A treatment-refractory aggressive MDS-MLD with multiple highly complex chromosome 5 intrachromosomal rearrangements:...

A patient with a myelodysplastic neoplasm exhibited a karyotype with multiple complex chromosome 5 rearrangements. This patient appeared to have a catastrophic cytogenetic event that manifested as a treatment-refractory aggressive form of disease, which lead to patient demise within one year. Both the clinical presentation and disease course were unusual based on the medical history and morphologic findings. Such cases of myelodysplastic syndrome with multilineage dysplasia (MDS-MLD) with complex abnormalities are not reported in the literature.

The patient was a 62-year-old female who presented with pancytopenia and dyspnea. The morphologic appearance of the peripheral blood smear and bone marrow biopsy, along with flow cytometric findings, favored the diagnosis of MDS-MLD unclassifiable. Myelodysplastic syndrome (MDS) with multilineage dysplasia (MDS-MLD), is an MDS characterized by one or more cytopenias and dysplastic changes in two or more of the myeloid lineages (i.e., erythroid, granulocytic, and megakaryocytic). The bone marrow, in particular, showed prominent dysplasia, including the presence of atypical megakaryocytes with small hypolobated morphology reminiscent of those typically seen in MDS with isolated 5q deletion. Cytogenetic analysis, including interphase and metaphase FISH, karyotype and SNP chromosomal microarray were performed, as well as DNA sequencing studies. Cytogenetic analysis showed a very complex karyotype featuring multiple 5q intrachromosomal rearrangements including a pericentric inversion with multiple interspersed deletions and monosomy 7. FISH studies showed a partial deletion of the PDGFRβ gene, and SNP chromosomal microarray and targeted panel-based sequencing identified biallelic loss of function of the TP53 gene. Based on the pathologic findings, the patient was treated for MDS but did not respond to either lenalidomide or azacitidine.

The genetic changes described, in particular, the complex intrachromosomal rearrangements of chromosome 5, suggest the occurrence of a sudden catastrophic event that led to an aggressive course in the patient's disease. Conventional karyotyping, metaphase and interphase FISH, SNP chromosomal microarray and NGS helped to identify the complex genetic changes seen in this case. This highlights the importance of utilizing a multimodality approach to fully characterize complex chromosomal events that may significantly impact disease progression, treatment and survival.