cases (60%) carry a JAK2 V617F mutation identical to that in MPN; occasional cases show a MPL W515K/L mutation

Myelodysplastic Syndromes

•. هستند خونسازی کلونال اختالالت

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MDS. است شده گزارش ها

The Who classification of MDS

Refractory cytopenia with unilineage dysplasia (anemia (RA),thrombocytopenia, or neutropenia)

Refractory anemia with ringed sideroblastsRefractory cytopenia with multilineage dysplasiaRefractory anemia with excess blasts (RAEB)5q− syndromeMyelodysplastic Syndrome, UnclassifiedChildhood Myelodysplastic Syndrome; Refractory

Cytopenia of Childhood

Refractory Cytopenia with Unilineage Dysplasia

• dysplasia affecting >10% of one myeloid cell lineage, and cytopenia of the affected cell line, with <10% dysplasia of other lineages.

• Del (20q), +8, abnormalities ofchromosome 5 or 7

• Refractory Anemia• Refractory Neutropenia• Refractory Thrombocytopenia

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. است متغیر متوسط تاo در بالست از PBمیزان در% 1کمتر از BMو % 5کمتر

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o بقا و 66میزان درصد 6حدود AMLبه transformationماه. باشد می

Refractory NeutropeniaThe absolute neutrophil count is <1.8 × 109/L.Toxic/secondary neutropenia is excluded.Dysplasia usually consists of nuclear hypolobation

and hypogranulation.

Refractory ThrombocytopeniaPlatelets are <100 × 109/LMore than 10% of at least 30 megakaryocytes

evaluated in smears and sections show dysplastic features of hypolobation, binucleation or multinucleation, and/or micromegakaryocytes.

Refractory Anemia with Ring Sideroblasts

• Similar to RA with >15% ringed sideroblasts in BM

• Survival is similar to RA, with a lower progression to AL (≤2%).

Refractory Cytopenia with Multilineage Dysplasia

PB with cytopenias of ≥2 cell lines, <1% blasts, <1 × 109/L monocytes.

BM with dysplasia of ≥10% of precursors of ≥2 cell lines, <5% blasts

Ring sideroblasts may be present; when numerous (>15%), the case is still classified as RCMD and is not categorized separately, as in prior classifications.

Survival is ≈33 months, and AL conversion is 11%

RA and RARS, which infrquently show cytogenetic abnormalities (<10%)

RCMD and RCMD with ring sideroblasts (RCMD-RS) show cytogenetic abnormalities in up to 50%. These include trisomy 8, monosomy 7, del(7q), monosomy 5, del(5q), del(20q)

Refractory Anemia with Excess Blasts

• RAEB-1: PB with <5% blasts, <1 × 109/L monocytes; BM with hypercellularity, dyspoiesis, 5%–9% blasts

without Auer rods; Survival is usually less than 2 years(18month) in RAEB-1• with progressive marrow failure and cytopenias or

progression to AL in 25%• Clusters of 5–8 blasts and promyelocytes in the

marrow interstitium are frequently seen on sections and have been referred to as abnormal localization of immature precursors(ALIP).

Cases of RAEB with concurrent myelofibrosis are referred to as RAEB with fibrosis (RAEB-F). Megakaryocytes are increased and dysplastic, and reticulin fibrosis is significant, often resulting in a dry tap.

RAEB-2:

PB with 5%–9% blasts, or 10%–19% BM blasts, or Auer rods

Survival is usually less than 2 years(10 month) in RAEB-2

progressive marrow failure and cytopenias or progression to AL in 33% for RAEB-2.

Cytogenetic abnormalities include +8, -5, del(5q), -7, del(7q), and del(20q)

Myelodysplastic Syndrome with Isolated del(5q)

• PB with thrombocytosis, <5% blasts;• BM with increased, hypolobulated

megakaryocytes, <5% blasts• isolated deletion of chromosome region 5q.• Some cases also exhibit a JAK2 V617F

mutation.

• 5q-syndrome. blood smear showing macrocytic anemia and thrombocythemia. Macrocytic RBCs with cellular diameters that exceed the nucleus of a small mature lymphocyte are seen.

• 5q-syndrome. Aspirate smear show increased numbers of the characteristic unilobular megakaryocytes.

Myelodysplastic Syndrome, Unclassified

• The myelodysplastic syndrome, unclassified category is used when clinical and hematologic findings of myelodysplasia exist, but without specific features to allow placement in one of the other categories.

Childhood Myelodysplastic Syndrome;Refractory Cytopenia of Childhood

• Persistent cytopenia with <5% blasts in the BM, dysplasia at least unilineage but usually multilineage, in the marrow and marrow is also frequently hypocellular.

• <2% in the blood, Pancytopenia is frequent, with macrocytic anemia showing anisopoikilocytosis.

• The cytogenetic abnormality of monosomy 7 is the most common genetic abnormality and is associated with progressive disease.

• Cases with trisomy 8 may show a long stable period.

• This disorder may be morphologically indistinguishable from results of infection, vitamin deficiency (B12, folate, vitamin E), metabolic or autoimmune disease, paroxysmal nocturnal hemoglobinuria (PNH), or acquired aplastic anemia.