Acute Lymphoblastic Leukemia/Lymphoma

    • Acute Lymphoblastic Leukemia/Lymphoma
      • neoplasms composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts
      • About 85% are B-ALLs, which typically manifest as childhood acute “leukemias.”;
      • T-ALLs tend to present in adolescent males as thymic “lymphomas.”(MCQ)
      • ALL is the most common cancer of children.
      • slightly more frequent in boys than in girls
      • B-ALL peaks in incidence at about the age of 3
      • peak incidence of T-ALL is in adolescence
      • Morphology.
        • In leukemic presentations, the marrow
          • hypercellular
          • packed with lymphoblasts, which replace the normal marrow elements.
        • T-ALLs
          • Mediastinal thymic masses occur in 50% to 70% (MCQ)
          • more likely to be associated with lymphadenopathy and splenomegaly
        • myeloblasts vs lymphoblasts
          • lymphoblasts (MCQ)
            • have more condensed chromatin
            • less conspicuous nucleoli
            • smaller amounts of cytoplasm that usually lacks granules.
            • myeloperoxidase-negative
            • often contain periodic acid–Schiff-positive cytoplasmic material
    • Immunophenotype
      • Immunostaining is done for terminal deoxynucleotidyl-transferase (TdT) (MCQ)
        • a specialized DNA polymerase (MCQ)
        • it  is expressed only in pre-B and pre-T lymphoblasts
        • is positive in more than 95% of cases
      • B-ALL vs  T-ALLs
        • B-ALLs
          • In most of B-ALLs  lymphoblasts usually express the(MCQ)
            • pan B-cell marker CD19
            • transcription factor PAX5
            • CD10.
          • In very immature B-ALLs (MCQ)
            • CD10 is negative
          • more mature “late pre-B” ALLs express (MCQ)
            • CD10, CD19, CD20
            • cytoplasmic IgM heavy chain (μ chain).
        • T-ALLs
        • In most cases of T-ALLs  the cells are positive for (MCQ)
          • CD1, CD2, CD5, and CD7
        • The more immature tumors are usually negative for (MCQ)
          • surface CD3, CD4, and CD8
        • “late” pre-T cell tumors are positive for (MCQ)
          • surface CD3, CD4, and CD8
    • Molecular Pathogenesis.
      • Approximately 90% of ALLs have numerical or structural chromosomal changes.
        • Most common is hyperploidy (>50 chromosomes) (MCQ)
        • hyperdiploidy and hypodiploidy are seen only in B-ALL.
      • Many of the chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors that are required for normal B- and T-cell development.
        • NOTCH1 gene(MCQ)
          • Up to 70% of T-ALLs have gain-of-function mutations in NOTCH1
          • NOTCH1 is a gene that is essential for T-cell development.
        • a high fraction of B-ALLs have
          • loss-of-function mutations in genes that are required for B-cell development, such as PAX5, E2A, and EBF (MCQ)
          • a balanced t(12;21) involving the genes TEL and AML1, two genes that are needed in very early hematopoietic precursors. (MCQ)
        • All of these varied mutations seem to disturb the differentiation of lymphoid precursors and promote maturation arrest
    • Clinical Features of ALL
      • Abrupt stormy onset within days to a few weeks of the first symptoms
      • Symptoms related to depression of marrow function
      • Mass effects caused by neoplastic infiltration
        • bone pain resulting from marrow expansion and infiltration of the subperiosteum
        • generalized lymphadenopathy
        • splenomegaly, and hepatomegaly
        • testicular enlargement
        • in T-ALL, complications related to compression of large vessels and airways in the mediastinum(MCQ)
      • Central nervous system manifestations
        • headache, vomiting
        • nerve palsies resulting from meningeal spread
    • Prognosis. (A Very Very High yield topic for MD Entrance, MBBS Exams, USMLE)
      • Pediatric ALL is one of the great success stories of oncology
      • With aggressive chemotherapy
        • about 95% of children with ALL obtain a complete remission(MCQ)
        • 75% to 85% are cured
      • Factors consistently associated with a worse prognosis(MCQ)
        • age under 2, (MCQ)
          • largely because of the strong association of infantile ALL with translocations involving the MLL gene
        • presentation in adolescence or adulthood;
        • peripheral blood blast counts greater than 100,000
        • reflects a high tumor burden
      • the presence of particular cytogenetic aberrations such as the t(9;22) (the Philadelphia chromosome) (MCQ)
        • t(9;22) is present in only 3% of childhood ALL, but up to 25% of adult cases
    • Favorable prognostic markers include
      • an age of 2 to 10 years
      • a low white cell count
      • hyperploidy(MCQ)
      • trisomy of chromosomes 4, 7, and 10, (MCQ)
      • the presence of a t(12;21) (MCQ)
      • the molecular detection of residual disease after therapy is predictive of a worse outcome in both B- and T-ALL
    • BCR-ABL-positive B-ALL
      • generates mutations at a high rate, a phenomenon referred to as genomic instability (MCQ)
      • contributes to the clinical progression and therapeutic resistance of many aggressive malignant tumors.

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