Classify MDS subtypes, identify dysplastic morphology, and interpret cytogenetics for ASCP BOC hematology exam.
ASCPprep.com | Hematology
Chapter 20 — MYELODYSPLASTIC SYNDROMES
ASCP Board Exam · Lab-Focused Study Guide
Etiology & Apoptosis · Dyserythropoiesis · Dysmyelopoiesis · Dysmegakaryopoiesis · Differential Diagnosis · Abnormal Function · FAB vs WHO 2008 Classification (RCUD, RARS, RCMD, RAEB-1/2, del(5q), MDS-U, Childhood) · MDS/MPN (CMML, aCML, JMML, RARS-T) · Cytogenetics & Molecular · IPSS-R · Treatment · Practice Questions
1 · Priority Table & Quick Foundation
| Topic | Priority | Why It’s Tested |
|---|---|---|
| MDS definition: clonal, progressive cytopenias despite cellular marrow + dyspoiesis | HIGH | Rodak Q2; the core concept |
| Dyspoietic morphology in each lineage (Boxes 34-1 to 34-3) | HIGH | Film recognition (Rodak Q3) |
| Ring sideroblast definition: ≥5 iron granules circling ≥⅓ of the nucleus | HIGH | Rodak Q4 |
| WHO 2008 blast cutoffs: RCUD/RCMD <5% marrow, RAEB-1 5–9%, RAEB-2 10–19%, AML ≥20% | HIGH | Rodak Q5; Table 34-1 |
| Exclude B₁₂/folate deficiency before diagnosing MDS | HIGH | Rodak Q6; case study |
| MDS with isolated del(5q): women, anemia, normal/↑ platelets, hypolobulated megakaryocytes, lenalidomide | HIGH | Rodak Q7 |
| CMML: monocytes >1 × 10⁹/L, BCR-ABL1 negative, <20% blasts — MDS/MPN | HIGH | Rodak Q10 |
| FAB vs WHO differences (30% vs 20% blasts; CMML and RAEB-t removed) | MEDIUM | Classification history |
| Cytogenetics: +8 and −7 most common; del(5q) specific; IPSS-R | MEDIUM | Prognosis |
| Therapy-related MDS (4–7 years after therapy; now t-myeloid neoplasm) | MEDIUM | Etiology |
| Treatment: supportive, growth factors, azacitidine/decitabine, lenalidomide, HSCT | MEDIUM | Management |
| aCML, JMML (NF1), RARS-T (JAK2) | LOW | Recognition |
🎯 KEY POINT — Where to spend your time
Focus: the dyspoietic features (oval macrocytes, dimorphic RBCs, ring sideroblasts, pseudo-Pelger-Huët and agranular neutrophils, micromegakaryocytes), WHO 2008 blast thresholds, del(5q) syndrome, CMML criteria, and ruling out B₁₂/folate deficiency. Skim: IPSS-R point values, epigenetic mechanisms, individual gene frequencies.
Quick Foundation — from zero
- MDS = a group of acquired clonal stem cell disorders. The marrow is usually full of cells, but the cells are made badly and many die before release → cytopenias in the blood (ineffective hematopoiesis).
- The cells that do come out look abnormal (dyspoiesis) and often work abnormally.
- The disease mostly affects the elderly (median age 70) and can stay stable for years or progress to acute myeloid leukemia.
- The key number is the blast percentage: MDS has <20% blasts; ≥20% is AML (WHO).
- Always rule out the look-alikes — especially B₁₂/folate deficiency, which also causes macrocytes and dysplasia.
💡 Analogy
Picture a factory with a broken quality-control line. The shop floor (marrow) is crowded with workers, but most products are defective and get scrapped before shipping (apoptosis in the marrow). The few that leave the factory are oddly shaped (oval macrocytes, agranular neutrophils, giant platelets) and don’t work well. Over time the machines can go haywire and start pumping out unfinished parts (blasts) — that’s the shift to AML.
🏥 Why this matters clinically
Many elderly patients with unexplained anemia or macrocytosis have MDS. Missing B₁₂/folate deficiency and labeling it MDS would withhold a simple cure; missing MDS delays prognostic workup. Blast counts and karyotype decide whether a patient gets supportive care, lenalidomide, hypomethylating agents or a stem cell transplant.
| Concept | Plain-English Explanation |
|---|---|
| Dyspoiesis (dysplasia) | Abnormal-looking cell development in a lineage |
| Ineffective hematopoiesis | Marrow is busy, but cells die before reaching the blood |
| Ring sideroblast | Erythroid precursor with iron-loaded mitochondria circling the nucleus |
| Unilineage / multilineage dysplasia | Dysplasia in one / two or more myeloid lines |
| Blast | Very immature cell; ≥20% means acute leukemia (WHO) |
| Therapy-related MDS (t-MDS) | MDS that follows chemotherapy or radiation |
| MDS/MPN | Overlap diseases with both dysplastic and proliferative features (e.g., CMML) |
| IPSS-R | Scoring system predicting survival and AML risk in MDS |
2 · Core Content Tables
2.1 History & Definition
| Feature | Details |
|---|---|
| Old names | Refractory anemia, smoldering leukemia, oligoblastic leukemia, preleukemia |
| FAB (1982) | French-American-British group defined MDS by morphology |
| WHO (1997, revised 2008) | Adds molecular, cytogenetic and immunologic criteria |
| Definition | Acquired clonal disorders with progressive cytopenias reflecting defects in erythroid, myeloid and/or megakaryocytic maturation |
| Common to all MDS | (1) Progressive cytopenias despite cellular marrow · (2) dyspoiesis in one or more lines |
| Age | Median 70; rare <50 unless after chemo/radiation; fastest-growing group >60 |
2.2 Etiology
| Feature | Details |
|---|---|
| Primary (de novo) | Proliferation of abnormal stem cells — defect at the myeloid stem cell level (erythroid, myeloid, megakaryocytic lines affected); rarely → ALL (stem cell may have lost lymphoid potential) |
| Causes / associations | Cumulative environmental exposure; chemicals, radiation, viral infection; smoking; inherited hematologic disorders |
| Apoptosis paradox | Early MDS: ↑ apoptosis → peripheral cytopenias · later (toward leukemia): ↓ apoptosis → survival and expansion of the clone |
| Other factors | Antiangiogenic cytokines, TNF, immune system, marrow microenvironment; ↑ angiogenic factors (VEGF) |
| Therapy-related MDS | After chemotherapy/radiotherapy; median onset 4–7 years after therapy; G-CSF/GM-CSF also ↑ risk; more aggressive, quickly → AML. WHO 2008 places t-MDS with therapy-related myeloid neoplasms (AML category) |
2.3 Morphologic Evidence of Dyspoiesis (Rodak Boxes 34-1, 34-2, 34-3)
| Dyserythropoiesis | Dysmyelopoiesis | Dysmegakaryopoiesis |
|---|---|---|
| Oval macrocytes (most common blood finding) | Persistent basophilic cytoplasm (nuclear-cytoplasmic asynchrony) | Giant platelets |
| Hypochromic microcytes (with adequate iron) | Abnormal granulation: hypo-/agranular or larger granules | Platelets with abnormal granulation (hypo-/agranular); large fused granules |
| Dimorphic RBC population (clonality) | Abnormal nuclear shapes: hyposegmentation (pseudo-Pelger-Huët), hypersegmentation, nuclear rings | Circulating micromegakaryocytes |
| RBC precursors with >1 nucleus | Uneven cytoplasmic staining (dense basophilic rim) | Large mononuclear megakaryocytes |
| Abnormal nuclear shapes: lobes, buds, fragments, internuclear bridging | Agranular promyelocytes/myelocytes (can be mistaken for blasts) | Micromegakaryocytes or micromegakaryoblasts |
| Uneven cytoplasmic staining; basophilic stippling | Occasional Auer rod | Bilobed or multiple small separated nuclei |
| Ring sideroblasts; megaloblastoid development with normal B₁₂/folate | Monocytic hyperplasia common in marrow | |
| Also: poikilocytosis, Howell-Jolly bodies, siderocytes | Agranular bands misclassified as monocytes |
2.4 Additional Marrow Findings
| Feature | Details |
|---|---|
| Erythroid | Hyperplasia or hypoplasia |
| Myeloid | Hypoplasia or hyperplasia |
| ALIP* | Abnormal localization of immature precursors: myeloblasts/promyelocytes cluster centrally in biopsy sections instead of along the endosteal surface — characteristic of MDS |
| Ring sideroblast | Erythroid precursor with ≥5 iron granules whose mitochondria circle ≥⅓ of the nucleus (Prussian blue) |
*The acronym ALIP is standard terminology; Rodak describes the finding without the abbreviation.
2.5 Differential Diagnosis — Dysplasia Is Not Enough
| Feature | Details |
|---|---|
| Vitamin B₁₂ or folate deficiency | Pancytopenia + dysplasia (megaloblastic) — always check levels |
| Heavy metals | Exposure (e.g., arsenic, lead*) can cause dysplasia |
| Copper deficiency | Reversible myelodysplasia |
| Congenital | Fanconi anemia, congenital dyserythropoietic anemia |
| Infections | Parvovirus B19, HIV |
| Drugs | Chemotherapeutic agents |
| PNH | Similar features |
| Key step | Thorough history and physical, including drug and chemical exposures |
*Specific metals are general-reference examples; Rodak says ‘exposure to heavy metals’.
2.6 Abnormal Cellular Function
| Feature | Details |
|---|---|
| Granulocytes | ↓ Adhesion, deficient phagocytosis, ↓ chemotaxis, impaired microbicidal capacity; ↓ MPO and alkaline phosphatase |
| RBCs | Shortened survival; erythroid precursors respond poorly to EPO |
| Platelets | Increased bleeding despite adequate platelet numbers |
| Depends on | The specific stem cell mutation |
2.7 FAB vs WHO Classification
| Feature | FAB (1982) | WHO (2008) |
|---|---|---|
| Basis | Morphology only (dysplasia + marrow blasts) | Morphology + molecular, cytogenetic, immunologic |
| AML blast threshold | ≥30% | ≥20% |
| Categories | RA · RARS · RAEB · CMML · RAEB-t | RCUD · RARS · RCMD · RAEB-1/2 · del(5q) · MDS-U · childhood (provisional) |
| CMML | In MDS | Moved to MDS/MPN |
| RAEB-t (20–29% blasts) | In MDS | Now AML |
| Therapy-related, childhood MDS | Not addressed | Therapy-related myeloid neoplasms; refractory cytopenia of childhood |
2.8 WHO 2008 MDS Categories (Rodak Table 34-1)
| Disease | Blood | Bone Marrow |
|---|---|---|
| RCUD (RA, RN, RT) | Unicytopenia (bicytopenia occasionally); no/rare blasts (<1%) | Unilineage dysplasia ≥10% of one lineage; <5% blasts; <15% of erythroid precursors are ring sideroblasts |
| RARS | Anemia; no blasts | ≥15% ring sideroblasts; erythroid dysplasia only; <5% blasts |
| RCMD | Cytopenia(s); <1% blasts; no Auer rods; monocytes <1 × 10⁹/L | Dysplasia ≥10% in two or more lineages; <5% blasts; no Auer rods; ± 15% ring sideroblasts |
| RAEB-1 | Cytopenia(s); <5% blasts (2–4%); no Auer rods; monocytes <1 × 10⁹/L | Uni- or multilineage dysplasia; 5–9% blasts; no Auer rods |
| RAEB-2 | Cytopenia(s); 5–19% blasts; ± Auer rods; monocytes <1 × 10⁹/L | Uni- or multilineage dysplasia; 10–19% blasts; ± Auer rods |
| MDS-U | Cytopenia(s); ≤1% blasts | Unequivocal dysplasia in <10% of cells in ≥1 lineage with a cytogenetic abnormality presumptive of MDS; <5% blasts |
| MDS with isolated del(5q) | Anemia; platelets usually normal or ↑; <1% blasts | Normal to ↑ megakaryocytes with hypolobulated nuclei; <5% blasts; isolated del(5q); no Auer rods |
Footnotes: pancytopenia in RCUD → MDS-U. Marrow <5% blasts but blood 2–4% → RAEB-1. RCUD/RCMD with 1% blood blasts → MDS-U. Auer rods with <5% blood and <10% marrow blasts → RAEB-2.
2.9 WHO Categories — Clinical Details
| Feature | Details |
|---|---|
| RCUD | Symptoms from the cytopenia (fatigue/dyspnea, infections, bleeding). Includes RA (<15% ring sideroblasts), refractory neutropenia, refractory thrombocytopenia. Cytogenetic abnormalities in up to 50% of RA (none specific). Median survival 2–5 years; only 2% → AML |
| RARS | Anemia + dyserythropoiesis; >15% ring sideroblasts; dimorphic blood picture; older patients; mean survival 69–108 months. RARS with marked thrombocytosis + JAK2 V617F → MDS/MPN (RARS-T). Acquired sideroblastic anemia is not MDS |
| RCMD | One or more cytopenias, dysplasia in ≥2 lines, <1% blood and <5% marrow blasts, no Auer rods (Auer rods → RAEB-2). RCMD with >15% ring sideroblasts stays RCMD — more aggressive than RARS |
| RAEB | Trilineage cytopenias, marked dysmyelopoiesis/dysmegakaryopoiesis; blood 2–19%, marrow 5–19% blasts; RAEB-1 vs RAEB-2 by blast %. Auer rods → RAEB-2 regardless of blast count. >10% marrow blasts = more aggressive |
| del(5q) (5q− syndrome) | Mostly women, median age 67; refractory anemia ± thrombocytosis; hypolobulated megakaryocytes; erythroid hypoplasia; <5% blasts; no Auer rods; long stable course (median survival 145 months). Lenalidomide effective |
| MDS-U | Lacks features for a specific category; reclassify if features develop |
| Childhood MDS | De novo very rare; provisional refractory cytopenia of childhood |
2.10 Myelodysplastic/Myeloproliferative Neoplasms (Rodak Box 34-5)
| Disorder | Key Criteria | Notes |
|---|---|---|
| CMML | Persistent monocytosis >1.0 × 10⁹/L; no BCR-ABL1; <20% blasts + promonocytes in blood and marrow; dysplasia in ≥1 myeloid line | ↑ WBC with absolute monocytosis; dysgranulopoiesis; neutrophil precursors <10% of WBCs; splenomegaly (leukemic infiltration). Cytogenetic abnormalities in up to 40% (none specific). CMML-1: <5% blood, <10% marrow blasts+promonocytes; CMML-2: 5–19% blood or 10–19% marrow (worse) |
| Atypical CML, BCR-ABL1 negative | Leukocytosis with dysplastic neutrophils and precursors; multilineage dysplasia; basophilia not prominent | Pelger-Huët–like cells, hypogranularity, bizarre segmentation; poor prognosis (AML or marrow failure) |
| JMML | Clonal granulocytic + monocytic proliferation in children 1 month–14 years | Strong association with neurofibromatosis type 1; allogeneic HSCT effective in ~50% |
| MDS/MPN, unclassifiable | Meets MDS/MPN criteria but no subcategory | Provisional RARS-T: RARS + thrombocytosis + JAK2 V617F |
2.11 Cytogenetics, Molecular Alterations & Epigenetics
| Feature | Details |
|---|---|
| Frequency | Chromosome abnormalities in ~50% of de novo MDS and 90–95% of t-MDS |
| Importance | Karyotype strongly affects prognosis; may predict response to treatment |
| Balanced translocations | Common in AML but rare in de novo MDS |
| Specificity | Except del(5q), no abnormality is specific to a subtype |
| Common chromosomes | 5, 7, 8, 11, 13, 20 |
| Most common single abnormalities | Trisomy 8 and monosomy 7; less common 12p−, iso 17, −22, loss of Y |
| Mutations | TP53, RUNX1, TET2 most common (not specific); NRAS in a small percentage (~20% in treatment section). Multistep process to AML. TET2 = more favorable; TP53 = higher transformation risk |
| Epigenetics | Gene expression changes without DNA sequence change; tumor-suppressor/apoptosis genes hypermethylated; demethylating agents slow progression |
2.12 Revised International Prognostic Scoring System (IPSS-R, Rodak Table 34-2)
| Parameter | 0 | 0.5 | 1 | 1.5 | 2 | 3 | 4 |
|---|---|---|---|---|---|---|---|
| Cytogenetics | Very good | — | Good | — | Intermediate | Poor | Very poor |
| Marrow blasts (%) | ≤2 | — | >2 to <5 | — | 5–10 | >10 | — |
| Hemoglobin (g/dL) | ≥10 | — | 8 to <10 | <8 | — | — | — |
| Platelets (× 10⁹/L) | ≥100 | 50 to <100 | <50 | — | — | — | — |
| ANC (× 10⁹/L) | ≥0.8 | <0.8 | — | — | — | — | — |
| Risk Group (Score) | Median Survival | Karyotype Group | Examples |
|---|---|---|---|
| Very low (≤1.5) | 8.8 years | Very good | −Y, del(11q) |
| Low (>1.5–3) | 5.3 years | Good | Normal, del(5q), del(12p), del(20q), double incl. del(5q) |
| Intermediate (>3–4.5) | 3.0 years | Intermediate | del(7q), +8, +19, i(17q), any other single/double |
| High (>4.5–6) | 1.6 years | Poor | −7, inv(3)/t(3q)/del(3q), double incl. −7/del(7q), complex 3 abnormalities |
| Very high (>6) | 0.8 years | Very poor | Complex >3 abnormalities |
IPSS (1997) used cytogenetics, marrow blasts and cytopenias; IPSS-R (2012) split cytogenetics into five groups, refined blast groups and added depth of cytopenias. Age, ferritin, performance status and LDH affect survival but not AML transformation.
2.13 Treatment
| Feature | Details |
|---|---|
| Goal | Improve quality of life and prolong survival (many patients elderly with comorbidities) |
| Supportive care | Main mode for most: RBC and platelet transfusions; prevent/treat infection |
| Low-risk | Growth factors (EPO, TPO, G-CSF) — some respond despite normal levels; immunosuppression (antithymocyte globulin, cyclosporine) ↓ leukemic transformation |
| Lenalidomide (Revlimid, 2005) | Thalidomide analogue for low/intermediate-risk MDS, especially del(5q): transfusion independence 64%, median Hb +3.9 g/dL, complete cytogenetic remission 55%; immunomodulatory and antiangiogenic; can cause myelosuppression |
| Hypomethylating agents | Azacitidine and decitabine (DNMT inhibitors) — high-risk MDS; low dose, minimal side effects |
| Farnesyltransferase inhibitors | Target NRAS-mutated MDS (~20%) |
| Cure | Hematopoietic stem cell transplant — consider for IPSS intermediate-2 or higher, or >10% blasts; best if <70 without comorbidity |
| Future | Apoptosis-controlling drugs; customized plans; informed patient decisions |
3 · Visual Memory Hooks
🧠 MDS in one line
“Busy marrow, empty blood, ugly cells”.
“Busy marrow, empty blood, ugly cells”.
🧠 Apoptosis paradox
“Early MDS kills too many; late MDS kills too few”.
“Early MDS kills too many; late MDS kills too few”.
🧠 Top blood clue
“Oval macrocytes + normal B₁₂/folate = think MDS”.
“Oval macrocytes + normal B₁₂/folate = think MDS”.
🧠 Ring sideroblast
“Five beads around a third” — ≥5 granules, ≥⅓ of the nucleus.
“Five beads around a third” — ≥5 granules, ≥⅓ of the nucleus.
🧠 RARS threshold
“15 rings = RARS” (≥15% ring sideroblasts).
“15 rings = RARS” (≥15% ring sideroblasts).
🧠 Blast ladder
“<5 Calm (RCUD/RCMD), 5–9 RAEB-1, 10–19 RAEB-2, 20 = AML”.
“<5 Calm (RCUD/RCMD), 5–9 RAEB-1, 10–19 RAEB-2, 20 = AML”.
🧠 Auer rods
“An Auer rod Automatically upgrades to RAEB-2”.
“An Auer rod Automatically upgrades to RAEB-2”.
🧠 FAB vs WHO
“FAB needed 30, WHO needs 20”.
“FAB needed 30, WHO needs 20”.
🧠 5q−
“5q− = Female, Fine platelets (normal/high), Floppy (hypolobulated) megakaryocytes, lenalidomide”.
“5q− = Female, Fine platelets (normal/high), Floppy (hypolobulated) megakaryocytes, lenalidomide”.
🧠 RCMD vs RARS
“More lines = More trouble” — multilineage beats ring sideroblasts.
“More lines = More trouble” — multilineage beats ring sideroblasts.
🧠 CMML
“Monocytes over 1, no Philly, blasts under 20”.
“Monocytes over 1, no Philly, blasts under 20”.
🧠 JMML
“JMML Joins NF1”.
“JMML Joins NF1”.
🧠 RARS-T
“Rings + Thrombocytosis + JAK2”.
“Rings + Thrombocytosis + JAK2”.
🧠 Cytogenetics
“8 up, 7 down” — trisomy 8, monosomy 7 most common.
“8 up, 7 down” — trisomy 8, monosomy 7 most common.
🧠 Mutations
“TP53 = Terrible; TET2 = Tolerable”.
“TP53 = Terrible; TET2 = Tolerable”.
🧠 Treatment
“Low risk: Lenalidomide/growth factors · High risk: Aza/Decitabine · Cure: transplant”.
“Low risk: Lenalidomide/growth factors · High risk: Aza/Decitabine · Cure: transplant”.
Pattern Triggers
| If you see… | Think… | Because… |
|---|---|---|
| Elderly, pancytopenia, MCV 110, normal B₁₂/folate, cellular marrow | MDS | Ineffective hematopoiesis |
| Same picture but low B₁₂, hypersegmented neutrophils | Megaloblastic anemia | Treatable mimic |
| Dimorphic RBCs, ≥15% ring sideroblasts, erythroid dysplasia only | RARS | |
| Ring sideroblasts + dysplasia in neutrophils and megakaryocytes | RCMD | Multilineage wins |
| Marrow blasts 7% | RAEB-1 | |
| Marrow blasts 4% with Auer rods | RAEB-2 | Auer rod rule |
| Marrow blasts 23% | AML (WHO) | ≥20% |
| Elderly woman, macrocytic anemia, platelets 550, hypolobulated megakaryocytes, isolated del(5q) | MDS with isolated del(5q) | Lenalidomide |
| Monocytes 2.5 × 10⁹/L, dysplasia, splenomegaly, BCR-ABL1 − | CMML | MDS/MPN |
| Child with NF1, monocytosis, splenomegaly | JMML | |
| Leukocytosis with dysplastic, hypogranular, Pelger-like neutrophils, Ph − | Atypical CML | |
| MDS 5 years after breast cancer chemotherapy | Therapy-related myeloid neoplasm | Complex karyotype, aggressive |
| Agranular ‘monocytes’ in a differential | Agranular neutrophils/bands (dysmyelopoiesis) | Misclassification risk |
| Normal platelet count but bleeding | Platelet dysfunction in MDS | Abnormal function |
Commonly Confused Pairs
| Feature | A | B |
|---|---|---|
| MDS vs megaloblastic anemia | Normal B₁₂/folate; ring sideroblasts, dimorphism | Low B₁₂/folate; corrects with vitamins |
| MDS vs aplastic anemia* | Cellular dysplastic marrow | Hypocellular marrow without dysplasia |
| RARS vs acquired sideroblastic anemia | Clonal MDS | Reversible (alcohol, drugs) — not MDS |
| RARS vs RCMD | Erythroid dysplasia only; better survival | ≥2 lineages; more aggressive |
| RAEB-1 vs RAEB-2 | Marrow 5–9%, blood <5% | Marrow 10–19%, blood 5–19%, or Auer rods |
| RCUD vs MDS-U | Unicytopenia | Pancytopenia, 1% blood blasts, or <10% dysplasia + cytogenetics |
| FAB RAEB-t vs WHO | 20–29% blasts = MDS | = AML |
| CMML vs CML | Monocytosis, BCR-ABL1 − | Basophilia, BCR-ABL1 + |
| CMML-1 vs CMML-2 | Blood <5%, marrow <10% blasts+promonocytes | 5–19% / 10–19% |
| Pseudo-Pelger-Huët vs true PHA | Acquired, hypogranular, MDS | Inherited, normal granulation |
| Agranular promyelocyte vs blast | Dysplastic granule loss | True blast — affects AML count |
*Aplastic anemia comparison from Ch. 11 of this course, not Rodak Ch. 34.
Timeline Table
| Event | Timing / Value | Key Point | Best Exam Use |
|---|---|---|---|
| FAB classification | 1982 | Morphology, 30% blasts | History |
| WHO classification | 1997, revised 2008 | 20% blasts | History |
| Therapy-related MDS onset | 4–7 years after therapy | Aggressive | Etiology |
| IPSS / IPSS-R | 1997 / 2012 | Prognosis | Scoring |
| Lenalidomide FDA approval | 2005 | Low/int risk, del(5q) | Treatment |
| RCUD survival | 2–5 years; 2% → AML | Low risk | Prognosis |
| RARS survival | 69–108 months | Low risk | Prognosis |
| del(5q) survival | Median 145 months | Best | Prognosis |
| IPSS-R very high | 0.8 years | Worst | Prognosis |
4 · Diagnostic Flowcharts
Flowchart 1 — Cytopenia with macrocytosis in an older adult
| Pancytopenia/anemia + ↑ MCV | → | Check B₁₂, folate, copper, drugs, alcohol, HIV/parvovirus |
| Deficiency found | → | Treat and reassess — not MDS |
| All normal, dysplasia on film | → | Marrow aspirate + biopsy with iron stain |
| Cellular marrow, dysplasia ≥10% in a lineage | → | MDS → count blasts, ring sideroblasts |
| Karyotype | → | Classify (del(5q)) and score IPSS-R |
| ⚠️ Common mistake: labeling macrocytic dysplasia as MDS without measuring B₁₂ and folate. | ||
Flowchart 2 — WHO 2008 classification by blasts
| Marrow blasts ≥20% (or blood ≥20%) | → | AML |
| Marrow 10–19% or blood 5–19% or Auer rods | → | RAEB-2 |
| Marrow 5–9% or blood 2–4% | → | RAEB-1 |
| Marrow <5%, blood <1% | → | Go to Flowchart 3 (lineages/ring sideroblasts/del(5q)) |
| Blood exactly 1% with RCUD/RCMD features | → | MDS-U |
| ⚠️ Common mistake: forgetting that blood blasts alone (2–4%) upgrade a case to RAEB-1. | ||
Flowchart 3 — Low-blast MDS subtypes
| Isolated del(5q), hypolobulated megakaryocytes | → | MDS with isolated del(5q) |
| Dysplasia in ≥2 lineages | → | RCMD (even with ≥15% ring sideroblasts) |
| Erythroid dysplasia only + ≥15% ring sideroblasts | → | RARS |
| One lineage dysplastic, <15% ring sideroblasts, uni/bicytopenia | → | RCUD (RA, RN, RT) |
| Pancytopenia with unilineage dysplasia, or <10% dysplasia + MDS karyotype | → | MDS-U |
| ⚠️ Common mistake: calling a case RARS because of many ring sideroblasts when neutrophils and megakaryocytes are also dysplastic. | ||
Flowchart 4 — Monocytosis with dysplasia
| Monocytes >1 × 10⁹/L persistently | → | Exclude reactive causes |
| BCR-ABL1 test | → | Positive → CML · negative → continue |
| Blasts + promonocytes <20% + dysplasia | → | CMML |
| Blood <5% / marrow <10% | → | CMML-1 · higher → CMML-2 |
| Child 1 month–14 years, NF1 | → | JMML |
| ⚠️ Common mistake: counting promonocytes as mature monocytes — they count with blasts. | ||
Flowchart 5 — Case study reasoning
| 43-year-old: pancytopenia, MCV 132, normal B₁₂/folate | → | Differential: megaloblastic anemia, MDS, drugs/alcohol, liver disease, HIV/parvovirus |
| Marrow: dysplastic megaloblastoid erythroid line, adequate megakaryocytes, dup(1q) | → | Probable MDS (dyserythropoiesis with clonal karyotype) |
| 6 years later: dysplasia in erythroid, granulocytic and megakaryocytic lines + 50–60% ring sideroblasts | → | Multilineage dysplasia |
| WHO 2008 | → | RCMD (ring sideroblasts don’t make it RARS when ≥2 lineages are dysplastic)* |
| ⚠️ Common mistake: choosing RARS because of the ring sideroblasts. | ||
*My interpretation — the case answer key isn’t in the upload. At presentation, pancytopenia with erythroid-only dysplasia would fall into MDS-U per the Table 34-1 footnote.
Flowchart 6 — Choosing therapy
| Low risk, symptomatic anemia | → | Transfusion ± EPO/growth factors |
| Isolated del(5q) | → | Lenalidomide |
| Hypoplastic/low risk | → | Immunosuppression (ATG, cyclosporine) |
| High risk | → | Azacitidine or decitabine |
| IPSS int-2 or higher, or >10% blasts, <70, fit | → | Allogeneic HSCT (only cure) |
| ⚠️ Common mistake: giving aggressive chemotherapy to a stable del(5q) patient — supportive care and lenalidomide are preferred. | ||
5 · 25 High-Yield Facts
| # | Fact |
|---|---|
| 1 | MDSs are acquired clonal stem cell disorders with progressive cytopenias and dyspoiesis. |
| 2 | Progressive cytopenias despite a cellular marrow are common to all MDS. |
| 3 | The median age at MDS diagnosis is about 70; MDS is most common in people older than 50. |
| 4 | Apoptosis is increased in early MDS and decreased as the disease progresses toward leukemia. |
| 5 | Therapy-related MDS appears 4–7 years after chemotherapy or radiation and is often aggressive. |
| 6 | Oval macrocytes are the most common peripheral blood finding of dyserythropoiesis. |
| 7 | A dimorphic RBC population is evidence of clonality in MDS. |
| 8 | Target cells are not a characteristic diagnostic clue for MDS. |
| 9 | A ring sideroblast has at least 5 iron granules encircling at least one third of the nucleus. |
| 10 | Dysmyelopoiesis includes hypogranular neutrophils, pseudo-Pelger-Huët nuclei and nuclear rings. |
| 11 | Agranular bands can be misclassified as monocytes, and agranular promyelocytes as blasts. |
| 12 | Dysmegakaryopoiesis includes giant platelets, abnormal granulation and micromegakaryocytes. |
| 13 | Abnormal localization of immature precursors (central clusters) is characteristic of MDS biopsies. |
| 14 | Vitamin B₁₂ and folate deficiency must be excluded before diagnosing MDS. |
| 15 | MDS neutrophils may have decreased myeloperoxidase and alkaline phosphatase. |
| 16 | WHO lowered the AML blast threshold from 30% (FAB) to 20%. |
| 17 | RARS requires ≥15% ring sideroblasts with erythroid-only dysplasia. |
| 18 | RAEB-1 has 5–9% marrow blasts; RAEB-2 has 10–19% marrow blasts or Auer rods. |
| 19 | MDS with isolated del(5q) affects mainly women, shows hypolobulated megakaryocytes and responds to lenalidomide. |
| 20 | CMML requires monocytes >1 × 10⁹/L, no BCR-ABL1, and <20% blasts + promonocytes. |
| 21 | WHO classifies CMML as a myelodysplastic/myeloproliferative neoplasm. |
| 22 | JMML is strongly associated with neurofibromatosis type 1. |
| 23 | Trisomy 8 and monosomy 7 are the most common single cytogenetic abnormalities in MDS. |
| 24 | MDS often converts to AML; neuropathy is not a usual cause of death. |
| 25 | Azacitidine and decitabine are hypomethylating agents; stem cell transplant is the only cure. |
⭐ EXAM TIP — The single most testable pattern
Older adult + cytopenias + oval macrocytes + normal B₁₂/folate + cellular dysplastic marrow = MDS. Then classify by blasts (<5, 5–9, 10–19, ≥20 = AML), lineages (one vs ≥2), ring sideroblasts (≥15%) and del(5q). Monocytes >1 × 10⁹/L → CMML (MDS/MPN).
Quick Interpretation Table
| Lab Finding | Clinical Interpretation |
|---|---|
| 43-year-old: WBC 2.2, Hb 6.1, platelets 51, MCV 132, normal B₁₂/folate; later trilineage dysplasia + 50–60% ring sideroblasts | MDS — RCMD (Rodak case study, my interpretation) |
| 60-year-old woman: Hb 8, platelets 550, WBC 3.8, erythroid hypoplasia, hypolobulated megakaryocytes, isolated del(5q) | MDS with isolated del(5q) → supportive care; lenalidomide if it progresses (Rodak Q7) |
| Anemia, oval macrocytes, hypersegmented neutrophils | Order B₁₂ and folate first (Rodak Q6) |
| Marrow blasts 12%, blood blasts 3% | RAEB-2 |
| Marrow 3% blasts, Auer rods present | RAEB-2 |
| Blood 3% blasts, marrow 4% | RAEB-1 |
| Monocytes 3.2 × 10⁹/L, blasts + promonocytes 12% marrow, BCR-ABL1 − | CMML-2 |
| Karyotype: 4 unrelated abnormalities | Very poor IPSS-R cytogenetics |
🎴 Flashcards — Active Recall Practice
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📝 Practice Quiz — Test Your Knowledge
How it works: tap an answer for each case. You’ll get instant feedback with the full explanation and the examiner’s trap. Your final score appears once all 10 are answered.
🪤 Trap Questions — Beat the Examiner
Harder on purpose. Each question targets a real misconception. After answering you’ll see the correct reasoning, the trap explained, why the examiner wrote it, and the wrong answer most students choose.
8 · Rapid Revision Sheet
📖 READ THIS 2 HOURS BEFORE YOUR EXAM
Basics
- Clonal myeloid stem cell disorder
- Cytopenias + cellular marrow + dyspoiesis
- Median age 70; rare <50
- Early ↑ apoptosis → late ↓ apoptosis
- t-MDS 4–7 yr after therapy; aggressive
Dyserythropoiesis
- Oval macrocytes (most common)
- Dimorphic RBCs · hypochromic microcytes
- Multinuclear, buds, bridging, stippling
- Ring sideroblasts: ≥5 granules, ≥⅓ nucleus
- Megaloblastoid with normal B₁₂/folate
Dysmyelo & Dysmegakaryo
- Hypo/agranular neutrophils, pseudo-PHA, rings
- Persistent basophilic cytoplasm
- Agranular bands ≠ monocytes
- Giant platelets, agranular platelets
- Micromegakaryocytes, mononuclear megas
Differential & Function
- Exclude B₁₂/folate, copper, metals
- Parvovirus B19, HIV, drugs, PNH
- Fanconi, CDA
- ↓ MPO and ALP in neutrophils
- Bleeding with normal platelet count
FAB vs WHO
- FAB 1982: RA, RARS, RAEB, CMML, RAEB-t
- FAB AML ≥30% · WHO ≥20%
- WHO: RCUD, RARS, RCMD, RAEB-1/2, 5q−, MDS-U
- CMML → MDS/MPN · RAEB-t → AML
- Childhood: refractory cytopenia of childhood
WHO Blast Rules
- RCUD/RCMD: <1% blood, <5% marrow
- RAEB-1: 2–4% blood or 5–9% marrow
- RAEB-2: 5–19% blood or 10–19% marrow
- Auer rods → RAEB-2
- Pancytopenia in RCUD → MDS-U
Subtypes
- RCUD: 2–5 yr, 2% → AML
- RARS: ≥15% RS, erythroid only, 69–108 mo
- RCMD: ≥2 lines; worse than RARS
- 5q−: women, 67 yr, ↑/N plts, hypolobulated megas
- 5q− survival 145 mo → lenalidomide
MDS/MPN
- CMML: mono >1, BCR-ABL1 −, <20% blasts+promono
- CMML-1 vs CMML-2 (5/10% cutoffs)
- aCML: dysplastic neutrophils, Ph −
- JMML: 1 mo–14 yr, NF1
- RARS-T: rings + thrombocytosis + JAK2
Genetics & Prognosis
- Abnormal karyotype 50% de novo, 90–95% t-MDS
- +8 and −7 most common
- Only del(5q) subtype-specific
- TP53 (bad), RUNX1, TET2 (better), NRAS
- IPSS-R: 5 groups, 0.8–8.8 yr
Treatment
- Supportive: transfusions, antibiotics
- Low risk: EPO/G-CSF, ATG/cyclosporine
- Lenalidomide: del(5q)
- High risk: azacitidine, decitabine
- Cure: HSCT (<70, int-2+ or >10% blasts)
9 · Final Memory Map
- 🧩 MYELODYSPLASTIC SYNDROMES
- Etiology
- Primary vs therapy-related
- Clonal myeloid stem cell · apoptosis paradox
- Morphology
- Dyserythropoiesis · ring sideroblasts
- Dysmyelopoiesis · pseudo-PHA · agranular cells
- Dysmegakaryopoiesis · micromegakaryocytes · ALIP
- Differential
- B₁₂/folate · copper · metals · drugs
- Parvovirus, HIV, PNH, congenital
- Classification
- FAB (30%) → WHO 2008 (20%)
- RCUD · RARS · RCMD · RAEB-1/2 · 5q− · MDS-U · childhood
- MDS/MPN
- CMML-1/2 · aCML · JMML · RARS-T
- Genetics & Prognosis
- +8, −7, del(5q) · TP53, RUNX1, TET2, NRAS
- Epigenetic hypermethylation · IPSS-R
- Treatment
- Supportive · growth factors · immunosuppression
- Lenalidomide · azacitidine/decitabine · HSCT
- Etiology