5.3 Acute & Chronic Leukaemias and Lymphomas
Key Takeaways
- Acute Leukaemias are defined by ≥20% blasts in the bone marrow or peripheral blood; Acute Promyelocytic Leukaemia (APML / M3) harbors t(15;17) PML-RARA and is treated with All-trans Retinoic Acid (ATRA) + Arsenic Trioxide.
- Chronic Myeloid Leukaemia (CML) is characterized by the t(9;22) Philadelphia chromosome creating the constitutively active BCR-ABL1 tyrosine kinase, targeted by Imatinib.
- Chronic Lymphocytic Leukaemia (CLL) features mature B-cell proliferation (CD5+, CD19+, CD23+) with classic 'smudge cells' on blood film.
- Classical Hodgkin Lymphoma is diagnosed by Reed-Sternberg cells (CD30+, CD15+, CD20-) and spreads predictably by contiguity.
- Burkitt Lymphoma is driven by t(8;14) MYC-IGH translocation and displays a characteristic 'starry sky' appearance on lymph node biopsy.
Acute & Chronic Leukaemias and Lymphomas
Hematological malignancies are classified by clinical acuity (Acute vs Chronic) and lineage (Myeloid vs Lymphoid). UPSC CMS questions focus heavily on cytogenetic translocations, specific cell surface markers (CD markers), diagnostic microscopic features (Auer rods, Smudge cells, Reed-Sternberg cells, Starry sky), and targeted treatment regimens.
1. Acute Leukaemias
Acute leukaemias are rapid clonal proliferations of immature hematopoietic progenitor cells (blasts). Diagnosis requires ≥20% blasts in the bone marrow or peripheral blood.
Acute Myeloid Leukaemia (AML) vs. Acute Lymphoblastic Leukaemia (ALL)
| Feature | Acute Myeloid Leukaemia (AML) | Acute Lymphoblastic Leukaemia (ALL) |
|---|---|---|
| Peak Age Group | Adults (median age ~65 years) | Children (peak age 2 - 5 years) - most common childhood cancer |
| Blast Morphology | Large blasts, abundant cytoplasm, Auer rods (azurophilic needle-like granules of clumped MPO). | Small to medium blasts, scanty cytoplasm, fine chromatin, inconspicuous nucleoli. No Auer rods. |
| Cytochemistry | Myeloperoxidase (MPO) positive, Sudan Black B positive. | Periodic Acid-Schiff (PAS) positive, TdT (Terminal deoxynucleotidyl transferase) positive. |
| Immunophenotype | CD13+, CD33+, CD117+, MPO+ | B-ALL: CD10+ (CALLA), CD19+, CD22+<br/>T-ALL: CD2+, CD3+, CD7+, CD8+ (presents as mediastinal mass in teen males) |
| Cytogenetic Pearls | t(15;17) in APML (M3); t(8;21), inv(16) favorable risk. | t(12;21) ETV6-RUNX1 (favorable childhood); t(9;22) BCR-ABL1 (unfavorable adult). |
| Special Clinical Note | APML carries severe risk of fatal Disseminated Intravascular Coagulation (DIC) due to tissue factor release. | Mandatory CNS prophylaxis (Intrathecal Methotrexate) required in all protocols due to blood-brain barrier sanctuary. |
Acute Promyelocytic Leukaemia (APML / FAB M3)
- Cytogenetics: Translocation t(15;17)(q24;q21) resulting in the PML-RARA (Promyelocytic Leukaemia - Retinoic Acid Receptor Alpha) fusion gene.
- Pathophysiology: PML-RARA blocks myeloid differentiation at the promyelocyte stage.
- Management: Emergency treatment with All-Trans Retinoic Acid (ATRA) + Arsenic Trioxide (ATO). ATRA binds PML-RARA and induces promyelocytes to differentiate into mature neutrophils, dramatically reducing DIC mortality! Complication: Differentiation Syndrome (fever, pulmonary infiltrates, fluid retention treated with dexamethasone).
2. Chronic Leukaemias
Chronic Myeloid Leukaemia (CML)
- Pathogenesis: Myeloproliferative neoplasm driven by t(9;22)(q34;q11) translocation forming the Philadelphia Chromosome. This fuses BCR on chromosome 22 with ABL1 on chromosome 9, producing a constitutively active p210 BCR-ABL1 tyrosine kinase.
- Clinical Features: Marked splenomegaly (often giant / extending into right iliac fossa), fatigue, night sweats, hyperuricemia.
- Laboratory Findings: Extreme leukocytosis (WBC often >100,000/mm³) with the entire spectrum of myeloid differentiation present in peripheral blood (neutrophils, band forms, metamyelocytes, myelocytes, promyelocytes). Marked basophilia and eosinophilia.
- Key Diagnostic Marker: Leukocyte Alkaline Phosphatase (LAP) / Neutrophil Alkaline Phosphatase (NAP) score is LOW / ZERO in CML (differs from leukemoid reaction where LAP score is markedly high).
- Disease Phases: Chronic phase -> Accelerated phase -> Blast Crisis (conversion to AML [70%] or ALL [30%]).
- Targeted Therapy: Imatinib Mesylate (first-generation Tyrosine Kinase Inhibitor / TKI binding the ATP-binding pocket of BCR-ABL1). Second-generation TKIs: Dasatinib, Nilotinib.
Chronic Lymphocytic Leukaemia (CLL)
- Pathogenesis: Clonal expansion of morphologically mature but functionally incompetent B lymphocytes.
- Immunophenotype: CD5+ (T-cell marker aberrantly expressed on B cells), CD19+, CD20+ (weak), CD23+, with surface immunoglobulin (sIg) positivity.
- Peripheral Smear: Marked absolute lymphocytosis with characteristic Smudge cells / Basket cells (Gumprecht shadows - fragile CLL cells disrupted during slide preparation).
- Complications: Hypogammaglobulinemia (recurrent bacterial infections), Autoimmune Haemolytic Anaemia (warm IgG AIHA in 10-15%), and Richter Transformation (sudden transformation into aggressive Diffuse Large B-Cell Lymphoma / DLBCL).
3. Lymphomas & Multiple Myeloma
Hodgkin Lymphoma (HL) vs. Non-Hodgkin Lymphoma (NHL)
| Feature | Hodgkin Lymphoma (HL) | Non-Hodgkin Lymphoma (NHL) |
|---|---|---|
| Nodal Spread | Contiguous, orderly spread along adjacent node chains | Non-contiguous, erratic, widespread nodal involvement |
| Extranodal Involvement | Rare | Common (GI tract, bone marrow, brain) |
| Pathognomonic Cell | Reed-Sternberg (RS) Cell: Binucleated cell with prominent inclusion-like nucleoli ("owl's eye" appearance). | Absence of classic RS cells; monoclonal proliferation of B (85%) or T (15%) cells. |
| RS Immunophenotype | CD30+, CD15+, CD20- (in Classical HL) | CD20+ (B-cell NHLs, e.g., DLBCL, Follicular). |
| Histological Subtypes | Nodular Sclerosis (most common, collagen bands, lacunar RS cells, young females); Mixed Cellularity (associated with EBV); Lymphocyte Rich; Lymphocyte Depleted (worst prognosis). | Burkitt Lymphoma: t(8;14) MYC-IGH, "starry sky" pattern (tingible body macrophages among apoptotic blasts). Associated with EBV in endemic jaw tumor.<br/>DLBCL: Most common adult NHL, aggressive, CD20+. |
| Clinical Staging | Ann Arbor Staging: Stage I (single node region) to Stage IV (disseminated extranodal). Sub-classified by A (no B symptoms) or B (Fever >38°C, drenching night sweats, unexplained weight loss >10% over 6 months). | |
| Chemotherapy Regimen | ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine. | R-CHOP: Rituximab (anti-CD20), Cyclophosphamide, Hydroxydaunorubicin, Oncovin (Vincristine), Prednisone. |
Multiple Myeloma
Multiple Myeloma is a malignant plasma cell dyscrasia producing monoclonal immunoglobulin (most commonly IgG [55%] or IgA [20%]).
- Diagnostic CRAB Criteria:
- C - Hypercalcaemia: Serum Calcium >11 mg/dL (due to osteoclast activating factors MIP-1α, RANKL).
- R - Renal Insufficiency: Serum Creatinine >2 mg/dL (Light chain cast nephropathy / Bence-Jones proteinuria forming tubular casts).
- A - Anaemia: Normocytic normochromic (Hb <10 g/dL due to marrow replacement).
- B - Bone Lesions: Multiple punched-out lytic lesions on X-ray (skull, spine, pelvis); pathological fractures; severe back pain.
- Laboratory & Smear Findings:
- Bone marrow aspirate shows ≥10% clonal plasma cells (eccentric nucleus, "clock-face" / "radially arranged" chromatin, perinuclear halo).
- Serum Protein Electrophoresis (SPEP): Sharp M-spike in gamma-globulin region.
- Peripheral smear: Rouleaux formation (stacked coin appearance of RBCs due to elevated monoclonal antibodies neutralizing electrostatic repulsive charge).
A 42-year-old female presents with severe bleeding from the gums and petechial rashes over her legs. Laboratory workup demonstrates Hb 7.2 g/dL, WBC 2.4 x 10^9/L, Platelets 18 x 10^9/L, and bone marrow biopsy shows 45% promyelocytes packed with Auer rods. Coagulation profile shows PT 24 sec, APTT 52 sec, and Fibrinogen 90 mg/dL (marked DIC). Cytogenetics reveals a t(15;17) translocation. Which of the following targeted agents must be urgently initiated?
A 68-year-old male presents for a routine checkup. Complete blood count reveals WBC 48 x 10^9/L with 85% small, mature-appearing lymphocytes. Peripheral blood smear demonstrates numerous broken, disrupted lymphocytes known as 'smudge cells' (Gumprecht shadows). Immunophenotyping shows lymphocytes expressing CD19, CD20, CD23, and aberrantly expressing CD5. What is the most likely diagnosis?
A 22-year-old college student presents with painless cervical lymphadenopathy and fever with drenching night sweats for 2 months. Excisional biopsy of a cervical lymph node reveals giant binucleated cells with prominent eosinophilic inclusion-like nucleoli resembling 'owl's eyes'. Immunophenotyping shows these malignant cells are positive for CD30 and CD15, but negative for CD20. What is the diagnosis?
A 70-year-old male presents with severe lower back pain, weakness, and fatigue. Serum biochemistry shows Calcium 12.4 mg/dL and Creatinine 2.8 mg/dL. Skull X-ray demonstrates multiple well-defined 'punched-out' radiolucent lytic lesions. Serum protein electrophoresis (SPEP) displays a prominent monoclonal M-spike. Which of the following bone marrow aspirate findings confirms this diagnosis?