Case study 19.1
A 34-year-old female is complaining of increased skin bruising, dyspnea on exertion, palpitations, and petecchiae for a duration of 2 weeks. Her vital signs are significant for tachypnea (respiratory rate = 23), tachycardia (heart rate = 118 beats/min), and fever (102 °F). On physical examination, she has blood blisters in her mouth, and small petecchiae and ecchymoses on both lower extremities; the patient has no palpable lymphadenopathies or organomegalies. A complete blood count (CBC) shows a hemoglobin (Hgb) of 7.8 g/dL, a mean corpuscular volume (MCV) of 102 fL, a leukocyte [white blood cell (WBC)] count of 800/µL, an absolute neutrophil count (ANC) of 215/µL, an absolute lymphocyte count (ALC) of 600/µL, and a platelet (PLT) count of 9000/µL. Her absolute reticulocyte count (ARC) is 23,000/µL. A bone marrow (BM) biopsy is performed and shows a BM cellularity of <5% with some mild erythroid dysplasia. The megakaryocytes are absent with no dysplastic changes. Metaphase cytogenetics (MC) shows no growth. The fluorescence in situ hybridization (FISH) for MDS is unremarkable. The patient is concerned that she has myelodysplastic syndrome (MDS) and would like to know if there is another test that can help clarify her diagnosis.
1. Which laboratory technique may be helpful to clarify the patient’s diagnosis?
- Spectral karyotyping
- Paroxysmal nocturnal hemoglobinuria (PNH) flow cytometry
- Testing for a JAK2V617F mutation
- Single nucleotide polymorphism array (SNP-A) karyotyping
An important variant of MDS called hypocellular MDS can present with a hypocellular BM similar to aplastic anemia (AA) as well as other clinicopathologic features of MDS. Morphologic criteria for MDS and persistent cytogenetic abnormalities characteristic of MDS, including −7 and −7q, can be helpful in differentiating between both diseases (Maciejewski and Selleri 2004). However, the distinction between AA and hypocellular MDS can be sometimes difficult. This is especially true in cases of minimal dysplasia with no other overt morphologic MDS-related changes and when the MC and FISH for MDS show a normal karyotype. A study using SNP-A karyotyping showed chromosomal abnormalities in 30% of AA patients with previously normal karyotype by MC at presentation (Afable et al. 2011). This technique may be useful in distinguishing between hypocellular MDS and AA (Afable et al. 2011). Flow cytometry to quantify the percentage of granulocytes, monocytes, and red cells deficient in glycosyl-phosphatidylinositol (GPI)-linked proteins (CD55, CD59, CD14, CD24, and CD52) can be used to diagnose the presence of PNH. Although PNH clones are more frequently found in AA patients, they also can be found in MDS patients and they are not helpful in differentiating between hypocellular MDS and AA. JAK2V617F mutations are primarily seen in myeloproliferative neoplasms (MPNs) and are less commonly found in MDS. Spectral karyotyping is a molecular cytogenetic technique that utilizes fluorophores binding to each chromosome to identify structural chromosomal abnormalities in cancer cells. Its clinical application in AA is still unclear.
2. She also inquired about whether she may have an inherited type of AA. What additional tests may be helpful to exclude congenital causes of AA?
- Chromosome breakage testing with mitomycin C
- Chromosome breakage testing with diepoxybutane
- Telomere length (TL) measurements
- All of the above
The majority of AA patients, regardless of age, have acquired idiopathic immune-mediated AA (Visconte 2012; Young 2005). However, a small proportion of patients has inherited AA. Most cases of inherited AA are due to Fanconi anemia (FA), dyskeratosis congenita (DC), Shwachman–Diamond syndrome, and amegakaryocytic thrombocytopenia and are diagnosed between the ages of 2 and 5 years. FA is the most common type of inherited AA (Alter 2007). Patients can present with congenital malformations, early cancers, and variable degrees of cytopenias. The diagnosis is made based on the presence of increased chromosome breakage in lymphocytes cultured with either mitomycin C or diepoxybutane. DC is commonly associated with the triad of leukoplakia, dystrophic nails, and a hyperpigmented rash. However, the vast majority of patients do not have these clinical features. Clinical history and physical examination for associated anomalies together with genetic testing can be helpful in the diagnosis of some cases. TL analysis can also be helpful in some cases with a strong clinical suspicion. The finding of TL <1 percentile for age in three different lymphocyte subsets may be useful in the diagnosis.
17: Management of Therapy-Related Myeloid Neoplasms
11: Minimal Residual Disease in Acute Myeloid Leukemia
71: Secondary Brain and Spinal Cord Tumors
