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Stem
A 73-year-old man is referred with four months of fatigue and exertional dyspnoea, and two recent chest infections. He takes no regular medication and has never had chemotherapy or radiotherapy. On examination he is pale with scattered bruises over the shins; there is no hepatosplenomegaly or lymphadenopathy. Investigations: haemoglobin 78 g/L (MCV 106 fL), white cell count 2.6 x 10^9/L (neutrophils 0.8 x 10^9/L), platelets 64 x 10^9/L, reticulocytes 0.4 percent. Blood film shows macrocytosis, hypogranular hyposegmented (Pelgeroid) neutrophils and 2 percent blasts. Vitamin B12 410 ng/L, folate 9 microg/L, ferritin 320 microg/L. Bone marrow is hypercellular with dyserythropoiesis, dysplastic micromegakaryocytes and 7 percent myeloblasts; karyotype 46,XY,del(20)(q11.2)[20].
Questions
a) What is the most likely diagnosis, and state the three criteria that must be fulfilled to make it? (2 marks)
The most likely diagnosis is myelodysplastic syndrome (MDS with excess blasts, MDS-EB1). The three diagnostic criteria are: (1) dysplasia of at least 10 percent in one or more myeloid lineages (here trilineage dysplasia); (2) persistent unexplained cytopenia (pancytopenia); and (3) exclusion of secondary/reactive causes (B12, folate, alcohol, infection and drugs excluded). The 7 percent blasts place this in MDS-EB1 (5 to 9 percent), which is below the 20 percent AML threshold.
b) Outline the investigations you would perform to confirm the diagnosis, exclude mimics and risk-stratify. (4 marks)
- Bone-marrow aspirate and trephine with Prussian-blue (iron) stain — quantify dysplasia per lineage, blast percentage, micromegakaryocytes and ringed sideroblasts (this case: MDS-EB1, no excess ringed sideroblasts reported).
- Cytogenetics — conventional G-banding karyotype plus FISH for common lesions (-7/del(7q), del(5q), del(20q), trisomy 8, complex); here del(20q) (an intermediate-good lesion).
- Molecular/next-generation sequencing — TP53, SF3B1, ASXL1, RUNX1, TET2, EZH2, NRAS refine prognosis and increasingly guide therapy.
- Screen to exclude mimics — B12, folate, copper, HIV and viral serology, alcohol history, drug history (this patient's B12/folate already normal — always add copper, especially post-gastric-surgery or with zinc excess).
- Baseline prognostic bloods — LDH, EPO level (ESA-response prediction), hepatitis/iron studies, and renal/liver function.
- Risk stratification — apply the Revised International Prognostic Scoring System (IPSS-R) from blast percentage, cytogenetic category, haemoglobin and platelet count.
c) Describe the stepwise management, including risk-stratified disease-specific therapy and supportive care. (3 marks)
- Risk-stratify: this patient has higher-risk disease (MDS-EB1, pancytopenia, del(20q) — likely IPSS-R intermediate/high).
- Disease-specific therapy: start a hypomethylating agent — azacitidine 75 mg/m2 subcutaneous/IV for 7 days every 28 days (or decitabine); HMA plus venetoclax is an option. Because he is fit, begin a donor search for allogeneic haematopoietic stem-cell transplant, the only curative modality.
- Supportive care: red-cell transfusion for symptomatic anaemia (leucodepleted/irradiated if a transplant candidate); platelet transfusion for bleeding or prophylaxis under 10 to 20; prompt empirical antibiotics for neutropenic fever; iron-chelate (deferasirox) when ferritin exceeds about 1000 microg/L; antimicrobial prophylaxis as indicated.
d) State two diagnostic pitfalls specific to MDS and one prognostic implication of the blast percentage. (1 mark)
- Pitfalls: (i) mistaking B12, folate or copper deficiency (or alcohol) for MDS — copper deficiency causes anaemia/neutropenia with vacuolated precursors and ringed sideroblasts; (ii) overcalling reactive dysplasia or diagnosing MDS from dysplasia alone without a persistent cytopenia or a clone.
- Prognostic implication: a higher marrow blast percentage predicts shorter survival and a higher rate of transformation to AML; blasts of at least 20 percent reclassify the disease as AML.