WBC Disorders & Myeloproliferative Neoplasms
Learning objectives
- LO 1Review normal hematopoiesis and separate the myeloid from the lymphoid cell lines.
- LO 2Tell a reactive neutrophilia from a neoplastic one.
- LO 3Define a myeloproliferative neoplasm and name the four types.
- LO 4Describe each MPN's key features, mechanism and driver mutation.
- LO 5Lay out the work-up for a patient with each MPN.
- LO 6Connect the lab results to the clinical picture and the blood/marrow morphology.
- LO 7Build a differential diagnosis for each MPN.
- LO 8Describe how each MPN progresses and how it is treated.
MAPWhere the MPNs sit among blood cancers
LO 1Normal hematopoiesis: myeloid vs lymphoid
Q1. How are blood disorders studied?
- Clinical suspicion → lab data (CBC, peripheral smear) → lymph node assessment (imaging, biopsy) → bone marrow (aspirate + biopsy)
- Ancillary tests: flow cytometry, immunohistochemistry, cytochemistry, cytogenetics, FISH, PCR, next-generation sequencing
Marrow biopsy (core)
- Best for cellularity
- Pattern of focal processes (metastases, lymphoma)
- Stroma (fibrosis)
Marrow aspirate (fluid)
- Morphology of individual cells
- Differential counts
Site: posterior iliac crest. Indications: definitive diagnosis of most hematologic diseases; fever of unknown origin; some infections.
Normal child
- Mostly cells, little fat
Elderly adult
- Mostly fat (cellularity ≈ 100 − age)
Leukemia
- Packed, ~100% cellular
Q2. Which cells are myeloid and which are lymphoid?
Myeloid
- Granulocytes (mostly neutrophils; eosinophils, basophils), monocytes
- Red cells and platelets (megakaryocytes) too
- Stimulus → reactive increase; precursor mutation → MPN
Lymphoid
- B, T and NK cells
- Originate in marrow; T cells mature in thymus
- B and T cells are not distinguishable by morphology (need CD markers)
Myeloid vs lymphoid
- Both arise from the blood stem cell
Myelopoiesis
- Stages visible by morphology
Trap
"Myeloid" isn't just white cells: RBCs and platelets are myeloid too. That's why PV and ET are myeloid neoplasms.
Q3. How do leukemia, lymphoma, acute and chronic differ?
- Leukemia: mainly marrow + circulating tumor cells. Lymphoma: discrete tissue masses in lymph nodes or extranodal sites (Hodgkin, non-Hodgkin B or T)
| Acute | Chronic | |
|---|---|---|
| Cells | Immature "blasts" | Mature and maturing cells |
| Pathogenesis | Maturation arrest | Increased proliferation |
| Clinical | Early marrow failure: bleeding, infections, fatigue | Non-specific; organ infiltration; marked leukocytosis; late marrow failure |
| Treatment | Urgent | Non-urgent |
Oncoproteins in white cell neoplasms (non-random translocations, acquired mutations): block maturation, turn on growth signaling, alter the epigenome, inhibit apoptosis, impair tumor suppressors.
In-house exam
Myeloid disease manifestations depend on where in differentiation the transformed cell sits and how the mutation affects differentiation. Myeloid diseases can overlap and evolve into one another with extra mutations.
ApplyLO 1 application questions
A1Which marrow specimen is best for cellularity, and which for a differential count?
LO 2Reactive vs neoplastic neutrophilia
Q1. What raises or lowers the white count?
Leukocytosis (↑)
- Reactive: infection, inflammatory disorders, drugs
- Neoplastic
Leukopenia (↓)
- Inherited or acquired immunodeficiency
- Drugs, infections, malnutrition
The peripheral count depends on the marrow storage pool, the rate of release, the fraction marginated on vessel walls, and the rate of extravasation into tissue.
Causes by cell type
- Basophilia is rare → think MPN (CML)
Step 1
Steroids and epinephrine demarginate neutrophils → ↑ count without infection.
Q2. How do I tell infection-driven neutrophilia from CML?
| Reactive (infection) | Neoplastic (CML) | |
|---|---|---|
| WBC | <30 ×10⁹/L | >50 ×10⁹/L (50–400) |
| Left shift | Bands | All precursor forms (myelocytes → blasts) |
| Basophils | Absent | Absolute basophilia |
| Spleen | Not enlarged | Splenomegaly |
| Fever | Yes | No |
| Genetics | Normal | t(9;22) |
High yield
Basophilia + splenomegaly + every stage of maturation + no fever = CML until proven otherwise.
Step 1
LAP score (leukocyte alkaline phosphatase): high in a leukemoid reaction, low in CML. Leukemoid reaction may show toxic granulation and Döhle bodies.
ApplyLO 2 application question
A1WBC 180,000 with myelocytes, bands and 8% basophils; no fever; spleen palpable. Reactive or neoplastic, and which test?
LO 3What is a myeloproliferative neoplasm?
Q1. What do all MPNs share?
- Mutated, constitutively activated tyrosine kinases
- Clonal proliferation in the marrow of one or more myeloid lineages (granulocytic, erythroid, megakaryocytic)
- Maturation is effective → high peripheral counts
- Extramedullary hematopoiesis → splenomegaly, hepatomegaly
- Variable "spent phase" (marrow fibrosis) and transformation to acute leukemia
Tyrosine kinase = enzyme that moves a phosphate from ATP to a tyrosine on a target protein, switching it on without external regulation → promotes growth and survival but does not impair differentiation.
In-house exam
Tyrosine kinases promote growth and survival but do NOT impair differentiation; that's why MPN cells mature and counts go up.
Analogy — the stuck accelerator
An MPN is a factory with the accelerator stuck down but a normal assembly line: too many finished products. Acute leukemia is a broken assembly line: half-built parts (blasts) pile up.
Q2. What are the four MPNs?
| MPN | Lineage that dominates | Driver |
|---|---|---|
| Chronic myeloid leukemia (CML) | Neutrophils | BCR-ABL, t(9;22) |
| Polycythemia vera (PV) | Red cells | JAK2 >97% |
| Essential thrombocytosis (ET) | Platelets (megakaryocytes) | JAK2 50–60%, CALR 30%, MPL 5–10% |
| Primary (chronic idiopathic) myelofibrosis | Megakaryocytes → fibrosis | JAK2, CALR or MPL ≈90% |
Memory tool
One lineage each: CML = Cells that fight (neutrophils) · PV = Plethora (red) · ET = Excess platelets · PMF = Packed with Fibers.
LO 4The four MPNs: features, mechanism, genetics
Q1. CML: how does t(9;22) cause it?
- Most common MPN
- t(9;22)(q34;q11) reciprocal in 95% → Philadelphia chromosome
- Fuses BCR (chr 22) with ABL proto-oncogene (chr 9) → chimeric BCR-ABL tyrosine kinase → phosphorylates many downstream effectors
- Result: ↑ proliferation, stem cell expansion, delayed apoptosis, premature release of immature granulocytes
- Adults (25–60, median 55): gradual fatigue, weight loss, night sweats; abdominal discomfort / early satiety from splenomegaly
Massive splenomegaly
- Early satiety, abdominal fullness
CML blood and marrow
- Neutrophils at every stage + basophils; hypercellular marrow
In-house exam
59-year-old man, tired, early satiety → CML. Ph chromosome = BCR (chr 22) + ABL (chr 9) → always-on kinase.
Memory tool
"Philadelphia CreaML cheese": t(9;22) → CML. "9 to 22 is a long shift, so you're always on."
Q2. Polycythemia vera: why too many red cells?
- Proliferation of all myeloid lines, but erythroid dominant; maturation intact; independent of normal erythropoiesis controls
- JAK2 in >97%: valine → phenylalanine (V617F) in the JAK/STAT pathway, downstream of the EPO receptor → growth-factor independent; less potent kinase than BCR-ABL
- ¼ have two mutated JAK2 copies → higher WBC, more organomegaly, pruritus, more spent-phase progression
- Mean age 60; symptoms from ↑ red cell mass and abnormal flow: venous stasis, thrombosis, hemorrhage (abnormal platelet function), hypertension, headache, weakness, sweating, intense pruritus, ↑ peptic ulcer disease
- Hb 14–28 g/dL; Hct >60%
PV smear
- Packed red cells
In-house exam
68-year-old man with headache, dizziness and hypertension → PV. Symptoms: headache, weakness, sweating, dizziness.
Step 1
Aquagenic pruritus (itch after a hot shower, histamine from basophils), erythromelalgia, Budd-Chiari (hepatic vein thrombosis). EPO is low in PV but high in secondary polycythemia.
Q3. Essential thrombocytosis: what drives it?
- Clonal MPN of the megakaryocytic lineage; the least common MPN
- JAK2 50–60% · CALR 30% (activates the thrombopoietin receptor) · MPL 5–10% (the TPO receptor itself)
- Sustained platelets >600 ×10⁹/L; large, mature megakaryocytes in marrow
- Insidious, age 50–60: thrombosis (MI, stroke), bleeding (GI; weakness, fatigue), or asymptomatic; splenomegaly in 30–60%
- Too many and dysfunctional platelets → both clots and bleeds
ET smear
- Too many platelets, clumping
Abnormal platelets
- Giant, odd shapes
ET marrow
- Clusters of large, weird megakaryocytes
In-house exam
56-year-old woman with fatigue and erythromelalgia (burning, red hands/feet from platelet microthrombi) → ET.
Q4. Primary myelofibrosis: how does the marrow scar?
- Obliterative marrow fibrosis + significant extramedullary hematopoiesis → splenomegaly
- Most common >60; slow onset; splenomegaly or anemia (fatigue, weight loss, bleeding); hyperuricemia (↑ turnover)
- Early: WBC and platelets ↑ (marked thrombocytosis), mild spleen; late: progressive leukopenia, thrombocytopenia, worsening anemia, marked spleen ± liver
Leukoerythroblastosis
- Teardrops (dacrocytes), nucleated RBCs, granulocyte precursors
Marrow fibrosis
- Collagen replaces cells
Liver EMH
- Sinusoids filled with hematopoietic cells
In-house exam
Liver biopsy with hematopoietic cells in the sinusoids = extramedullary hematopoiesis (PMF). Megakaryocyte PDGF and TGF-β drive the fibrosis.
Memory tool
Teardrop logic: RBCs get squeezed out of a scarred marrow, so they "cry."
Step 1
Aspirate is a "dry tap"; reticulin/trichrome stains show fibrosis. JAK2 inhibitor ruxolitinib shrinks the spleen.
ApplyLO 4 application questions
A1Which MPN has a mutation in the thrombopoietin receptor itself?
A2Why do PV patients both clot and bleed?
LO 5The work-up for each MPN
Q1. Which tests confirm each MPN?
| MPN | Blood | Marrow | Molecular |
|---|---|---|---|
| CML | WBC 50–400 ×10⁹/L, all granulocytic stages, basophilia | Hypercellular, maturing granulocytes, ↑ megakaryocytes | BCR-ABL: karyotype t(9;22), FISH, PCR |
| PV | Hb 14–28, Hct >60%; ± ↑ WBC, platelets; low EPO | Panmyelosis (erythroid + megakaryocytic) | JAK2 |
| ET | Platelets >600k, large, odd shapes, clumping | Clusters of large atypical megakaryocytes | JAK2, CALR, MPL; rule out BCR-ABL |
| PMF | Leukoerythroblastosis, dacrocytes, ovalocytes | Fibrosis, ↓ cellularity (late) | JAK2, CALR, MPL |
| PV WHO criteria (in-house) | |
|---|---|
| Major | Red cell mass >25% above predicted · no cause of secondary erythrocytosis · splenomegaly · clonal abnormality other than Ph |
| Minor | Platelets >400 ×10⁹/L · WBC >12 ×10⁹/L · marrow panmyelosis · low serum EPO |
High yield
ET and PMF are partly diagnoses of exclusion: always rule out BCR-ABL (CML) and reactive causes first.
LO 6Matching labs, clinic and morphology
Q1. Which picture goes with which MPN?
| Stem says… | Think |
|---|---|
| Fatigue, early satiety, huge spleen, WBC 150k, basophils | CML |
| Headache, dizziness, HTN, ruddy, itch after showering, Hct >60%, low EPO | PV |
| Erythromelalgia, stroke or MI, GI bleed, platelets >600k | ET |
| Older adult, fatigue, abdominal fullness, infections, teardrops + nucleated RBCs, dry tap | PMF |
| CML patient with new lymphadenopathy or blasts | Blast crisis (acute transformation) |
In-house exam
CML has no lymphadenopathy in chronic phase; new lymphadenopathy signals transition to the acute phase (blast crisis).
LO 7Differential diagnosis
Q1. What else causes each picture?
| MPN | Differential | Tie-breaker |
|---|---|---|
| CML | Leukemoid / reactive neutrophilia (infection, drugs, steroids) | <30k, bands only, fever, no basophils, no spleen, normal genetics (high LAP) |
| PV | Secondary polycythemia: hypoxia (COPD, altitude, smoking), EPO-secreting tumors (RCC, HCC); relative (dehydration) | EPO high in secondary, low in PV; O₂ sat; JAK2 |
| ET | Reactive thrombocytosis: iron deficiency, inflammation, infection, splenectomy, cancer; other MPNs | Low ferritin or high CRP → reactive; BCR-ABL negative |
| PMF | Other causes of marrow fibrosis or leukoerythroblastosis: metastatic carcinoma, hairy cell leukemia, other MPNs in spent phase | Tumor clusters in marrow; hairy cell = BRAF V600E, pancytopenia |
Trap
Any MPN can end in a "spent," fibrotic phase that looks like PMF. Leukoerythroblastosis also occurs whenever marrow is infiltrated (metastatic cancer).
LO 8Natural history and treatment
Q1. How does each MPN progress, and how is it treated?
| MPN | Course | Treatment |
|---|---|---|
| CML | Chronic phase (3–4-year median survival, pre-TKI) → accelerated phase in 50% (therapy failure, cytopenias, extra chromosome abnormalities, fibrosis) → blast crisis (AML 60%, ALL 30%) | Tyrosine kinase inhibitors (imatinib): sustained remissions, few side effects, ↓ BCR-ABL+ cells, ↓ transformation; don't extinguish the stem cell; resistance → 2nd/3rd-gen TKIs. Potential cure: allogeneic stem cell transplant early in chronic phase |
| PV | Indolent, progressive; untreated → death in months; treated ≈10-year survival; post-polycythemic spent phase (fibrosis, cytopenias); AML 2% | Phlebotomy (↓ viscosity) + low-dose aspirin (prevent thrombosis); alkylators occasionally (↑ AML/NHL risk) |
| ET | Indolent; long symptom-free intervals interrupted by thrombotic or hemorrhagic episodes; near-normal life expectancy; median survival 10–15 years; fibrosis or blast crisis <5% | Younger asymptomatic may need none; if thrombosis: antimetabolites (hydroxyurea), gentle chemo, low-dose aspirin |
| PMF | Worsening anemia and fibrosis; death from infection, thrombosis, bleeding; survival 3–5 years; AML 5–20% | Mainly symptomatic (Step 1: JAK2 inhibitor ruxolitinib; transplant is the only cure) |
High yield
Transformation to AML: PV 2% < ET <5% < PMF 5–20%; CML blast crisis is the rule without therapy.
In-house exam
Imatinib targets the ABL kinase from t(9;22). TKIs control counts and lower transformation risk but do not kill the stem cell.
Step 1
CML on imatinib for years now with CD19+ TdT+ blasts → lymphoid blast crisis (treat as ALL + TKI).
ApplyLO 8 application questions
A1Which MPN has the highest rate of transformation to AML?
A2What two therapies form the base of PV treatment?
IDImage ID
Image 1 — smear
Image 2 — smear
Image 3 — marrow
Image 4 — liver
Image 5 — marrow
Image 6 — smear
Image 7 — marrow
Image 8 — abdomen
MCQExam-style questions
1A 59-year-old man has fatigue and early satiety. WBC 180,000 with myelocytes, metamyelocytes, bands and 8% basophils. No fever. Spleen 6 cm below the costal margin. Most likely genetic finding?
2Which finding best favors a reactive neutrophilia over CML?
3What do the mutated tyrosine kinases of MPNs do to differentiation?
4A 68-year-old man has headache, dizziness and hypertension. Hct 62%, O₂ saturation normal, serum EPO low. Most likely mutation?
5A 56-year-old woman has burning red fingers and toes. Platelets 850,000; BCR-ABL negative; ferritin and CRP normal. Marrow shows clusters of large atypical megakaryocytes. Diagnosis?
6In primary myelofibrosis, which cells release the growth factors that drive marrow fibrosis?
7A 69-year-old man has fatigue, abdominal fullness and recurrent infections. Smear: teardrop cells, nucleated RBCs and myelocytes. Marrow aspirate is a dry tap. Most likely diagnosis?
8A liver biopsy shows sinusoids filled with erythroid precursors, myeloid cells and megakaryocytes. What process is this?
9How does imatinib treat CML?
10A patient with chronic-phase CML develops new lymphadenopathy, cytopenias and 25% blasts. What has happened?
11Which therapy pair is first-line for polycythemia vera?
12Which MPN is most likely to transform to AML?
!Numbers that differ between in-house and Step 1
| Item | In-house | Step 1 / board review |
|---|---|---|
| CALR | "Calretinin" | Calreticulin (calretinin is a mesothelioma marker) |
| ET platelet threshold | >600 ×10⁹/L | Current WHO ≥450 ×10⁹/L |
| ET name | Essential thrombocytosis | Essential thrombocythemia |
| ET JAK2 | Slides 50%; handout 50–60% | ≈50–60% |
| CML chronic-phase survival | 3–4-year median | Pre-TKI figure; with TKIs, near-normal life expectancy |
| CML age | Median 55 (25–60) | Typically 45–85 |