Distinguishing between acquired aplastic anemia (AA) and myelodysplastic syndrome (MDS) with a low blast cell percentage is often difficult and problematic, as both diseases are syndromes primarily defined by morphological findings, and their diagnostic criteria do not necessarily reflect the pathophysiology of their bone marrow (BM) failure. As a result, many patients with benign BM failure that should be managed as AA are diagnosed as having MDS, due to the absence of BM hypocellularity and the presence of dysplastic signs in the BM, and are treated inappropriately with toxic therapies, such as hypomethylating agents, and stem cell transplantation from unrelated donors. BM failure syndromes need to be managed in ways appropriate to their pathophysiology, which is more accurately determined by using markers such as the presence of glycosylphosphatidylinositol-anchored protein-deficient cells and HLA-A lacking leukocytes. We recently found that plasma thromobopoietin level is one of the most useful markers for distinguishing benign and pre-leukemic BM failure syndromes.
KeywordsAcquired aplastic anemia Myelodysplastic syndrome GPI-AP-deficient cells Plasma thrombopoietin level Immunosuppressive therapy
The differentiation of aplastic anemia (AA) from low-risk myelodysplastic syndrome (MDS) has long been a matter of clinical importance to hematologists. Although several markers have been shown to be useful for differentiating between these conditions, none has been widely accepted due to their low reliability.
One reason for the difficulty in differentiating these two diseases is that their diagnostic criteria were established separately, without considering the distinctions between them. Thus, AA is diagnosed based on the presence of pancytopenia and bone marrow (BM) hypoplasia without apparent dysplasia in immature and mature blood cells , while MDS is diagnosed when cytopenias and dysplastic signs are present . Not surprisingly, patients who are diagnosed with AA by a physician may be diagnosed with MDS by other physicians, due to the presence of equivocal dysplasia . Despite the fact that the diagnosis of both syndromes relies primarily on morphological findings, AA, and MDS are defined as benign and premalignant BM failure, respectively, and this mismatch between diagnostic criteria and disease concepts may further confound correct diagnosis. Since the diagnoses of the two syndromes are not mutually exclusive, attempts to differentiate between them by following conventional diagnostic criteria are of limited value. Instead, it is clinically relevant to distinguish a benign subset of BM failure, which is likely to respond to immunosuppressive therapy (IST), from other types of BM failure, including those with pre-leukemic features and inherited BM failure syndromes . In this review article, we discuss the adverse outcomes of a misdiagnoses of AA and low-risk MDS, citing two representative cases, and introduce markers that can help to differentiate immune pathophysiology from non-immune pathophysiology in BM failure. In this review, we refer to benign and preleukemic BM failure syndromes, respectively, as AA and MDS.
Case presentation 1
Reasons for the difficulty in diagnosing Case 1
BM distribution is inconsistent in patients with non-severe AA
Bone marrow aspiration and trephine biopsy are essential for the differential diagnosis of BM failure syndromes, and hypocellular BM is a prerequisite for diagnosing AA. However, assessing BM cellularity in patients with BM failure is often difficult, particularly when the patient’s cytopenia is not severe. Even when the BM failure of a patient is caused by a decrease in hematopoietic stem cells and the BM is grossly replaced with fat tissue, some hematopoietic nests remain and may show hypercellularity due to increased BM activity that compensates for the decreased hematopoiesis in other BM sites. BM aspiration or biopsy from the hot spots can produce erroneous results, as shown in Case 1. When the pathological reports of the BM examination show hyper- or normocellularity, the attending physicians do not generally consider a differential diagnosis of AA. Care should thus be taken with respect to cellularity when interpreting results of BM examinations. It is prudent to consider that BM cellularity cannot be accurately determined by BM biopsies from limited sites in the iliac bone. MRI of the thoracolumbar spine can be used to supplement the cellularity assessment by BM biopsies. However, MRI of elderly patients often produces equivocal results, due to age-related fatty changes in the BM. Thus, hematologists should keep it in mind that BM hypercellularity does not necessarily preclude a diagnosis of AA.
Dysplasia is common in the BM of patients with AA
The presence of dysplastic signs in the BM is thought to be a hallmark of MDS. However, dysplastic signs in erythroblasts, such as nuclear deformities and karyorrhexis, are often detectable in the BM of patients with non-severe AA . These dysplastic signs are detectable even in the BM of healthy individuals [6, 7]. Physicians nonetheless tend to interpret these dysplastic signs as significant, and make a diagnosis of refractory cytopenia with unilineage dysplasia (RCUD) or RCMD, particularly when BM examination does not reveal hypocellularity. In the end, many of the patients with non-severe AA are currently being diagnosed with MDS, as seen in Case 1. The pathophysiology of patients with increased GPI-AP-deficient blood cells diagnosed with RCUD or RCMD is essentially the same as that of AA . The therapeutic plan should therefore be based on the pathophysiology of BM failure deduced from markers, rather than the degree of dysplasia.
Signs of inefficient erythropoiesis are common in chronic AA
Ineffective erythropoiesis characterized by macrocytosis, erythroid hyperplasia in the BM, and intramedullary hemolysis is commonly seen in patients with MDS, but is also observed in patients with chronic AA, where the pancytopenia gradually progresses. This is particularly common in patients possessing increased GPA-AP-deficient blood cells . Although it is unclear how ineffective erythropoiesis occurs in these patients based on immune pathophysiology, inflammatory cytokines produced by pathogenic T cells may cause reversible dyserythopoiesis . In fact, the signs of ineffective erythropoiesis usually disappear when patients respond to IST and achieve remission . Thus, it is essential for physicians to avoid making a premature diagnosis of MDS based on the presence of ineffective erythropoiesis.
Case presentation 2
Reasons for the choice of IST for Case 2
Significance of TPO measurement in the management of MDS
Classification of BM failure according to the plasma TPO levels
Measurement of the TPO levels is recommended for all BM failure patients with thrombocytopenia as an aid in selecting the most appropriate therapeutic approach. The precise role of TPO levels in the management of MDS will need to be evaluated by a large prospective study.