Leukemia — Pathology (Detailed)

1. General Pathogenesis

• Class I mutations activate signaling pathways (tyrosine kinases, RAS) that promote proliferation and survival but do not block differentiation on their own.
• Class II mutations disrupt transcription factors that normally drive myeloid or lymphoid differentiation (e.g., RUNX1, CEBPA, PML-RARA), causing a block in maturation and accumulation of immature blasts.
• Neither mutation class alone is sufficient - acute leukemia requires cooperation between a differentiation-blocking lesion and a proliferation-driving lesion (Robbins Basic Pathology, p. 365-366).
• Chromosomal translocations creating fusion oncoproteins (e.g., BCR-ABL1 in CML, PML-RARA in acute promyelocytic leukemia) are recurrent drivers, as are epigenetic regulator mutations (IDH1/2, DNMT3A, TET2) and RNA splicing factor mutations, particularly in older adults and secondary/therapy-related leukemias.
• Predisposing factors: ionizing radiation, benzene/alkylating agent exposure, prior chemotherapy, Down syndrome, Fanconi anemia, and viral agents (HTLV-1 in adult T-cell leukemia/lymphoma).

2. Acute Leukemias (ALL and AML)

• B-ALL/T-ALL: Lymphoblasts have scant basophilic cytoplasm, finely stippled ("delicate") chromatin, and small nucleoli.
• AML: Myeloblasts are larger, with fine chromatin, prominent nucleoli, and variable cytoplasmic granules. By definition, blasts/promyelocytes must comprise >20% of marrow cellularity for a diagnosis of AML.
• Auer rods - needle-like azurophilic cytoplasmic inclusions - are pathognomonic for AML, especially prominent in acute promyelocytic leukemia (APL), where promyelocytes show abnormally coarse, numerous granules.
• Immunophenotyping (flow cytometry) and cytogenetic/molecular studies are required for definitive subclassification since morphology alone is insufficient - e.g., TdT positivity supports lymphoblastic lineage; myeloperoxidase and CD13/CD33 support myeloid lineage.
• Certain AML subtypes are now defined by specific driver lesions rather than morphology alone (e.g., PML-RARA in APL, core-binding factor rearrangements, NPM1 and FLT3 mutations). About 10% of AMLs carry IDH1/IDH2 mutations, which generate the oncometabolite 2-hydroxyglutarate and block differentiation; these are targetable with IDH inhibitors.

3. Chronic Myeloid Leukemia (CML)

• Pathogenesis: Defined by the t(9;22) Philadelphia translocation, generating the BCR-ABL1 fusion gene that encodes a constitutively active tyrosine kinase driving unchecked myeloid proliferation.
• Presentation: Marked leukocytosis (granulocytes at all stages of maturation), often with thrombocytosis and splenomegaly (extramedullary hematopoiesis).
• Natural history: Chronic phase can transform to an accelerated phase and then blast crisis (transformation to acute leukemia, myeloid or lymphoid), which is often fatal without treatment.
• Tyrosine kinase inhibitors (imatinib and successors) targeting BCR-ABL1 have transformed prognosis.

4. Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma

• A neoplasm of small, mature-appearing B cells (co-expressing CD5 and CD23) that accumulate in blood, marrow, and lymphoid tissue owing to defective apoptosis rather than rapid proliferation alone.
• Peripheral smear shows numerous small round lymphocytes with dense chromatin and scant cytoplasm; fragile cells rupture during smear preparation, producing characteristic "smudge cells."
• Clinically indolent in most patients but can undergo Richter transformation to an aggressive large B-cell lymphoma.

5. Other Notable Entities

• Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis, in addition to CML) represent a pathogenetic spectrum related to AML, sharing overlapping driver mutations (JAK2, CALR, MPL in MPNs).
• Adult T-cell leukemia/lymphoma is caused by HTLV-1 infection, endemic in southern Japan, the Caribbean, and West Africa.