Myelodysplastic Syndromes

Overview

MDS = heterogeneous clonal stem cell disorders, abnormal marrow lineage development (dysmyelopoiesis). Signature: cytopenias despite CELLULAR marrow (ineffective haematopoiesis — marrow busy but output defective). Also called preleukaemic/dysmyelopoietic syndromes.

Classification

Both schemes built around marrow blast % (dividing line from AML).

FAB (AML cutoff >30% blasts), 5 types: RA (blood blast<1%, marrow<5%), RARS (same + ring sideroblasts>15%), RAEB (marrow 5-20%), RAEB-t (marrow 21-30%), CMML (monocytosis).

WHO (AML cutoff ≥20%): RAEB-t → reclassified as AML. CMML → removed from MDS, goes to hybrid myelodysplastic/myeloproliferative category. 8 WHO types:

1. RA — anaemia, no blood blasts, marrow<5%
2. RARS — same as FAB
3. RCMD — 2-3 lineage cytopenia, no blasts, marrow<5%
4. RCMD-RS — RCMD + ring sideroblasts>15%
5. RAEB-1 — marrow blasts 5-9%
6. RAEB-2 — marrow blasts 10-19%
7. MDS-U (unclassified) — cytopenia, no blasts, marrow dysplasia<5%
8. MDS with isolated del(5q) — anaemia, blasts<5%, hypolobated megakaryocytes, 5q deletion

Pathophysiology

Primary: idiopathic (radiation, benzene implicated). Secondary/therapy-related: post-anticancer Rx, immunosuppression for aplastic anaemia, Fanconi anaemia — NOT age-related, ~decade after causative therapy. Cytogenetic abnormalities in ~50% (trisomy, translocation, deletion); leukaemic transformation cases → more aneuploidy. Molecular: N-RAS + p53 mutations + suppressed immunity → ↑marrow apoptosis. Mitochondrial gene mutations → ring sideroblasts/disordered iron metabolism.

Clinical features

6th decade, slight male preponderance (therapy-related not age-linked). Often non-specific/incidental (routine CBC). Anaemia, fever, weight loss, Sweet syndrome (some), splenomegaly (20%).

Lab findings

Blood: bi/pancytopenia. Anaemia macrocytic/dimorphic. TLC usually normal (high TLC → think CMML, not MDS). Neutrophils hyposegmented/hypogranulated. Myeloblasts on smear correlate with marrow blasts. Platelets: thrombocytopenia + large agranular platelets.

Marrow: variable cellularity. Dyserythropoiesis (abnormal nuclei, ring sideroblasts, megaloblasts). Hypogranular/hyposegmented myeloid precursors. Reduced, abnormal megakaryocytes.

Treatment/prognosis

Poor response to cytotoxic chemo. Stem cell transplant = only real cure. Prognosis by subtype: RA/RARS/5q-deletion = years; RAEB-1/2 = months. Death from infection (cytopenia) or AML transformation.

Clinical relevance

Core paradox — cytopenic blood + cellular marrow — distinguishes MDS from aplastic anaemia (cytopenic because marrow itself is EMPTY), despite both showing peripheral cytopenias. FAB→WHO reclassification (RAEB-t→AML, CMML out of MDS) shows blast-cutoff isn’t arbitrary — chosen because it tracks clinical behaviour. MDS with del(5q) = distinct favourable-prognosis genetic entity, rare example of targetable cytogenetic lesion in MDS. “Preleukaemic” label reflects genuine, substantial AML-transformation risk built into the natural history, not just a descriptive name.

Overview

Myelodysplastic syndromes (MDS) are a heterogeneous group of haematopoietic clonal stem cell disorders with abnormal development of the marrow’s cell lineages (dysmyelopoiesis), typically presenting with cytopenias despite a cellular marrow — the marrow is often busy, but its output is defective (ineffective haematopoiesis). This combination — cytopenic blood but a cellular marrow — is the conceptual signature of MDS, and is why these disorders are also called preleukaemic or dysmyelopoietic syndromes.

Classification

Two classification schemes exist, both built around the marrow blast percentage as the key dividing line from acute myeloid leukaemia.

FAB Classification

The FAB (French-American-British) scheme set the AML cut-off at marrow blasts >30%, giving 5 MDS categories:

WHO Classification

The WHO scheme revised the AML cut-off down to marrow blasts ≥20%, with two important consequences: RAEB-t (FAB group 4) is reclassified as AML, and CMML is removed from MDS entirely, placed instead in a hybrid myelodysplastic/myeloproliferative category (since it behaves more like a myeloproliferative disorder). This leaves 8 WHO categories:

1. Refractory anaemia (RA) — same as FAB; anaemia, no blood blasts, marrow blasts <5%.
2. Refractory anaemia with ringed sideroblasts (RARS) — same as FAB.
3. Refractory cytopenia with multilineage dysplasia (RCMD) — cytopenia of 2–3 lineages, no blasts; marrow blasts <5%.
4. RCMD with ringed sideroblasts (RCMD-RS) — as RCMD, plus >15% ringed sideroblasts.
5. RAEB-1 — blood cytopenia, <5% blasts, monocytosis; marrow blasts 5–9%.
6. RAEB-2 — as RAEB-1, but marrow blasts 10–19%.
7. MDS unclassified (MDS-U) — cytopenia without blasts; marrow shows myeloid/thrombocytic dysplasia, blasts <5%.
8. MDS with isolated del(5q) — anaemia, blasts <5% (blood and marrow); normal/increased, often hypolobated, megakaryocytes; characteristic isolated 5q deletion.

Pathophysiology

• Primary MDS is idiopathic, with implicated risk factors including radiation exposure and benzene.
• Secondary (therapy-related) MDS follows prior anti-cancer treatment, immunosuppressive therapy for aplastic anaemia, or occurs in Fanconi anaemia — typically not age-related, appearing roughly a decade after the causative therapy.
• Cytogenetic abnormalities (trisomy, translocations, deletions) are present in ~50% of cases; cases that evolve into leukaemia more often show aneuploidy.
• Molecularly, mutations in the N-RAS oncogene and p53 anti-oncogene, combined with suppressed immunity, accelerate marrow apoptosis. Mitochondrial gene mutations likely underlie the ringed sideroblast/disordered iron metabolism seen in some MDS subtypes.

Clinical Features

More frequent past the 6th decade, with slight male preponderance (therapy-related MDS is not age-linked). Presentation is often non-specific — sometimes an incidental finding on routine CBC:

• Anaemia (pallor, fatigue, weakness).
• Fever, weight loss.
• Sweet syndrome (neutrophilic dermatosis) in some cases.
• Splenomegaly in ~20%.

Laboratory Findings

Blood: cytopenia affecting two or three lineages. Anaemia usually macrocytic or dimorphic. Total leucocyte count usually normal (a high TLC points toward CMML, now excluded from MDS proper). Neutrophils are hyposegmented and hypogranulated; myeloblasts may appear on peripheral smear, correlating with marrow blast count. Platelets show thrombocytopenia with large agranular platelets.

Marrow: cellularity ranges normal-to-hypercellular-to-hypocellular. Dyserythropoiesis (abnormal nuclei, ring sideroblasts, occasional megaloblasts); hypogranular/hyposegmented myeloid precursors with variably increased blasts; reduced, abnormally-nucleated megakaryocytes.

Treatment and Prognosis

Poor response to cytotoxic chemotherapy; stem cell transplantation offers the only realistic cure and prolonged survival. Prognosis varies sharply by subtype — RA, RARS, and 5q-deletion syndrome patients survive for years, while RAEB-1/RAEB-2 patients have poor survival measured in months. Patients typically succumb either to infection (from cytopenia) or to transformation into acute myeloid leukaemia.

Clinical Relevance

• The core MDS paradox — cytopenic blood despite a cellular, even hypercellular, marrow — is the single most important concept to internalise, since it is what distinguishes MDS from aplastic anaemia (which is cytopenic because the marrow itself is empty) despite both presenting with peripheral cytopenias.
• The FAB-to-WHO reclassification (RAEB-t moving into AML, CMML moving out of MDS into a myeloproliferative/myelodysplastic hybrid category) is a genuinely high-yield example of how a blast-percentage cut-off is not an arbitrary number but is chosen because it correlates with clinical behaviour — RAEB-t behaves like AML, so it was reclassified as AML, and CMML behaves like a myeloproliferative disorder, so it was moved out of MDS.
• MDS-with-isolated-del(5q) is worth remembering as a distinct, favourable-prognosis genetic entity, since it is one of the relatively few haematologic malignancies with a specific, targetable cytogenetic lesion and a correspondingly better clinical course than most other MDS subtypes.
• The eventual fate of most MDS patients (death from infection due to cytopenia, or transformation to AML) is the clinical logic behind calling MDS a “preleukaemic” syndrome — it is not merely a descriptive label but reflects the genuine, substantial risk of leukaemic transformation built into the disease’s natural history.

No Rendered Diagram for This Topic

MDS is a classification-heavy topic (FAB vs WHO schemes, 8 WHO subtypes distinguished mainly by blast percentage and lineage involvement) rather than a single multi-step mechanism — the tables in notes.md already carry the structure that matters, and a diagram would just redraw them.

Hand-Draw Suggestion

Draw a single number line from 0% to 30% marking marrow blast percentage, and place each WHO subtype at its blast-count range along the line (RA/RARS/RCMD/RCMD-RS/MDS-U/del(5q) all <5%, RAEB-1 at 5-9%, RAEB-2 at 10-19%, AML starting at ≥20%). This one picture captures the single most-tested fact in the topic — where each subtype sits relative to the AML cutoff — better than a process diagram would.