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LEUKEMIAS - Complete MUHS Exam Notes (2nd MBBS Pathology)

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PART A: DEFINITION AND CLASSIFICATION OF LEUKEMIA

Definition

Classification

LEUKEMIA
├── ACUTE (blasts ≥ 20% in marrow/blood)
│   ├── Acute Myeloid Leukemia (AML) - M0 to M7 by FAB
│   └── Acute Lymphoblastic Leukemia (ALL) - L1, L2, L3 by FAB
│
└── CHRONIC (mature/maturing cells)
    ├── Chronic Myeloid Leukemia (CML)
    ├── Chronic Lymphocytic Leukemia (CLL)
    ├── Hairy Cell Leukemia
    └── Others

• Acute leukemia = blasts ≥ 20% in bone marrow or blood (WHO criterion)
• Chronic leukemia = predominantly mature or maturing cells

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PART B: ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Definition

Epidemiology

• Most common cancer in children (peak age: 3-5 years)
• ~85% are B-ALL (pre-B cell origin)
• ~15% are T-ALL (adolescent males, thymic mass)
• Slight male predominance

Pathogenesis

• BCR-ABL fusion (Ph chromosome, t(9;22)) in ~25% adult ALL
• t(12;21) - ETV6::RUNX1 fusion - 25% of B-ALL (good prognosis)
• Mutations in NOTCH1 (T-ALL), PAX5, TCF3 (B-ALL)
• Block in lymphoid differentiation → accumulation of non-functional blasts

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PERIPHERAL BLOOD SMEAR FINDINGS - ALL

╔══════════════════════════════════════════════════════╗
║          PERIPHERAL BLOOD SMEAR - ALL                ║
╠══════════════════════════════════════════════════════╣
║  • Normocytic normochromic ANEMIA                    ║
║  • THROMBOCYTOPENIA (low platelets)                  ║
║  • WBC count - variable (↑, normal or ↓)             ║
║  • LYMPHOBLASTS seen in peripheral blood:            ║
║    - Small to medium sized cells                     ║
║    - Scant cytoplasm                                 ║
║    - Round/oval nucleus                              ║
║    - Fine (stippled) nuclear chromatin               ║
║    - Inconspicuous nucleoli (L1) OR                  ║
║      prominent nucleoli (L2)                         ║
║    - No Auer rods (KEY FEATURE - differentiates      ║
║      from AML)                                       ║
║  • Smudge cells (basket cells) may be seen           ║
╚══════════════════════════════════════════════════════╝

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BONE MARROW ASPIRATION FINDINGS - ALL

╔══════════════════════════════════════════════════════╗
║        BONE MARROW ASPIRATION - ALL                  ║
╠══════════════════════════════════════════════════════╣
║  GROSS: Marrow is HYPERCELLULAR (packed marrow)      ║
║                                                      ║
║  MICROSCOPY:                                         ║
║  • ≥ 20% lymphoblasts (often 60-100%)                ║
║  • Normal erythroid, myeloid, and megakaryocytic     ║
║    precursors are REPLACED / markedly reduced        ║
║  • Lymphoblasts: scant cytoplasm, round nucleus,     ║
║    fine chromatin, inconspicuous/absent nucleoli     ║
║  • NO Auer rods                                      ║
║  • TdT (Terminal Deoxynucleotidyl Transferase)       ║
║    POSITIVE - nuclear stain (HALLMARK OF ALL)        ║
║  • Mitotic figures common                            ║
║                                                      ║
║  CYTOCHEMISTRY:                                      ║
║  • PAS (Periodic Acid Schiff) - POSITIVE (chunky/    ║
║    block pattern)                                    ║
║  • MPO (Myeloperoxidase) - NEGATIVE                  ║
║  • Sudan Black B - NEGATIVE                          ║
║  • TdT - POSITIVE (nuclear marker)                   ║
╚══════════════════════════════════════════════════════╝

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FAB Classification of ALL (L1, L2, L3)

MUHS exam tip: L1 is most common in children (75%), L2 in adults, L3 (Burkitt) is associated with t(8;14) and EBV.

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Clinical Features of ALL

• Bone marrow failure symptoms (commonest presentation):
  • Fatigue, pallor (anemia)
  • Fever, infections (neutropenia)
  • Bleeding, petechiae (thrombocytopenia)
• Tissue infiltration:
  • Lymphadenopathy, splenomegaly, hepatomegaly
  • CNS involvement (headache, vomiting - requires CNS prophylaxis)
  • Mediastinal mass (T-ALL - superior vena caval syndrome)
  • Bone pain (marrow expansion)
• Testicular involvement (males - sanctuary site)

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PART C: CHRONIC MYELOID LEUKEMIA (CML)

Definition

Pathogenesis

• t(9;22) translocation creates BCR::ABL chimeric gene
• Encodes a 210 kDa constitutively active tyrosine kinase (p210)
• Mimics growth factor receptor signaling (RAS, JAK/STAT pathways)
• Does NOT block differentiation initially - hence cells still mature (unlike acute leukemia)
• Cell of origin: pluripotent HSC

Chromosome 9    +    Chromosome 22
    ABL gene               BCR gene
       ↓  t(9;22) translocation ↓
  Philadelphia Chromosome (Ph)
         ↓
    BCR-ABL fusion
         ↓
  p210 BCR-ABL tyrosine kinase
         ↓
  Constitutive cell proliferation
  (granulocytic and megakaryocytic)

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PERIPHERAL BLOOD SMEAR FINDINGS - CML ★★ (Most asked)

╔══════════════════════════════════════════════════════╗
║         CML - PERIPHERAL BLOOD SMEAR                 ║
╠══════════════════════════════════════════════════════╣
║  • LEUKOCYTOSIS (WBC often > 100,000 cells/μL)       ║
║    - "Leukaemic hiatus" is ABSENT (unlike AML)       ║
║                                                      ║
║  • MYELOID SERIES - ALL STAGES present:              ║
║    - Segmented neutrophils (predominant)             ║
║    - Band cells                                      ║
║    - Metamyelocytes                                  ║
║    - Myelocytes ← MOST PREDOMINANT IMMATURE FORM     ║
║    - Promyelocytes                                   ║
║    - Myeloblasts (< 10% in chronic phase)            ║
║                                                      ║
║  • BASOPHILIA - increased basophils (CHARACTERISTIC) ║
║  • EOSINOPHILIA - increased eosinophils              ║
║  • THROMBOCYTOSIS (platelets often markedly ↑)       ║
║  • Mild normochromic normocytic ANEMIA               ║
║  • Nucleated RBCs may be seen                        ║
║                                                      ║
║  SPECIAL TEST:                                       ║
║  • Leukocyte Alkaline Phosphatase (LAP) score        ║
║    → MARKEDLY DECREASED / LOW (key distinguisher)   ║
║    → Leukemoid reaction: LAP score HIGH              ║
╚══════════════════════════════════════════════════════╝

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BONE MARROW FINDINGS - CML

╔══════════════════════════════════════════════════════╗
║           CML - BONE MARROW FINDINGS                 ║
╠══════════════════════════════════════════════════════╣
║  GROSS:                                              ║
║  • MARKEDLY HYPERCELLULAR                            ║
║  • Fatty marrow replaced by cellular marrow          ║
║  • Increased myeloid:erythroid ratio (10:1 or more)  ║
║                                                      ║
║  MICROSCOPY:                                         ║
║  • Massively increased granulocytic precursors       ║
║    (myelocytes predominate)                          ║
║  • Megakaryocytes INCREASED - often small,           ║
║    dysplastic (dwarf megakaryocytes)                 ║
║  • Erythroid precursors - normal or mildly ↓         ║
║  • SEA-BLUE HISTIOCYTES - characteristic finding     ║
║    (macrophages with abundant wrinkled, green-blue   ║
║    cytoplasm - pseudo-Gaucher cells)                 ║
║  • Increased reticulin deposition (mild)             ║
║  • Blasts < 10% (chronic phase)                      ║
║  • Eosinophils and basophils increased               ║
╚══════════════════════════════════════════════════════╝

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Clinical Features of CML

• Fatigue, weakness, weight loss, anorexia (hypermetabolism)
• Dragging sensation/heaviness in left hypochondrium - due to massive splenomegaly (most characteristic)
• Left upper quadrant pain (splenic infarction)
• Night sweats

• Massive splenomegaly (most prominent finding - due to extramedullary hematopoiesis)
• Hepatomegaly (mild-moderate)
• Sternal tenderness (marrow expansion)
• Lymphadenopathy (mild)

• WBC: >100,000/μL with full myeloid spectrum
• LAP score: Low/absent (important exam fact)
• Ph chromosome (BCR-ABL): POSITIVE
• Uric acid: elevated (hyperuricemia from cell turnover)
• Vitamin B12 levels: elevated (from WBC)

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Natural History / Phases of CML

CHRONIC PHASE (3-4 years average)
    ↓ (additional mutations)
ACCELERATED PHASE (6-12 months)
  - Increasing anemia & thrombocytopenia
  - Basophilia ↑↑
  - Blasts 10-19%
  - New cytogenetic abnormalities
    ↓
BLAST CRISIS (resembles acute leukemia)
  - Blasts ≥ 20% (WHO criterion)
  - 70% = Myeloid blast crisis (AML-like)
  - 30% = Lymphoid blast crisis (B-ALL-like)
  → This proves CML arises from pluripotent HSC

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PART D: ACUTE LEUKEMIAS - FAB CLASSIFICATION

Background

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FAB CLASSIFICATION OF ALL (L1-L3)

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FAB CLASSIFICATION OF AML (M0-M7)

╔══════════════════════════════════════════════════════════════════════╗
║              FAB CLASSIFICATION OF AML (M0 - M7)                    ║
╠═══════╦═══════════════════════════════╦═══════════════════════════╗  ║
║  FAB  ║  NAME                         ║  KEY FEATURES             ║  ║
╠═══════╬═══════════════════════════════╬═══════════════════════════╣  ║
║  M0   ║ AML, Minimally Differentiated ║ No differentiation;       ║  ║
║       ║                               ║ MPO negative by cytochem; ║  ║
║       ║                               ║ Myeloid markers by flow   ║  ║
╠═══════╬═══════════════════════════════╬═══════════════════════════╣  ║
║  M1   ║ AML without maturation        ║ >3% MPO+ blasts;          ║  ║
║       ║                               ║ <10% maturing cells       ║  ║
╠═══════╬═══════════════════════════════╬═══════════════════════════╣  ║
║  M2   ║ AML with maturation           ║ ≥10% maturing granulocytes║  ║
║       ║                               ║ t(8;21); Auer rods        ║  ║
╠═══════╬═══════════════════════════════╬═══════════════════════════╣  ║
║  M3   ║ Acute Promyelocytic Leukemia  ║ HYPERGRANULAR             ║  ║
║       ║ (APL)                         ║ PROMYELOCYTES; MULTIPLE   ║  ║
║       ║                               ║ AUER RODS (faggot cells); ║  ║
║       ║                               ║ t(15;17) PML-RARA;        ║  ║
║       ║                               ║ DIC common; ATRA therapy  ║  ║
╠═══════╬═══════════════════════════════╬═══════════════════════════╣  ║
║  M4   ║ Acute Myelomonocytic Leukemia ║ Both myeloid + monocytic  ║  ║
║       ║ (AMMoL)                       ║ differentiation;          ║  ║
║       ║                               ║ ≥20% monocytic component; ║  ║
║       ║                               ║ inv(16) in M4Eo           ║  ║
╠═══════╬═══════════════════════════════╬═══════════════════════════╣  ║
║  M5   ║ Acute Monocytic Leukemia      ║ ≥80% monocytic cells;     ║  ║
║       ║                               ║ gum infiltration & skin   ║  ║
║       ║                               ║ rash (leukemia cutis)     ║  ║
╠═══════╬═══════════════════════════════╬═══════════════════════════╣  ║
║  M6   ║ Acute Erythroid Leukemia      ║ >50% dysplastic erythroid ║  ║
║       ║ (Di Guglielmo disease)        ║ precursors; PAS positive  ║  ║
║       ║                               ║ erythroblasts             ║  ║
╠═══════╬═══════════════════════════════╬═══════════════════════════╣  ║
║  M7   ║ Acute Megakaryoblastic        ║ Blasts with megakaryocytic║  ║
║       ║ Leukemia                      ║ markers (CD41, CD61);     ║  ║
║       ║                               ║ Marrow fibrosis; Down     ║  ║
║       ║                               ║ syndrome association      ║  ║
╚═══════╩═══════════════════════════════╩═══════════════════════════╝  ║
╚══════════════════════════════════════════════════════════════════════╝

MUHS EXAM MNEMONIC: "My Mother Makes Perfectly Moist Fried Muffins" M0-Minimal, M1-Myeloblastic no maturation, M2-Myeloblastic with maturation, M3-Promyelocytic, M4-Myelomonocytic, M5-Monocytic, M6-Erythroid, M7-Megakaryoblastic

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PART E: ACUTE MYELOID LEUKEMIA (AML) - DETAILED

Definition

Epidemiology

• Most common acute leukemia in adults (peak age: >60 years)
• Incidence rises with age (10/100,000 per year after age 60)
• Risk factors: benzene exposure, radiation, prior cytotoxic therapy, smoking

Diagnostic criterion: ≥ 20% myeloid blasts in blood or bone marrow

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PERIPHERAL BLOOD SMEAR - AML

╔══════════════════════════════════════════════════════╗
║          AML - PERIPHERAL BLOOD SMEAR                ║
╠══════════════════════════════════════════════════════╣
║  • Normocytic normochromic ANEMIA                    ║
║  • THROMBOCYTOPENIA                                  ║
║  • WBC: variable (↑, normal, or ↓)                   ║
║                                                      ║
║  MYELOBLASTS (key cells to identify):                ║
║  • Large cells (larger than lymphoblasts)            ║
║  • Abundant cytoplasm (more than ALL)                ║
║  • AUER RODS: eosinophilic rod-shaped cytoplasmic    ║
║    inclusions (fused primary granules)               ║
║    → PATHOGNOMONIC of AML (NEVER in ALL)             ║
║    → Most prominent in M3 (APL) - "faggot cells"    ║
║    → Stain +ve: MPO, Sudan Black B, CAE, acid phosph ║
║  • Prominent nucleoli (3-5 usually)                  ║
║  • Fine (uncondensed) nuclear chromatin              ║
║  • Cytoplasmic azurophilic granules                  ║
║                                                      ║
║  "LEUKAEMIC HIATUS" (seen in AML):                   ║
║  • Gap between blasts and mature forms               ║
║  • Intermediate forms (promyelocytes, myelocytes)    ║
║    markedly reduced                                  ║
╚══════════════════════════════════════════════════════╝

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BONE MARROW FINDINGS - AML

╔══════════════════════════════════════════════════════╗
║          AML - BONE MARROW FINDINGS                  ║
╠══════════════════════════════════════════════════════╣
║  GROSS:                                              ║
║  • HYPERCELLULAR (packed marrow)                     ║
║  • Normal architecture replaced by blasts            ║
║  • Grey-white appearance (loss of fat cells)         ║
║                                                      ║
║  MICROSCOPY:                                         ║
║  • ≥ 20% myeloblasts (often 60-100%)                 ║
║  • Large blasts with:                                ║
║    - Delicate nuclear chromatin                      ║
║    - 3-5 prominent nucleoli                          ║
║    - Fine azurophilic cytoplasmic granules           ║
║    - AUER RODS (pathognomonic)                       ║
║  • Normal precursors (RBC, WBC, platelet) REPLACED   ║
║  • In M3: Hypergranular promyelocytes, faggot cells  ║
║  • In M5: Monoblasts with folded/irregular nuclei    ║
║  • In M7: Megakaryoblasts + marrow fibrosis          ║
║                                                      ║
║  CYTOCHEMICAL STAINS (KEY FOR MUHS EXAM):            ║
║  • MPO (Myeloperoxidase) - POSITIVE (>3% blasts)     ║
║  • Sudan Black B (SBB) - POSITIVE                    ║
║  • Chloroacetate Esterase (CAE) - POSITIVE           ║
║  • Non-specific esterase (NSE/ANAE) - POSITIVE       ║
║    (especially in M4 & M5 monocytic types)           ║
║  • NSE inhibited by NaF = monocytic lineage          ║
║  • PAS - variable (block positive in M6 erythroid)  ║
║  • TdT - NEGATIVE (positive only in ALL)             ║
╚══════════════════════════════════════════════════════╝

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PART F: CYTOCHEMICAL STAINS - SUMMARY TABLE (★★★ High Yield)

MUHS exam tip: TdT positive = ALL (lymphoblastic). MPO/SBB positive = AML (myeloblastic). This is the single most tested cytochemistry point.

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PART G: COMPARISON TABLE - AML vs ALL (MUHS Favourite)

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PART H: LABORATORY FINDINGS - ACUTE LEUKEMIA (LAQ TOPIC)

General Lab Findings in ALL/AML:

1. CBC: Anemia (normocytic normochromic), thrombocytopenia, variable WBC
2. Peripheral smear: Blasts present, reduced normal cells
3. Bone marrow: ≥20% blasts, hypercellular
4. Cytochemistry: As above table
5. Immunophenotyping (flow cytometry): Definitive lineage assignment
6. Cytogenetics/FISH: Prognostic significance (t(15;17) = good, t(9;22) = poor)
7. Serum: Elevated LDH, uric acid, potassium (tumor lysis)
8. Coagulation: DIC in APL (M3) - prolonged PT, PTT, low fibrinogen, raised FDP

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PART I: DIAGRAM SUMMARY FOR EXAM DRAWING

Easy-to-Draw CML Blood Smear Diagram:

NORMAL BLOOD:         CML BLOOD SMEAR:
                       
  O O O O               O O O O O    ← RBCs (normal/↓)
  O O O O               O O O O O
    [N]                   [N][N][N]  ← Neutrophils (↑↑)
                          [Band][Meta] ← Band + metamyelocytes
                          [Myelo]    ← Myelocytes (↑↑↑)
                          [B][Eo]    ← Basophils + Eosinophils (↑)
                          [Blast]    ← Myeloblasts (<10%)
                          ◆ ◆ ◆      ← Platelets (↑↑)

Note: "Full Myeloid Spectrum" - hallmark of CML
Note: LAP score LOW (leukemoid reaction = HIGH)

Easy-to-Draw AML Myeloblast:

AML MYELOBLAST (for exam):

        ╭──────────────╮
       ╱   Large round  ╲
      │   nucleus with   │
      │  3-5 PROMINENT   │
      │    NUCLEOLI      │
      │                  │
       ╲  AUER ROD  ╱
        │  ══════► │    ← Auer rod (eosinophilic, rod-shaped)
        ╰──────────╯
    Abundant cytoplasm
  with azurophilic granules

KEY: Auer rods = pathognomonic of AML

Lymphoblast in ALL (for exam):

ALL LYMPHOBLAST:

        ╭──────╮
       ╱  LARGE ╲
      │  nucleus  │ ← fine/stippled chromatin
      │ (fills    │
      │  most of  │ ← nucleolus: absent(L1) or
      │   cell)   │   prominent(L2/L3)
       ╲         ╱
        ╰────╮──╯
         SCANT cytoplasm
         (very little compared to AML)

KEY: NO Auer rods; TdT POSITIVE

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QUICK REVISION - HIGH-YIELD MUHS EXAM POINTS

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