Acute Leukemias - Pathology (MBBS Standard)

Definition and Overview

PART 1: Acute Lymphoblastic Leukemia / Lymphoma (ALL)

Subtypes

• B-ALL: ~85% of all ALL; arises from pre-B cells; typical childhood leukemia
• T-ALL: ~15%; arises from thymic T-cell precursors; adolescent males; often presents as mediastinal mass

Pathogenesis

• B-ALL driver genes: PAX5, TCF3, ETV6, RUNX1, BCR::ABL1, KMT2A, PBX1
• T-ALL: predominantly NOTCH1 mutations (50-70%), which is essential for T-cell development

Morphology

• Scant basophilic cytoplasm (agranular)
• Nuclei somewhat larger than small lymphocytes
• Delicate, finely stippled nuclear chromatin
• Small but sharply demarcated nucleoli
• Nuclear membrane often deeply subdivided (convoluted appearance)
• High mitotic rate
• Interspersed macrophages create a "starry sky" appearance (in rapidly growing tumors)

Fig. 13.6: ALL lymphoblasts (A) and B-ALL flow cytometry showing TdT+/CD22+ (B) and CD10+/CD19+ (C) - Robbins, Cotran & Kumar

Immunophenotype

• ALL: MPO-negative, PAS-positive cytoplasmic material
• AML: MPO-positive, Auer rods

Clinical Features

• Abrupt, stormy onset within days to weeks
• Anemia: fatigue, pallor
• Neutropenia: fever, recurrent infections
• Thrombocytopenia: bleeding, petechiae, ecchymoses
• Mass effects (more prominent than in AML):
  • Bone pain from marrow expansion/periosteal infiltration
  • Generalized lymphadenopathy, hepatosplenomegaly
  • Testicular enlargement
  • Mediastinal mass (T-ALL) causing vascular/airway compression
• CNS spread: headache, vomiting, cranial nerve palsies (more common than AML)

Prognosis - ALL

• Age <2 years (KMT2A rearrangements, CNS involvement)
• Adolescence or adulthood
• Blast count >100,000/µL (high tumor burden)

• Age 2-10 years
• Low WBC
• Hyperdiploidy
• Trisomy of chromosomes 4, 7, 10
• t(12;21) - ETV6::RUNX1

PART 2: Acute Myeloid Leukemia (AML)

Definition

WHO Classification (Two Major Categories)

Pathogenesis - Four Categories of Driver Mutations

1. Transcription factor mutations - block myeloid differentiation
   • t(8;21): disrupts RUNX1/CBFB complex
   • t(15;17): PML-RARα fusion blocks retinoic acid-driven maturation
2. Signaling mutations - activate proliferation/survival pathways
   • FLT3 activating mutations (co-operate with PML-RARα)
   • RAS mutations
3. Epigenome mutations - alter DNA methylation or chromatin organization
   • IDH1/IDH2 mutations - produce oncometabolite 2-hydroxyglutarate
   • Cohesin complex mutations
4. TP53 mutations - complex karyotype, erythroid differentiation, very poor prognosis

Morphology

Fig. 13.31: AML myeloblasts with myeloid phenotype - Robbins, Cotran & Kumar

• Delicate nuclear chromatin
• 2-4 prominent nucleoli (more than lymphoblasts)
• Voluminous cytoplasm (more than lymphoblasts)
• Fine, peroxidase-positive azurophilic granules
• Auer rods - needle-like azurophilic granules (pathognomonic); most numerous in APL with t(15;17)
• Monoblasts: folded/lobulated nuclei, no Auer rods, nonspecific esterase-positive
• Aleukemic leukemia: occasionally blasts absent from blood - bone marrow biopsy is essential in any pancytopenic patient

Fig. 13.32: (A) APL with t(15;17) showing numerous Auer rods in bundles; (B) AML with monocytic differentiation - Robbins, Cotran & Kumar

Immunophenotype

Cytogenetics

• Chromosomal aberrations detected in 50-70% by standard methods; ~90% by high-resolution banding
• Young adults (de novo): t(8;21), inv(16), t(15;17) - generally favorable
• Post-chemo/radiation: deletions of chr 5 and 7, TP53 mutations - poor
• Post-topoisomerase II inhibitor therapy: KMT2A rearrangements (11q23)
• Elderly: often have mutations shared with clonal hematopoiesis (TET2, DNMT3A) and MDS (SRSF2, etc.)

Clinical Features

• Fatigue (anemia)
• Fever (neutropenia → opportunistic infections: fungi, Pseudomonas, commensals)
• Bleeding (thrombocytopenia): petechiae, ecchymoses, serosal/mucosal hemorrhages; worsened by DIC especially in APL
• Extramedullary spread: less prominent than ALL, but monocytic AML frequently infiltrates skin (leukemia cutis) and gingiva
• CNS spread: less common than ALL
• Myeloid sarcoma: localized soft tissue AML mass (inevitably becomes systemic without treatment)

Prognosis - AML

• ~60% achieve complete remission with chemotherapy
• Only 15-30% disease-free at 5 years overall
• APL t(15;17): >90% curable with all-trans retinoic acid (ATRA) + arsenic trioxide - best prognosis of any AML subtype
• t(8;21) and inv(16): relatively good prognosis
• Older adults, post-MDS, post-genotoxic AML: very poor; treated with HSC transplantation when possible
• Newer targeted therapies: IDH inhibitors (IDH-mutated AML), FLT3 inhibitors (FLT3-mutated AML), BCL2 inhibitors + hypomethylating agents (elderly patients)

Key Concepts Summary