Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria

Abstract

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of a haematopoietic stem cell clone with a PIG‐A mutation (the PNH clone) in an environment in which normal stem cells are lost or failing: it has been hypothesized that this abnormal marrow environment provides a relative advantage to the PNH clone. In patients with PNH, generally, the karyotype of bone marrow cells has been reported to be normal, unlike in myelodysplastic syndrome (MDS), another clonal condition in which cytogenetic abnormalities are regarded as diagnostic. In a retrospective review of 46 patients with a PNH clone, we found a karyotypic abnormality in 11 (24%). Upon follow‐up, the proportion of cells with abnormal karyotype decreased significantly in seven of these 11 patients. Abnormal morphological bone marrow features reminiscent of MDS were common in PNH, regardless of the karyotype. However, none of our patients developed excess blasts or leukaemia. We conclude that in patients with PNH cytogenetically abnormal clones are not necessarily malignant and may not be predictive of evolution to leukaemia.

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

“…Although we cannot rule out that this happens in exceptional cases, it is evident that PIG-A mutations do not necessarily lead to inexorable clonal expansion, even when they are associated with visible chromosomal abnormalities. 17 Our clinical findings are instead most consistent with the model of immunological selection in favor of PNH cells, 16,29 which also explains the presence of multiple PNH clones in some patients. 30,31 Auto-immune processes often wax and wane; if autoimmune selection in favor of the PNH clone wanes, one would expect to see clones that may be large but are no longer expanding, as we have observed.…”

“…For example, we have recently demonstrated significant morphologic dysplasia, a cytogenetic abnormality, or both in the marrows of about half of PNH patients. 17 Since PNH clones have been identified in 10% to 25% of patients with a diagnosis of MDS, flow cytometry aiming to identify such clones is increasingly becoming part of the work up of MDS. [17][18][19] As in MDS, evolution of PNH to leukemia is possible (reviewed in Ref.…”

“…17 Since PNH clones have been identified in 10% to 25% of patients with a diagnosis of MDS, flow cytometry aiming to identify such clones is increasingly becoming part of the work up of MDS. [17][18][19] As in MDS, evolution of PNH to leukemia is possible (reviewed in Ref. 20), although with a much lower frequency.…”

A patient with paroxysmal nocturnal hemoglobinuria, T cell large granular lymphocyte clonal expansion, and monoclonal gammopathy of undetermined significance

“…Cytogenetic analysis at time of diagnosis was not performed. Although the presence of cytogenetic abnormalities tends to increase confidence in a diagnosis of MDS, abnormal karyotypes can also be found in a subset of patients with PNH [16] and thus cannot be considered a distinguishing marker. Mild dyserythropoiesis can be observed as a consequence of the compensatory erythroid hyperplasia in response to brisk hemolytic anemia and is not necessarily indicative of underlying MDS.…”

Diagnostic problems in acquired bone marrow failure syndromes

“…In reality, however, even experienced hematologists often misdiagnose PNH with moderate hemolysis of MDS. This is because PNH patients with BM failure exhibit significant signs of dysplasia in immature BM cells, which cannot be discriminated from MDS by experienced pathologists [1]. Misdiagnosis leads to inappropriate management of PNH patients, such as red blood cell transfusions alone without eculizumab therapy and allogenic stem cell transplantation from unrelated donors.…”