# Myelodysplastic Syndromes and Myeloproliferative Neoplasms

## Overview

Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders that occupy opposite ends of a biological spectrum. MDS is defined by ineffective hematopoiesis resulting in peripheral cytopenias despite a cellular marrow, accompanied by morphologic dysplasia and carrying a risk of transformation to acute myeloid leukemia. MPNs are characterized by effective but excessive proliferation of one or more myeloid lineages, producing elevated peripheral blood counts. MDS/MPN overlap syndromes share features of both, with concurrent dysplasia and proliferation.

## Myelodysplastic Syndromes (MDS)

### Diagnostic Criteria

Diagnosing MDS requires persistent cytopenia(s) -- hemoglobin below 13 g/dL in males or below 12 g/dL in females, absolute neutrophil count below 1.8 x 10^9/L, or platelet count below 150 x 10^9/L -- combined with morphologic dysplasia in 10% or more of cells in one or more lineages, and/or an MDS-defining cytogenetic abnormality, and/or increased blasts (5-19%). Critically, reactive causes of dysplasia must be excluded before making the diagnosis, including B12 and folate deficiency, medication effects (particularly methotrexate and antiretrovirals), viral infections, and toxin exposure.

### Morphologic Features of Dysplasia

#### Dyserythropoiesis

Dysplastic features in the erythroid lineage include nuclear budding, internuclear bridging, and karyorrhexis. Multinucleation and megaloblastic change are also characteristic. Ringed sideroblasts -- defined as erythroid precursors with 5 or more iron granules encircling at least one-third of the nuclear circumference -- indicate abnormal mitochondrial iron accumulation. Cytoplasmic vacuolization and defective hemoglobinization reflect disordered maturation.

#### Dysgranulopoiesis

Granulocytic dysplasia manifests as hypogranularity or complete agranularity of neutrophils, the pseudo-Pelger-Huet anomaly (bilobed neutrophils with clumped chromatin), nuclear hypersegmentation (which paradoxically can also represent dysplasia), and abnormal nuclear shapes including ring forms.

#### Dysmegakaryopoiesis

Megakaryocytic dysplasia is recognized by micromegakaryocytes (abnormally small cells with hypolobated nuclei), non-lobated (monolobated) nuclei, separated nuclear lobes (pawn-ball megakaryocytes), and widely spaced nuclear lobes.

### WHO 5th Edition / ICC Classification

#### MDS with Low Blasts (MDS-LB)

This category encompasses cases with fewer than 5% marrow blasts and fewer than 2% peripheral blood blasts. It is subclassified by whether dysplasia involves a single lineage or multiple lineages, and whether ring sideroblasts are present or absent.

#### MDS with Low Blasts and Ring Sideroblasts (MDS-RS)

MDS-RS is defined by 15% or more ringed sideroblasts, or 5% or more if an SF3B1 mutation is present. SF3B1 mutation is found in more than 80% of cases and confers favorable prognosis. Patients typically present with isolated anemia and macrocytosis.

#### MDS with Increased Blasts (MDS-IB)

MDS-IB is subdivided into MDS-IB1 (5-9% marrow blasts or 2-4% blood blasts) and MDS-IB2 (10-19% marrow blasts, or 5-19% blood blasts, or the presence of Auer rods). Higher blast counts indicate greater risk of AML transformation.

#### MDS with Biallelic TP53 Inactivation (MDS-biTP53)

This newly recognized entity requires two or more TP53 mutations, or one mutation with loss of heterozygosity. It carries a very adverse prognosis, is frequently associated with complex karyotype, and has a high rate of AML transformation.

#### MDS with Isolated del(5q)

This entity is defined by an isolated 5q deletion (with at most one additional abnormality other than monosomy 7 or del(7q)). It shows female predominance and presents with macrocytic anemia and normal or elevated platelet counts. Characteristic hypolobated megakaryocytes are seen on biopsy. It responds to lenalidomide therapy and carries a favorable prognosis when TP53 is wild-type.

#### Hypoplastic MDS

Hypoplastic MDS shows cellularity below 25% (or below 30% in patients under 60). The critical diagnostic challenge is distinguishing it from aplastic anemia, which requires cytogenetics, flow cytometry for aberrant blast populations, and molecular testing.

### Risk Stratification: IPSS-R and IPSS-M

The Revised International Prognostic Scoring System (IPSS-R) incorporates cytogenetics, blast percentage, hemoglobin, platelet count, and absolute neutrophil count to stratify patients into very low, low, intermediate, high, and very high risk categories. The IPSS-M (molecular) adds mutation data from genes including TP53, ASXL1, RUNX1, EZH2, SRSF2, and others, significantly improving prognostic discrimination, particularly for patients in the intermediate-risk group. The IPSS-M is available as an online calculator and reclassifies up to 46% of patients compared to IPSS-R alone.

### Key Molecular Mutations in MDS

SF3B1 is a splicing factor mutation associated with ring sideroblasts and favorable prognosis. TP53 mutations, particularly biallelic inactivation, confer adverse prognosis and are associated with complex karyotype. ASXL1, RUNX1, and EZH2 mutations also indicate adverse prognosis. SRSF2, U2AF1, and ZRSR2 are splicing factor mutations common in MDS and chronic myelomonocytic leukemia. TET2 and DNMT3A are epigenetic regulators found in both MDS and clonal hematopoiesis of indeterminate potential (CHIP); their presence alone is insufficient for MDS diagnosis. IDH1/2 mutations are therapeutically targetable with ivosidenib and enasidenib.

## Myeloproliferative Neoplasms (MPN)

### General Features

MPNs are characterized by effective, non-dysplastic proliferation of one or more myeloid lineages, resulting in elevated peripheral blood counts rather than cytopenias. Clinical features include hepatosplenomegaly and increased risk of both thrombosis and hemorrhage. All MPNs carry risk of fibrotic transformation and progression to secondary AML (blast phase).

| MPN | Driver Mutations | Key BM Features | Megakaryocyte Morphology |
|---|---|---|---|
| CML | BCR-ABL1 (100%) | Granulocytic hyperplasia, small megakaryocytes | Small, hypolobated (dwarf) |
| PV | JAK2 V617F (>95%), JAK2 exon 12 | Panmyelosis, hypercellular | Pleomorphic, hyperlobated, loose clusters |
| ET | JAK2 (55%), CALR (25%), MPL (5%) | Normocellular, no granulocytic hyperplasia | Large, hyperlobated (staghorn), scattered |
| PMF | JAK2 (55%), CALR (25%), MPL (5%) | Fibrosis, sinusoidal dilation | Cloud-like nuclei, tight clusters |

### Chronic Myeloid Leukemia (CML)

CML is defined by the BCR-ABL1 fusion gene resulting from the Philadelphia chromosome, t(9;22)(q34.1;q11.2). Morphologically, the peripheral blood shows marked leukocytosis with full-spectrum granulocytic maturation including a characteristic "myelocyte bulge," along with basophilia and small hypolobated (dwarf) megakaryocytes. The bone marrow is hypercellular with granulocytic hyperplasia and increased megakaryocytes that are typically small and hypolobated. CML progresses through three phases: chronic phase (fewer than 10% blasts), accelerated phase (10-19% blasts with additional cytogenetic abnormalities), and blast phase (20% or more blasts, which may be myeloid or lymphoid). Treatment with tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) has transformed prognosis, and molecular monitoring by quantitative BCR-ABL1 RT-PCR guides treatment decisions. Treatment-free remission is now achievable for patients sustaining deep molecular response (MR4.5).

### Polycythemia Vera (PV)

PV presents with elevated hemoglobin and hematocrit, splenomegaly, aquagenic pruritus, erythromelalgia, and significantly increased thrombosis risk. JAK2 V617F mutation is found in more than 95% of cases, with JAK2 exon 12 mutations accounting for rare cases presenting with isolated erythrocytosis. The bone marrow is hypercellular with panmyelosis (expansion of all three lineages), pleomorphic megakaryocytes with hyperlobated nuclei forming loose clusters, and depleted iron stores. WHO diagnostic criteria require hemoglobin greater than 16.5 g/dL in males or 16.0 g/dL in females (or hematocrit greater than 49%/48%), a bone marrow biopsy showing age-adjusted hypercellularity with panmyelosis, and JAK2 mutation. The major risks include thrombosis, progression to post-PV myelofibrosis (15-20% at 15 years), and transformation to AML (approximately 5%).

### Essential Thrombocythemia (ET)

ET presents with sustained platelet count of 450 x 10^9/L or greater, with clinical risks of both thrombosis and hemorrhage. The molecular landscape includes JAK2 V617F (approximately 55%), CALR mutation (approximately 25%), MPL mutation (approximately 5%), and triple-negative cases (approximately 15%). The bone marrow is normocellular or mildly hypercellular with characteristic large mature megakaryocytes displaying hyperlobated (staghorn) nuclei. Importantly, there is no significant granulocytic or erythroid hyperplasia, and reticulin fibrosis is minimal (MF-0 to MF-1). ET is a diagnosis of exclusion: CML (BCR-ABL1), PV, PMF, and reactive thrombocytosis must all be excluded. CALR-mutated ET carries lower thrombosis risk than JAK2-mutated disease.

### Primary Myelofibrosis (PMF)

PMF presents with a characteristic leukoerythroblastic blood picture featuring teardrop red blood cells (dacrocytes), nucleated red blood cells, and immature granulocytes, along with progressive splenomegaly and constitutional symptoms. The molecular profile parallels ET: JAK2 V617F (approximately 55%), CALR (approximately 25%), MPL (approximately 5%), and triple-negative (approximately 10%). PMF is divided into two stages. Prefibrotic PMF shows a hypercellular marrow with granulocytic hyperplasia and atypical megakaryocytes with cloud-like or balloon-like hyperchromatic nuclei forming dense clusters, with minimal fibrosis (MF-0 to MF-1). Overt PMF shows reticulin and collagen fibrosis (MF-2 to MF-3) with osteosclerosis, dilated sinusoids with intraluminal hematopoiesis, and the same atypical megakaryocyte morphology. The key to distinguishing PMF from ET lies in megakaryocyte morphology: tight clusters with cloud-like nuclei favor PMF, while scattered large hyperlobated (staghorn) megakaryocytes favor ET. Risk stratification uses the DIPSS/DIPSS-Plus system, which guides transplant decisions.

## MDS/MPN Overlap Syndromes

### Chronic Myelomonocytic Leukemia (CMML)

CMML requires persistent monocytosis of 0.5 x 10^9/L or greater constituting 10% or more of the white blood cell count, dysplasia in at least one lineage, and fewer than 20% blasts. Morphology shows dysplastic monocytes and promonocytes, with flow cytometry demonstrating an increased immature monocyte fraction. Common molecular findings include TET2, SRSF2, ASXL1, and RUNX1 mutations, with JAK2 V617F present in the proliferative subtype. CMML is subclassified by blast count: CMML-0 (fewer than 2% blood blasts, fewer than 5% marrow), CMML-1 (2-4% blood, 5-9% marrow), and CMML-2 (5-19% blood or marrow, or Auer rods). The distinction between proliferative type (WBC 13 x 10^9/L or greater) and dysplastic type (WBC below 13 x 10^9/L) has clinical and prognostic relevance.

### MDS/MPN with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T)

This overlap entity combines features of MDS-RS (15% or more ringed sideroblasts) with persistent thrombocytosis (450 x 10^9/L or greater). The common molecular signature is a combination of SF3B1 mutation and JAK2 V617F.

## Clonal Hematopoiesis of Indeterminate Potential (CHIP)

CHIP is defined by the presence of somatic mutations (at a variant allele frequency of 2% or greater) in myeloid neoplasm-associated genes in individuals without cytopenias, morphologic dysplasia, or increased blasts. Prevalence increases significantly with age, exceeding 10% in individuals over 70. The most commonly mutated genes are DNMT3A, TET2, and ASXL1. CHIP confers a risk of approximately 0.5-1% per year of progression to a frank myeloid neoplasm and is associated with increased cardiovascular risk. It does not constitute a diagnosis of MDS or MPN.

<image>A medical illustration comparing the bone marrow and peripheral blood morphologic features of the three classic BCR-ABL1-negative myeloproliferative neoplasms. Panel A (Polycythemia Vera): Hypercellular marrow with panmyelosis showing expansion of all three lineages, pleomorphic megakaryocytes with hyperlobated nuclei in loose clusters, and depleted iron stores on Prussian blue stain. Panel B (Essential Thrombocythemia): Normocellular marrow with large mature megakaryocytes displaying hyperlobated staghorn-like nuclei, scattered individually or in loose groups, without significant granulocytic hyperplasia. Panel C (Primary Myelofibrosis, overt): Dense reticulin fibrosis (reticulin stain inset showing MF-3), dilated sinusoids with intraluminal hematopoiesis, atypical megakaryocytes with cloud-like nuclei in tight clusters, and a peripheral blood smear inset showing teardrop red blood cells, nucleated red blood cells, and immature granulocytes (leukoerythroblastic picture).</image>

<image>A medical illustration demonstrating the key morphologic features of dysplasia in myelodysplastic syndromes on bone marrow aspirate smears. Top row (Dyserythropoiesis): nuclear budding, internuclear bridging, megaloblastic change, and multinucleation in erythroid precursors. Middle row (Dysgranulopoiesis): pseudo-Pelger-Huet bilobed neutrophil, hypogranular neutrophil, and ring-shaped nucleus. Bottom row (Dysmegakaryopoiesis): micromegakaryocyte, non-lobated (monolobated) megakaryocyte, and widely separated nuclear lobes. An additional panel shows the Prussian blue iron stain with ringed sideroblasts having five or more granules encircling the nucleus.</image>

## Clinical Pearls

Always exclude reactive causes of dysplasia (B12/folate deficiency, copper deficiency, medications including methotrexate and antiretrovirals) before diagnosing MDS; a trial of supplementation may be warranted when deficiency is possible. SF3B1 mutation defines a favorable MDS subtype, and patients with MDS-RS harboring isolated SF3B1 mutation have median survival exceeding 6 years. Biallelic TP53 inactivation in MDS confers very poor prognosis with median survival under 1 year; these patients are now classified as a separate entity in the WHO 5th edition. The distinction between ET and prefibrotic PMF is clinically important but morphologically challenging; the key lies in megakaryocyte morphology -- hyperlobated staghorn forms scattered in ET versus cloud-like clustered forms in PMF. CHIP is not a disease but rather a risk factor; finding DNMT3A, TET2, or ASXL1 mutations on NGS in a patient with normal blood counts and no dysplasia does not warrant a diagnosis of MDS. CML must be excluded by BCR-ABL1 testing in all cases of sustained leukocytosis or thrombocytosis before diagnosing a BCR-ABL1-negative MPN. IPSS-M incorporating molecular data significantly reclassifies patients compared to IPSS-R and should be calculated for all new MDS patients when molecular data is available.

## References
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