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    • Initial bone marrow biopsy was inadequate in size

    2019-06-20

    Initial bone marrow biopsy was inadequate in size for detailed examination and had severe crush artifact. The preserved focus of marrow showed hypercellularity with large, multinucleated, dysplastic megakaryocytes and megaloblastoid changes in erythroid series (Fig. 1B and C). There was no increase in reticulin fiber content in the marrow biopsy, making a myelophthisic process as the underlying cause of schistocytosis unlikely. Blood vessels were not appreciated in the bone marrow biopsy due to severe crush artifact. A skin biopsy showed deep subcutaneous hemorrhage and no evidence of microangiopathic changes. The marrow aspirate was also insufficient for further analysis by flow cytometry or cytogenetics. CMA of peripheral blood revealed multiple genomic imbalances in a mosaic state, including losses of portions of chromosome arms 5q, 7q and 13q, isodisomy of 17p, and gains of chromosomes/chromosomal MAFP manufacturer 1p, 5p, 6, 8, 19, 20p, 21 (Fig. 2), findings consistent with the diagnosis of MDS. Conventional cytogenetic analysis performed on a repeat bone marrow sample revealed an abnormal karyotype: 47-50,X,-X,der(?)t(?;1)(?;q21),+add(1)(q12)x2, del(5)(q14),+6,add(7)(q22),+8,+9,−13,+19,−20,+21,+0-2mar[cp15]/46,XX. The findings were similar to those of the peripheral blood CMA and confirmed the diagnosis of therapy-related MDS with complex cytogenetics.
    Discussion This is a case report of therapy-associated MDS and MAHA, a rare manifestation of MDS. The initial presentation was low platelet count and anemia, elevated bilirubin and schistocytosis in the peripheral blood smear. The patient presented with non-immune hemolytic anemia. Hemolytic anemias are common occurrences in patients with hematologic malignancies, particularly AML and chronic myeloid leukemia (CML), but are rarely observed in MDS, with only a few cases reported in the literature [11]. Abnormal RBC morphologies have previously been reported in cases of MDS. These include elliptocytosis [1,2,12], spherocytosis [13], acanthocytosis [14] and basophilic stippling [1–3]. However, marked schistocytosis by itself is rare. To the best of our knowledge, only 3 cases of schistocytosis with underlying MDS have been reported in the English literature [1,12]. In 1984, Hartz et al. reported a 78-year-old man who presented with refractory anemia with peripheral schistocytes [12]. The patient was subsequently diagnosed with MDS upon further work up. Rummens et al. described two cases of MDS (ages 59 and 60) who presented with schistocytosis on peripheral blood film [1]. Schistocytosis has also been reported in other malignant hematologic disorders. For example, Atkins and Muss described a series of 12 patients with erythroleukemia [13]. All of their patients had evidence of schistocytosis and elliptocytosis in peripheral blood. RBC fragmentation has been described as a general observation in patients with leukemia [13,15]. Our patient showed other morphologic abnormalities of RBCs, including occasional elliptocytes and basophilic stippling, which are commonly observed with MDS [1–3]. Karyotypic analysis has been invaluable for detection of chromosomal rearrangements specific to certain diseases, such as t(9;22) in CML and t(15;17) in acute promyelocytic leukemia [4,5], and can predict sensitivity to molecularly targeted drugs, such as imatinib in CML [16]. Cytogenetics have been part of the revised International Prognostic Scoring System (IPSS-R) and shown to have important prognostic implications in MDS patients, with detection of 5q- syndrome being a prominent example [6]. Whole genome scanning studies, such as CMA using SNP arrays, eliminate the need for dividing cells, have a much higher level of resolution than karyotypic analysis, and allow for detection of both DNA copy number and LOH throughout the genome in a single experiment [7]. CMA also uncovers acquired cn-LOH, which is indicative of somatic uniparental isodisomy. While cn-LOH occurs commonly in hematological malignancies [8], it is undetectable by classical cytogenetics [7,9]. Such was the case in our patient, in which CMA of peripheral blood demonstrated isodisomy of 17p, a site encompassing the TP53 tumor suppressor gene. Notably, recurrent mutations of TP53 have been previously described in myeloid malignancies [8].