A 42-year-old man is hospitalized due to fever and persistent sore throat. Temperature is 38.3 C (100.9 F), blood pressure is 120/80 mm Hg, pulse is 94/min, and respirations are 16/min. There are several bruises on his trunk, and blood oozes from his intravenous catheter venipuncture sites. Blood fibrinogen level is 110 mg/dL (normal: 150-400). Bone marrow aspirate shows a predominance of immature myeloid cells with numerous azurophilic, needle-shaped cytoplasmic granules. Chromosomal analysis of these immature cells is most likely to show which of the following abnormalities?
Chromosomal translocations associated with hematologic malignancies | |
Malignancy | Pathogenesis |
Acute promyelocytic | t(15;17) involving PML & RARA → PML-RARα oncoprotein → myeloid differentiation inhibited
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Burkitt | t(8;14) involving MYC & IGH → MYC overexpression → cell growth
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Chronic myeloid | t(9;22) involving ABL1 & BCR → BCR-ABL1 oncoprotein → cell proliferation
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Follicular | t(14;18) involving IGH & BCL2 → BCL2 overexpression → apoptosis evasion
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Mantle cell | t(11;14) involving CCND1 & IGH → cyclin D1 overexpression → cell cycle progression
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This patient with a predominance of immature myeloid cells containing numerous azurophilic, needle-shaped cytoplasmic granules likely has acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia. Acute leukemia can present with persistent fever and sore throat due to increased risk of infection conferred by fewer functional leukocytes.
APL is microscopically characterized by abnormal promyelocytes (immature myeloid cells) that may contain numerous needle-shaped cytoplasmic inclusions known as Auer rods (fused lysosomal granules) and often have bilobed nuclei. Cytogenetic studies show t(15;17) chromosomal translocation, which causes fusion of the retinoic acid receptor-alpha (RARA) gene to the promyelocytic leukemia (PML) gene.
A classic presentation of APL is bleeding in the setting of disseminated intravascular coagulation (DIC) (eg, oozing at venipuncture sites), as the malignant cells express prothrombotic factors (eg, tissue factor) that lead to widespread consumptive coagulopathy. DIC is characterized by decreased fibrinogen levels, increased fibrin degradation products, prolonged PT and PTT, and thrombocytopenia that is generally not low enough to result in spontaneous bleeding by itself. Prompt treatment of APL with all-trans retinoic acid is essential.
(Choice A) t(8;14) occurs in approximately 80% of cases of Burkitt lymphoma and results in movement of the MYC protooncogene from chromosome 8 to a region near the immunoglobulin promoter site on chromosome 14. In blood and bone marrow, Burkitt lymphoma cells often have basophilic, vacuolated cytoplasm.
(Choice B) t(9;22) forms the Philadelphia chromosome associated with chronic myeloid leukemia (CML). Most patients seek medical attention in the chronic, stable phase (eg, nonspecific symptoms, abdominal fullness, leukocytosis), in which mature and immature myeloid forms are seen. Auer rods are not typically present in CML.
(Choice C) Mantle cell lymphoma, a mature B-cell malignancy characterized by lymphoid cells with irregular nuclei, is associated with t(11;14). This translocation results in overexpression of cyclin D1.
(Choice D) t(14;18) is associated with follicular lymphoma. This abnormality places the BCL2 protooncogene from chromosome 18 near the immunoglobulin heavy-chain promoter region on chromosome 14. Circulating follicular lymphoma cells are typically small lymphoid cells with cleaved nuclei.
Educational objective:
Acute promyelocytic leukemia (APL) can present with persistent infection and coagulopathy, causing hemorrhagic signs and symptoms. Bone marrow examination classically reveals abnormal promyelocytes with intracytoplasmic Auer rods. APL is associated with a t(15;17) chromosomal translocation that fuses the retinoic acid receptor-alpha and promyelocytic leukemia genes.