By Craig Litz, M.D.
A 42-year-old male presented with pneumonia and was found to have pancytopenia. A bone marrow biopsy was performed and showed greater than 95% blasts. The blasts had round to oval nuclei, fine chromatin, and scant agranular basophilic cytoplasm (Fig. 1). Auer rods were not identified. The blasts were myeloperoxidase and non-specific esterase negative. The bone biopsy was solidly hypercellular and effaced by blasts (Fig. 2).
Immunophenotypic analysis of bone marrow showed a dominant population of medium-sized to large cells expressing B lymphoid antigens (CD 19, CD 20 and CD 22) but lacking surface immunoglobulin expression. This same population also expressed CD 34, partial terminal deoxynucleotidal transferase (Tdt) and CD 38— supportive of immature hematolymphoid cells. CD 10 was negative. There was an aberrant expression of myelomonocytic markers, including CD 13, CD 33 and CD 15. The findings indicated a precursor B-cell acute lymphoblastic leukemia/lymphoma with features of the 11q23 abnormality.
Karyotypic analysis by conventional banding was normal (46,XY).
Fluorescence in situ hybridization (FISH) revealed 21 of 200 cells to have a cryptic abnormality of chromosome 11q23.
Chromosome 11q23 aberrations are most commonly, but not exclusively, found in cases of precursor B-cell acute lymphoblastic leukemia/lymphoma (ALL) and acute myelogenous leukemia (AML) with monocytic differentiation. This abnormality generally implies a poor prognosis. The chromosome 11q23 aberrancy involves the mixed lineage leukemia (MLL) gene which produces a DNA-binding transcription protein and shows evolutionary conservation; there is a homologous gene identified in Drosophila. Leukemias with 11q23 abnormalities may arise de novo or may be therapy related. The latter has a strong association with the administration of epipodophyllotoxin/topoisomerase II inhibitors and have a mean latency period after chemotherapy of 34 months (range 12-130).
Figure 1 – Bone marrow aspirate from a patient showing clusters of blasts (arrows) with scant basophilic cytoplasm,
fine chromatin, and nucleoli. The blasts were myeloperoxidase and non-specific esterase negative.
The immunophenotype suggested the 11q23 abnormality (see text, Wright-Giemsa, 400X).
Reciprocal translocations of chromosome 11q23 are identified in 2-3% of ALL cases, most commonly with the chromosome 4 gene, AF 4. Other recombinatorial partner genes are located on chromosomes 9 and 19; these genes are not well characterized. The t(4;11) is most often found in “congenital” ALL, arising in infants less than one year of age and typically presenting with a high blood blast count. When present, the tumor frequently has a characteristic immunophenotype [CD 19 (+), CD 10 (-), CD 34 (+/-), CD 15 (+), and CD 24 (-)]. The t(v;11q23) is present in 5-6% of all AML cases. It is commonly associated with monocytic differentiation and younger patients. The immunophenotypic findings in AML with the 11q23 abnormality are nonspecific; myelomonocytic antigens such as CD33, CD13 and HLA-DR are commonly expressed, with or without CD 34. CD 14 is not uniformly expressed but several other monocytic markers are expressed, including CD 64, CD 36 and CD 11B.
Figure 2 – Bone marrow biopsy showing solidly hypercellular marrow effaced by lymphoblasts.
Translocations involving the MLL on chromosome 11q23 can be identified using conventional cytogenetics, but FISH methodology is more sensitive, as demonstrated in this patient. Occasionally, the presence of the 11q23 may be cryptic and not identified by high-resolution conventional chromosome band analysis; FISH probes commonly used are sensitive to rearrangement and deletion of the MLL. FISH probes are presently unavailable for partner genes.
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