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Isolated central nervous system (CNS) relapse is a rare, unpredictable event in patients with CML. Some studies have reported cases of isolated CNS relapse in CML [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]. However, very few studies have reported on isolated CNS relapse in the blast phase (BP) of CML in Korea [14, 15]. We report a case of BP CML with extramedullary lymphoblast proliferation in the CNS without evidence of disease in the peripheral blood (PB) and bone marrow (BM). A 54-yr-old man was diagnosed as having BCR/ABL1 (b2a2 type)-positive CML in July 2012. He was considered to be in the chronic phase on the basis of his blast count on PB smear and BM aspiration, and subsequently, he was administered imatinib (400 mg/day). Three months after diagnosis, he demonstrated a complete hematologic response, major cytogenetic response, and no major molecular response according to the National Comprehensive Cancer Network Guidelines in Oncology for CML (karyotype 46,XY,t(9;22)(q34;q11.2)[7]/46,XY[23], BCR-ABL1 fusion transcript of 0.933% based on the International Scale [IS]) [16]. Seven months after initial diagnosis, he was readmitted with a complaint of headache since two months. Diffusion brain magnetic resonance imaging with magnetic resonance angiography revealed abnormal leptomeningeal enhancement of both paramedian gyri, suggesting involvement of leukemic cells. In cerebrospinal fluid (CSF) study, his CSF was turbid and had increased number of white blood cells (WBCs) (3.5×109/L), and almost all WBCs were lymphoid cells. Wright stain of cytospin-smeared CSF showed lymphoid cells with high nuclear-to-cytoplasmic ratio and coarse chromatin pattern with prominent nucleoli. Lymphoid cells were negative on periodic acid-Schiff staining. In flow cytometric analysis, the lymphoid cells had an early pre-B phenotype with an aberrant CD33 expression (positive for CD45, CD34, CD33, terminal deoxynucleotidyl transferase (TDT), HLA-DR, CD19, and CD10). The result of reverse transcriptase-PCR for detecting BCR-ABL1 fusion transcript was positive (b2a2 type) in CSF. On complete blood count analysis, Hb level was 13.3 g/dL, WBC count was 11.41×109/L, and platelet count was 167×109/L. There was no morphologic evidence of lymphoblasts in PB and BM samples (Fig. 1). The patient was treated with dasatinib, intrathecal methotrexate, and cranial irradiation therapy. One week after initiation of treatment, CSF showed decreased WBCs (0.002×109/L) with no evident malignant cells. Two months after relapse, patient demonstrated a complete hematologic response, complete cytogenetic response, and major molecular response (karyotype 46,XY[30], BCR-ABL1 fusion transcript of 0.011% by IS). His laboratory findings are summarized in Table 1. Fig. 1 Cerebrospinal fluid (CSF) findings at seven months after initial diagnosis of CML. (A) Cytospin-smeared CSF showing numerous lymphoid cells with high nuclear-to-cytoplasmic ratio and coarse chromatin pattern with prominent nucleoli (Wright stain, ×1,000). ... Table 1 Brief laboratory data of the case This patient showed optimal response to imatinib therapy that was administered according to the European Leukemia Net recommendation [17]. However, spontaneous, isolated CNS relapse occurred after 7 months of imatinib therapy. In previous reports, isolated CNS relapse was observed in patients with imatinib-treated CML or Philadelphia chromosome-positive acute lymphoblastic leukemia [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. This phenomena raised the possibility that imatinib may poorly penetrate the blood-brain barrier. Some studies have demonstrated that imatinib does not reach therapeutic levels in CSF, and therefore, imatinib therapy alone may lead to a potential risk of CNS involvement [1, 10]. We present a summary of 15 cases of isolated CNS relapse in CML patients in Table 2. Isolated CNS relapse was predominantly observed in men (M:F=11:4) with a median age of 42 yr (range, 17-73 yr). The major presenting symptom of isolated CNS relapses was headache with or without other neurologic symptoms. Nine of 15 cases (60%) had complete cytogenetic response state at CNS relapse. The median time from treatment initiation to CNS relapse was 25 months (range, 4-58 months) in 15 cases. Findings from these cases show that isolated CNS relapse has no correlation with a response to imatinib therapy. No other sites were involved, except for CNS in all of the 15 cases, and eight cases had B-cell lymphoid phenotype of blasts [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. In our case, the patient was a middle-aged man experiencing headaches as the initial manifestation of CNS relapse. Excluding the case in a 17-yr-old patient [6], the time interval from the diagnosis to CNS relapse in our case was shorter (7 months) than the previously reported cases. Most of the previous cases had received additional treatment with intrathecal chemotherapy and cranial irradiation, and had showed good response [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. Nishimoto et al. [13] reported a case with successful treatment with dasatinib and allogeneic hematopoietic stem cell transplantation (HSCT). Our patient was also treated with dasatinib after CNS relapse in BP of CML, and is currently being prepared to receive HSCT. Brain imaging, CSF study, or CNS prophylaxis are not routinely undertaken in patients with chronic phase CML at diagnosis. To our knowledge, there are no recommendations on the evaluation of CNS disease in CML patients. There are prognostic classifications using four factors, such as age, size of spleen, platelet count, and blast count at diagnosis and they remain valid for imatinib treatment [18, 19, 20]. Our patient was at high risk according to risk stratifications by Hasford et al. [19] and Sokal et al. [20] (Hasford score 1,509 and Sokal score 1.35). However, risk factors of CNS relapse have not been investigated. Further studies are needed to identify risk factors of CNS relapse. Table 2 Cases of isolated CNS blast crisis in CML To our knowledge, this is the third report of isolated CNS lymphoblast proliferation in a Korean CML patient. It is important to consider CNS relapse in chronic phase CML patients optimally treated with imatinib, especially in patients presenting with neurological symptoms, including headache. This emphasizes the need for brain imaging study and CSF monitoring in imatinib-treated CML patients even without evidence of disease progression on PB smear and BM studies.

Background N-ras mutations are one of the most commonly detected abnormalities of myeloid origin. N-ras mutations result in a constitutively active N-ras protein that induces uncontrolled cell proliferation and inhibits apoptosis. We analyzed N-ras mutations in adult patients with AML at a particular institution and compared pyrosequencing analysis with a direct sequencing method for the detection of N-ras mutations. Methods We analyzed 90 bone marrow samples from 83 AML patients. We detected N-ras mutations in codons 12, 13, and 61 using the pyrosequencing method and subsequently confirmed all data by direct sequencing. Using these methods, we screened the N-ras mutation quantitatively and determined the incidence and characteristic of N-ras mutation. Results The incidence of N-ras mutation was 7.2% in adult AML patients. The patients with N-ras mutations showed significant higher hemoglobin levels (P=0.022) and an increased incidence of FLT3 mutations (P=0.003). We observed 3 cases with N-ras mutations in codon 12 (3.6%), 2 cases in codon 13 (2.4%), and 1 case in codon 61 (1.2%). All the mutations disappeared during chemotherapy. Conclusions There is a low incidence (7.2%) of N-ras mutations in AML patients compared with other populations. Similar data is obtained by both pyrosequencing and direct sequencing. This study showed the correlation between the N-ras mutation and the therapeutic response. However, pyrosequencing provides quantitative data and is useful for monitoring therapeutic responses.

Background : For the diagnosis of essential thrombocythemia (ET), no single clinical or laboratory finding of diagnostic value is available and a differential diagnosis of other myeloproliferative neoplasms or reactive thrombocytosis (RT) is needed. Following recent developments in automated blood cell analyzers, various platelet indices can now be measured. In this study, we analyzed whether platelet counts and 6 platelet indices can be used for the differentiation of ET from RT in patients with a platelet count of 600 ×10 3 /mL or more. Methods : The subjects studied were 31 patients with ET and 224 patients with RT. The platelet counts, mean platelet volume (MPV), plateletcrit (PCT), platelet distribution width (PDW), mean platelet mass (MPM), mean platelet component concentration (MPC) and large platelets (LPLT) were measured by ADVIA 120 (Bayer Diagnostics, USA). The mean values of each item were compared between the two patient groups and the sensitivity and specificity of each item in the diagnosis of ET were determined by ROC curve analysis. Results : In essential thrombocythemia, all parameters except MPC were significantly higher than in reactive thrombocytosis. For the diagnosis of ET, the sensitivity and specificity were: 74.2% and 84.4%, when the platelet count was ≥820×10 3 /mL; 80.6% and 80.0%, when the plateletcrit was ≥ 0.63%; and 64.5% and 99.1%, respectively, when LPLT was ≥23×10 3 /mL. Conclusions : The platelet counts and platelet indices are useful for the differential diagnosis of thrombocytosis. The plateletcrit and LPLT are particularly useful for the diagnosis of ET when the platelet count is markedly increased. (Korean J Lab Med 2009;29:505-9)

Dear Editor, Bone marrow (BM) oxalosis is a type of systemic oxalosis wherein oxalate is deposited in BM. It is characterized by cytopenias, leukoerythroblastosis, and hepatosplenomegaly [1] as well as BM findings of calcium oxalate crystals that are birefringent under polarized microscopy and granulomatous structures [2]. Hyperoxaluria (excessive urinary excretion of oxalate) can develop into systemic oxalosis when oxalate is deposited in organs [3]. Hyperoxaluria is classified as primary or secondary. Primary hyperoxaluria is an autosomal recessive disease with defective oxalate metabolism [3] in which the overproduction of oxalate results from an enzyme deficiency in the liver; its clinical presentation involves nephrocalcinosis and renal impairment. Systemic deposition of excess oxalate occurs in the bone and all organs and tissues, except the liver. The retina, arteries, peripheral nervous system, myocardium, thyroid, skin, and BM are the major areas of oxalate deposition. Bone is the most common site, although the bone lesions can mimic clinical renal osteo-dystrophy [4,5]. Primary hyperoxaluria includes three types of enzyme deficiency. The most common form is primary hyperoxaluria type I, with an incidence rate of approximately 1/120,000 live births per year in Europe. It is caused by a mutation in the AGXT gene resulting in a functional defect of the liver enzyme alanine-glyoxylate aminotransferase and represents 80% of primary hyperoxaluria. Primary hyperoxaluria type II is caused by a deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHPR), and type III is caused by a deficiency of the mitochondrial enzyme HOGA1 [2,3]. Secondary hyperoxaluria occurs when dietary and intestinal absorption of oxalate or intake of oxalate precursors is increased and the intestinal microflora is changed [3]. The clinical presentation of secondary hyperoxaluria is similar to that of primary hyperoxaluria, although systemic oxalosis is less common [3]. We present a case of BM oxalosis with pancytopenia in a patient who had been on hemodialysis after bilateral nephrectomy due to recurrent nephrocalcinosis. A 51-yr-old male patient underwent a BM biopsy due to pancytopenia. He had been on hemodialysis via an arterio-venous graft since 2009 when he underwent a bilateral nephrectomy owing to recurrent renal stones and renal failure. One of his siblings had died owing to end-stage renal disease in his or her 30s (the sex is unknown). The patient had no history of a high-oxalate diet or gastrointestinal symptoms. His complete blood count revealed a Hb level of 5.7 g/dL, white blood cell count of 1.2×109/L (absolute neutrophil count 0.81), and platelet count of 98×109/L. Anemia persisted for five years despite treatment with erythropoietin, and leukopenia and thrombocytopenia also developed. Radiography revealed diffuse sclerotic changes and osteolytic lesions in multiple sites that resulted in a spontaneous fracture in his elbow. Endocrinologically, subclinical hypothyroidism was present with an increased thyroid-stimulating hormone level of 5.344 mIU/L (reference range 0.55-4.78 mIU/L), and a near-normal free thyroxine level of 8.1 ng/L (reference range 8.9-17.8 ng/L). Laboratory data showed the following: blood urea nitrogen, 0.36 g/L, creatinine, 43 mg/L, and erythropoietin 33.2 IU/L (reference rage 4.3-29 IU/L). Tear drop cells and left-shifted neutrophils were observed on a peripheral blood smear. BM aspirates were hemodiluted and showed a few multinucleated giant cells. Extensive oxalate crystals depositions surrounded by macrophages and granulomatous formations were revealed on BM biopsy. The crystals were birefringent under polarized microscopy (Fig. 1). The patient demonstrated systemic oxalosis involving the bone, possibly thyroid, and BM, with no evidence of involvement in the retina, arteries, peripheral nervous system, myocardium, or skin. Fig. 1 (A) Pancytopenia showing tear drop cells indicated by the arrow (peripheral blood smear, Wright stain, ×1,000). (B) Bone marrow biopsy shows oxalate crystals surrounded by granuloma (Hematoxylin & Eosin stain, ×200). (C) Crystals ... The familial history of a sibling who had died of end-stage renal disease and the presentation of systemic oxalosis involving bone, thyroid, and BM, and no evidence of a secondary cause, such as diet, suggested a diagnosis of primary hyperoxaluria. However, genetic testing could not be performed because the patient was transferred to a secondary hospital and lost to follow-up. BM oxalosis is a rare disease presenting with cytopenia, especially treatment-resistant anemia and renal failure [2]. The development of pancytopenia is a rare and late finding [2,6]. BM aspirate is often hemodiluted owing to crystals. Calcium oxalate crystalline deposits surrounded by granulomatous structures are observed on BM biopsy [2]. Early diagnosis and appropriate conservative treatment is required to prevent the possible complications resulting from cytopenias. Kidney or combined liver and kidney transplantation is the treatment of choice for systemic oxalosis [7]. This is the first case report of BM oxalosis in Korea. BM oxalosis should be considered as a possible diagnosis in patients in renal failure with pancytopenia or treatment-resistant anemia.