Eunkyoung You

Mean platelet volume/platelet count ratio in hepatocellular carcinoma

Mean platelet volume (MPV) has been actively investigated in liver disease such as steatosis, cirrhosis and hepatitis. Recently, MPV/platelet count (PC) ratio has been proposed as a predictor of long-term mortality after myocardial infarction. As PC is known to be decreased in various liver diseases such as cirrhosis, hepatosplenomegaly and malignancy, we planned to evaluate MPV/PC ratio in patients with hepatocellular carcinoma (HCC) in this study. Mean of MPV levels showed significant difference, which were 8.69 fl (range 6.7–12.2 fl) in patients group and 8.02 fl in control group (range 6.7–11.0 fl). In receiver operating characteristic (ROC) curve analysis, the MPV/PC ratio (fl/(109/l)) presented 74.5% of sensitivity and 96.5% of specificity at the criterion > 0.0491 (area under the curve (AUC) = 0.884), while MPV alone showed 57.4% of sensitivity and 81.4% of specificity at the criterion > 8.4 fl. Further studies should evaluate underlying pathogenic mechanisms of MPV/PC ratio difference and various possibilities of this ratio as an indicator of presence of a tumor in HCC.

Factors influencing discordant results of the QuantiFERON-TB Gold In-tube test in patients with active TB

OBJECTIVES Indeterminate or negative results from the QuantiFERON-TB Gold In-tube test (QFT-GIT) for TB-confirmed patients indicate the lower sensitivity of this method. The aim of this study was to determine the factors associated with indeterminate and negative QFT-GIT results in active TB patients. METHODS We analyzed retrospectively the laboratory and clinical data of patients diagnosed with TB between December 2009 and April 2012 at a tertiary university hospital in Seoul, Korea. RESULTS Among 1301 patients who underwent QFT-GIT, TB-PCR and TB-culture, 168 (12.9%), those with positive TB-PCR or TB-culture were diagnosed with TB. Thirty-nine (23.2%) had indeterminate or negative results by QFT-GIT assay, which did not correlate with positive results of TB-PCR or TB-culture. These patients were older, had lower lymphocyte, total protein and albumin levels, and showed significantly higher CRP levels than the positive group. Multivariate logistic regression analysis showed that the probability of indeterminate and negative QFT-GIT results increased as CRP (odd ratio, 1.069; 95% CI, 1.013-1.127; P = 0.014) or age (1.030, 1.005-1.056, 0.02) increases. CONCLUSIONS When levels of markers of inflammation, such as CRP, are high or the patient is older, QFT-GIT results should be interpreted carefully and correlated with additional tests for TB.

A case series of autoimmune diseases accompanied by incidentally diagnosed monoclonal gammopathy: Is there a link between the two diseases?

Although the etiology of plasma cell dyscrasia is poorly understood, there is evidence for immune dysregulation or sustained immune stimulation playing a pivotal role in the pathogenesis of these diseases, including chronic infection and autoimmune disorders. In this study, we report four autoimmune disease cases where monoclonal gammopathy (MG) was incidentally found during follow‐up.

A Novel Case of Extreme Thrombocytosis in Acute Myeloid Leukemia Associated With Isochromosome 17q and Copy Neutral Loss of Heterozygosity

Dear Editor An isochromosome of the long arm of chromosome 17, i(17q) has been frequently reported in the blast phase of CML [1], and is also associated with various types of hematological diseases [2]. While it is believed that i(17q) as a sole abnormality is a distinctive clinicopathological entity with a high risk of leukemic progression, a subset may be present as de novo AML [3]. Extreme thrombocytosis is rare in AML, and only a few cases have been described with chromosome 3 abnormalities [4, 5]. In addition, the loss of heterozygosity (LOH) affecting chromosome 7q is common in AML and MDS, suggesting the essential role of this region in disease phenotypes and in clonal evolution. Presented here is a case of AML with myelodysplasia-related changes (AML-MRC) with extreme thrombocytosis, 7q LOH, and i(17q). A 76-yr-old Korean male was referred for thrombocytosis. The initial complete blood count (CBC) showed a Hb level of 8.9 g/dL, a platelet count of 1,746×109/L, and a white blood cell (WBC) count of 14.65×109/L with 43% blasts (Fig. 1A). The dysplastic features observed on a peripheral blood smear were marked anisocytosis of red blood cells (RBCs), pseudo-Pelger-Huet-like neutrophils, and extreme thrombocytosis with giant and large platelets (Fig. 1B). Bone marrow aspiration smears displayed hardly visible hematopoietic components owing to extreme thrombocytosis and dyspoietic megakaryocytes (Fig. 1C). Micromegakaryocytes with the dyspoietic features of binucleation or non-lobulated shapes were observed (Fig. 1D). From visible fields located at the periphery of aspiration slides, 37.8% of leukemic blasts were seen. Focal fibrosis of the bone marrow was observed from the biopsy section. The results of BCR-ABL1, JAK2 V617F, MPL W515L/K, and CALR exon 9 mutation tests were all negative. Immunophenotyping revealed that the blasts were positive for CD34, CD13, HLA-DR (moderate), CD33, and CD38 (dim), which was consistent with AML. The chromosome study showed a karyotype of 46,XY,i(17)(q10) in 18 out of 20 metaphase cells (Fig. 2A). The patient was diagnosed as having AML-MRC. Fig. 1 The findings of the peripheral blood (PB) smear and bone marrow (BM) aspiration. The PB smear shows leukemic blasts (horizontal arrow) (A). Dysplastic features were found on the PB smear such as marked anisopoikilocytosis in red blood cells (RBCs), pseudo-Pelger-Huet-like ... Fig. 2 Chromosome and microarray analyses. Giemsa-banded karyogram of the bone marrow cells at diagnosis: 46,XY,i(17)(q10). The arrow denotes the abnormal chromosome (A). Microarray analysis shows a single copy loss in chromosome 17 at bands p13.3 through p11.2, ... A high-resolution microarray analysis using a cytogenetics whole genome 2.7M array (Affymetrix, Santa Clara, CA, USA) was conducted after obtaining informed consent for further analysis. The microarray analysis also revealed abnormalities of chromosome 17, which was consistent with the conventional cytogenetic findings; the abnormalities were represented as arr 17p13.3p11.2(64,214-18,751,820)×1,17p11.2q25.3 (18,751,820-80,587,411)×3 (Fig. 2B). Incidentally, the microarray analysis also detected a copy neutral LOH as arr7q11.1q36(59,000,001-159,138,663)×2 homozygous (hmz) (Fig. 2C). After being diagnosed as having AML-MRC, the patient refused to continue with chemotherapy and expired 10 months after diagnosis. According to the study by Rashmi et al. [3], most cases of myeloid neoplasm with i(17q) show anemia, leukocytosis, thrombocytopenia, and splenomegaly. Morphologically, all cases show features of both myelodysplasia and myeloproliferation (pseudo-Pelger-Huet-like neutrophils, micromegakaryocytic hyperplasia, hypercellularity, fibrosis, and osteosclerosis) [3]. It has been suggested that granulocyte colony-stimulating factor and myeloperoxidase positioned at 17q21.1 and 17q23.1, respectively [6, 7], are responsible for myeloproliferative features in the presence of i(17q), where duplication of 17q occurs [3, 8]. In our case, most of the features were consistent with characteristic findings of myeloid neoplasms with i(17q). However, extreme thrombocytosis was a characteristic feature that differed from the previous report, which reported mostly thrombocytopenia [3]. Marked thrombocytosis is rarely associated with AML, and thrombocytosis with a platelet count over 1.0×1012/L is an extremely rare phenomenon, even for a patient with chromosome 3 abnormalities [4]. Our patient had a platelet count of 1,746×109/L at diagnosis, but no abnormalities of chromosome 3 were found. To our knowledge, this is the first reported case of marked thromobocytosis with AML associated with i(17q) and not with chromosome 3. During further investigation of i(17q) using a single nucleotide polymorphism array (SNP-A), copy neutral LOH 7q was incidentally detected. LOH 7q is common in AML and MDS and seems to play an important role in the phenotype and characteristics of these diseases [9]. A recent study by Jerez et al. [9] found a correlation between the presence of LOH 7q and diploid MDS/MPN. However, no AML-MRC cases had extreme thrombocytosis. Our case showed features that were consistent with i(17q) in myeloid neoplasms; most of the morphological and clinical features of our patient could be explained as characteristic features of i(17q). However, the finding of marked thromobocytosis and 7q LOH, seemed rather irrelevant and unrelated. A close follow-up of such unusual cases could provide further clinical information on AML-MRC with extreme thrombocytosis accompanied by i(17q) and 7q LOH, while additional studies are necessary to delineate and characterize the development of such unique cases.

Current routine practice and clinico-pathological characteristics associated with acute promyelocytic leukemia in Korea

Background Acute promyelocytic leukemia (APL) can be life threatening, necessitating emergency therapy with prompt diagnosis by morphologic findings, immunophenotyping, cytogenetic analysis, or molecular studies. This study aimed to assess the current routine practices in APL and the clinico-pathologic features of APL. Methods We reviewed the medical records of 48 Korean patients (25 men, 23 women; median age, 51 (20-80) years) diagnosed with APL in 5 university hospitals between March 2007 and February 2012. Results The WBC count at diagnosis and platelet count varied from 0.4 to 81.0 (median 2.0)×109/L and 2.7 to 124.0 (median 54.5)×109/L, respectively. The median values for prothrombin time and activated partial thromboplastin time were 14.7 (11.3-44.1) s and 29 (24-62) s, respectively. All but 2 patients (96%) showed a fibrin/fibrinogen degradation product value of >20 µg/mL. The D-dimer median value was 5,000 (686-55,630) ng/mL. The t(15;17)(q22;q12 and PML-RARA fusion was found in all patients by chromosome analysis and/or multiplex reverse transcriptase-polymerase chain reaction (RT-PCR), with turnaround times of 8 (2-19) d and 7 (2-13) d, respectively. All patients received induction chemotherapy: all-trans retinoic acid (ATRA) alone (N=11, 26%), ATRA+idarubicin (N=25, 58%), ATRA+cytarabine (N=3, 7%), ATRA+idarubicin+cytarabine (N=4, 9%). Conclusion Since APL is a medical emergency and an accurate diagnosis is a prerequisite for prompt treatment, laboratory support to implement faster diagnostic tools to confirm the presence of PML-RARA is required.

Plasma Cell Neoplasms Showing Multilobulated Nuclei

revealed a small monoclonal peak (M peak). Capillary immunofixation electrophoresis and gel electrophoresis identified the zone of restriction in the kappa region. Urine free light chain analysis quantified the amount of kappa light chain as 2,990 mg/l (reference range: 1.35– 24.19) and the kappa/lambda free light chain ratio was markedly increased to 221.48 (reference range: 2.04– 10.37). However, no abnormal findings were detected from serum electrophoresis. Bone marrow study showed proliferation of plasma cells of up to 67% of all nucleated cells with a notable finding of atypical morphology. Bizarre morphological features included cleaved nuclei resembling threeor four-leafed clovers, sometimes bilobulated or multilobulated ( fig. 1 ). Although a normal karyotype of 46,XY was seen in all 20 metaphase cells of bone marrow specimen analyzed, IgH (14q32) rearrangement was detected using interphase florescence in situ hybridization (32.7%). The patient was diagnosed as having multiple myeloma and was referred to the HematologyOncology Department for chemotherapy on a regimen of melphalan and prednisone. The patient was treated with 4 cycles of this regimen during which the M peak gradually decreased as shown on a series of urine capillary electrophoresis. Serum kappa free light chain and kappa/ lambda ratio also decreased, responding to treatment. Cases of plasma cell dyscrasias with excessively convoluted or multilobulated nuclei have been reported rarely [1–14] . Aggressive clinical courses were seen in these reports, supporting the notion that extensive nuclear lobulation correlates with poor prognosis. However, no detailed review of this topic has been conducted until now. Here we present a case of multiple myeloma with multilobulated nuclei and an extensive review of the literature reporting multilobulated plasma cells, in order to evaluate the characteristics of patients with unusual morphology. A 76-year-old Korean male visited our hospital for a routine follow-up. Complete blood count results were: a hemoglobin level of 8.4 g/dl, a platelet count of 239 × 10 9 /l and a white blood cell count of 3.8 × 10 9 /l. Chemistry analysis results were: a serum total protein level of 6.3 g/ dl (reference range: 5.8–8.0), an albumin level of 4.0 g/dl (reference range: 3.1–5.2), a calcium level of 8.7 mg/dl (reference range: 8.4–10.2) and a BUN/creatinine level of 31/2.3 mg/dl (reference range: 8–23/0.6–1.2). Amounts of IgG, IgA and IgM were quantified as 518 mg/dl (reference range: 694–1,618), 44 mg/dl (reference range: 68– 378) and 21.1 mg/dl (reference range: 60–263), respectively. Radiological study of the skeletal system showed no lytic bone lesions. Initial urine protein electrophoresis Received: December 5, 2012 Accepted after revision: December 20, 2012 Published online: March 27, 2013

The First Case of Therapy-Related Myelomastocytic Leukemia Based on the WHO 2008 Classification and the Recently Proposed Diagnostic Criteria

Dear Editor, AML is occasionally associated with bone marrow (BM) mastocytosis. Differential diagnoses include reactive mast cell (MC) hyperplasia, systemic mastocytosis (SM) with associated clonal hematological non-MC lineage disease, and MC leukemia (MCL) [1]. Myelomastocytic leukemia (MML) is a new classification for AML patients who show an increase in immature and atypical MCs, but who do not fulfill the criteria for MCL or SM [2-7]. Here, we describe for the first time a case of therapy-related MML, and review key elements of differential diagnosis in patients with myeloid neoplasms and BM mastocytosis [8, 9]. A 59-yr-old woman presented with fever. She had a history of ovarian carcinoma, which was treated by total abdominal hysterectomy, mass excision, and subsequent administration of the paclitaxel/taxol and carboplatin/carbo (TC) regimen 10 yr prior to the presentation. Five years later, she developed peritoneal metastasis and received additional chemotherapy, including gemcitabine and carboplatin (GEMC), repeated TC, peglylated liposomal doxorubicin (PLD), and bevacizumab. Overt tumor spread was repressed during chemotherapy, and the patient remained in stable condition. However, abdominal computed tomography (CT) scan performed at the current visit revealed recurrent peritoneal seeding of carcinoma. The patient had white blood cell counts of 33.7×10/L, hemoglobin level of 8.7 g/dL, and platelet counts of 43×10/L. The peripheral blood smear identified 28% blasts and 40% immature MCs. The BM aspirate smear showed dysplastic features with 46.0% myeloblasts and 22.0% immature atypical MCs (Fig. 1A, 1B). Flow cytometry analysis showed that the blasts were CD34, HLA-DR, CD13, CD33, CD117, CD65, CD15, CD7, CD2, CD3, cCD3, cCD22, CD10, CD19, and TdT. A small population of immature atypical MCs was also identified, which was phenotypically similar to the blast population, but was CD34, CD65, and CD7 (Fig. 1C). BM core biopsy sections were packed with immature cells and had a diffuse MC infiltrate. The immature cells were negative for CD25 (Fig. 1D). Cytogenetic analysis revealed a complex karyotype: 44,XX,-5,-7,inv(9)(p12q13),del(12)(p13),add(18)(p11.3) [11]/43,idem,-X,-3,+4[14]. No mutations were detected in FLT3, NPM1, CEBPA, or KIT. Serum tryptase level was not tested. The latency period from first exposure to carboplatin, an alkylating agent, was approximately 10 yr, and the duration of chemotherapy by this time was 33 months. She was diagnosed as having therapy-related AML according to the 2008 WHO classification [10] and MML according to a recent consensus proposal [8, 9].

Two Discrete κ Light Chain Peaks Discovered During Follow-up of a Patient With Multiple Myeloma

Monocloncal protein (M-protein) is a cloncal immnoglobulin produced by malignant plasma cells. It is not uncommon to detect more than 1 M-protein in multiple myeloma (MM) and this can stem from 2 kinds of M-proteins produced by a single B cell clone or from 2 separate clones. Herein, we report our detection, via urine immunoelectrophoresis, of 2 κ light chain peaks in a 77-year-old female patient with MM. The patient without significant adverse events in her medical history presented with clavicular fracture and was admitted to the Department of Orthopedics. There was no remarkable laboratory findings except a significant elevation of κ free light chain (FLC) and FLC ratio. After 10 months, bone marrow showed increased plasma cells in touch imprints and urine capillary electrophoresis revealed 2 separate peaks in the gamma region, which were found to be κ light chain (LC) via immunotyping. We found 2 separate FLCs in our patient that were not detected initially by immunoelectrophoresis, but were found during follow-up with BM examination; elevated LCs had previously been detected via FLC analysis. * MM : multiple myeloma; BM : bone-marrow; Igs : immunoglobulins; M-proteins : monoclonal proteins; CBC : complete blood count; Hb : hemoglobin; BUN : blood urea nitrogen; GE : gel electrophoresis; FLC : free light chain; rFLC : FLC ratio; CE : capillary electrophoresis

Waldenstrom's macroglobulinemia associated with eosinophilia

which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. A 73-year-old man with a history of diabetes and hypertension was referred to our hospital on suspicion of multiple myeloma. electrophoresis and immunofixation revealed a monoclonal peak of IgM and kappa light chain type. Peripheral blood smear shows both rouleaux formation and eosinophilia (A). Bone marrow (BM) aspirate indicates an increased number of plasma cells (18.8%) and eosinophils (9.4%) among the nucleated cells (B). Other BM fields locally show monotonous lymphoplasmacytic infiltration predominantly of small lymphocytes admixed with plasma cells and plasmacytoid lymphocytes (C). Lymphocytic cells express B-cell associated antigens (CD19, CD20) with kappa-restricted pattern on surface Ig analysis. Chromosome analysis of 20 metaphase cells indicates concurrent trisomy 3, 12, and 18 in 5 cells (D). The patient was diagnosed with eosinophilia associated Waldenstroms macroglobulinemia (WM). To our knowledge, WM accompanied by eosinophilia and cytogenetic abnormalities has not been reported in the literature.