A 4-year-old boy is brought to the pediatrician by his parents because he has been unusually tired for the past three weeks and has developed several large bruises on his shins and back without any significant trauma. His mother also notes that he has been waking up with night sweats and complaining of bone pain in his legs over the past two weeks. Past medical history is negative. On physical examination, the child is pale and has diffuse cervical and inguinal lymphadenopathy. Abdominal examination reveals palpable hepatosplenomegaly.
Laboratory studies show the following:
Hemoglobin: 7.8 g/dL
Platelet count: 35,000/μL
White blood cell count: 45,000/μL
Peripheral blood smear: 80% large cells with scant cytoplasm, fine chromatin, and inconspicuous nucleoli.
Terminal deoxynucleotidyl transferase (TdT) stain: Positive
Which of the following cytogenetic abnormalities is associated with a particularly favorable prognosis in this patient’s condition?
The correct answer is:
C) t(12;21) translocation
This patient is presenting with acute lymphoblastic leukemia (ALL), the most common malignancy in children. The clinical presentation is driven by the crowding out of normal hematopoiesis in the bone marrow by malignant lymphoblasts. Anemia leads to pallor and fatigue. Thrombocytopenia leads to petechiae and easy bruising. Neutropenia leads to recurrent infections and fever. Extramedullary spread leads to bone pain from marrow expansion as well as lymphadenopathy and hepatosplenomegaly. The diagnosis is confirmed by the presence of >20% lymphoblasts in the bone marrow or peripheral blood. These cells are characteristically TdT positive (a DNA polymerase found only in pre-B and pre-T lymphoblasts) and PAS positive. Cytogenetics are the most important prognostic factors in ALL:
t(12;21): Involves the ETV6-RUNX1 fusion gene. It is the most common translocation in pediatric B-ALL and carries an excellent prognosis.
Hyperdiploidy (>50 chromosomes) also is associated with a very favorable prognosis.
Answer choice A: t(1;19) translocation, is incorrect. This translocation involves the TCF3-PBX1 fusion and was historically associated with a poor prognosis, though modern intensive chemotherapy has improved outcomes.
Answer choice B: t(9;22) translocation, is incorrect. This is the Philadelphia chromosome (BCR-ABL1). While it is the hallmark of chronic myelogenous leukemia (CML), it occurs in a small percentage of ALL cases and is associated with a poor prognosis.
Answer choice D: 11q23 rearrangement, is incorrect. Rearrangements of the KMT2A (formerly MLL) gene are most commonly seen in infant ALL (children <1 year old) and carry a very poor prognosis.
Answer choice E: Hypodiploidy, is incorrect. Having fewer than 44 chromosomes is a high-risk cytogenetic feature associated with a poor response to therapy and a higher risk of relapse.
Key Learning Point
Acute lymphoblastic leukemia (ALL) typically affects children aged 2 to 5 years. It is characterized by TdT+ lymphoblasts and a clinical pentad of fever, bone pain, lymphadenopathy, hepatosplenomegaly, and cytopenias. The t(12;21) translocation and hyperdiploidy are markers of a favorable prognosis, while the t(9;22) translocation and infant age are markers of poor prognosis.
