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author:("Ko, Young-yeh")
1.  Primary Central Nervous System ALK Positive Anaplastic Large Cell Lymphoma with Predominantly Leptomeningeal Involvement in an Adult 
Yonsei Medical Journal  2013;54(3):791-796.
A 31-year-old Korean male presented with altered consciousness and severe headache. Brain MRI delineated focal leptomeningeal enhancement without any intracerebral lesions. Diagnosis was made based on a brain biopsy showing anaplastic large cell lymphoma (ALCL), immunohistochemical stains revealing positivity for anaplastic lymphoma kinase (ALK) and an absence of involvement in any other organs; specifically, the primary central nervous system ALK+ALCL. Complete remission was achieved following 5 cycles of systemic chemotherapy with a high dose of Methotrexate and a simultaneous 7 cycles of intrathecal triple chemotherapy. Diagnosis of primary leptomeningeal ALK+ALCL is challenging given its rarity and non-specific symptoms along with non-pathognomonic radiologic findings. We present the first case of primary leptomeningeal ALK-positive ALCL where the clinical course, pathologic characteristics and treatment modality are described as well as a review of literature.
doi:10.3349/ymj.2013.54.3.791
PMCID: PMC3635648  PMID: 23549832
ALK-positive; primary; CNS; anaplastic large-cell lymphoma; leptomeningeal
2.  Primary T-cell Lymphoma of the Thyroid Associated with Hashimoto's Thyroiditis, Histologically Mimicking MALT-Lymphoma 
Journal of Korean Medical Science  2010;25(3):481-484.
Most of thyroid lymphomas are B-lineage, and T-cell lymphomas are rare. Here, we report a case of primary thyroid T-cell lymphoma associated with Hashimoto's thyroiditis. A 48-yr-old woman presented with incidentally found neck mass. Histologically, the resected right lobe of the thyroid was replaced by monomorphic small atypical lymphoid cells with lymphoepithelial lesion-like change, most of which were immunoreactive for CD3, CD8, βF-1, and TIA-1. Peripheral T-cell lymphoma, unspecified, was finally diagnosed after molecular study for TCR-γ gene rearrangement. This is the second case of cytotoxic T-cell lymphoma reported in the thyroid gland so far. Unique association between thyroid follicles and neoplastic lymphocytes may be characteristic feature of this type of T-cell lymphoma.
doi:10.3346/jkms.2010.25.3.481
PMCID: PMC2826735  PMID: 20191052
Lymphoma, T-Cell; Thyroid Gland; T-Lymphocytes, Cytotoxic; Lymphoma, B-Cell, Marginal Zone
3.  The Spectrum of Epstein-Barr Virus-Associated Lymphoproliferative Disease in Korea: Incidence of Disease Entities by Age Groups 
Journal of Korean Medical Science  2008;23(2):185-192.
This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma.
doi:10.3346/jkms.2008.23.2.185
PMCID: PMC2526432  PMID: 18436998
Lymphoma; Epstein-Barr Virus; Lymphohistiocytosis, Hemophagocytic
4.  EBV and human cancer 
doi:10.1038/emm.2014.109
PMCID: PMC4314581  PMID: 25613727
5.  Spontaneous regression of metastatic cancer cells in the lymph node: a case report 
BMC Research Notes  2014;7:293.
Background
Spontaneous regression of a malignant tumor is the phenomenon of disappearance of cancer cells without any treatments and it can be induced by an enhanced tumor-targeting immune response. However, there has not been a comprehensive immunological overview to compare the tumor-regressed lymph nodes and metastatic lymph nodes in the same patient.
Case presentation
We conducted a histologic analysis of various immune cells in an Asian female patient with buccal cancer (squamous cell carcinomas), in which the spontaneous regression of metastatic lymphadenopathy was confirmed by surgical pathology. The immune cell profiles between the metastatic nodes and the tumor-regressed nodes were compared. Tumor regression was confirmed by hematoxylin & eosin and cytokeratin/Ki-67 staining. Distinct differences were observed in Foxp3(+) regulatory T (Treg) cells and CD56(+) natural killer (NK) cells; a higher density of Foxp3(+) Treg cells was found in metastatic lymph nodes and more infiltration of CD56(+) NK cells in tumor regressed lymph nodes. Other immune cell populations (CD4, CD8, CD20, CD68, CD86, CD123, CD11c, and mannose receptor) showed no discernible differences in marker expression in the nodes examined.
Conclusion
Less recruitment of Treg and high infiltration of NK cells were key features in tumor-regressed lymph nodes. Modulation of Treg or NK cells may be a good therapeutic method to control lymph node metastasis.
doi:10.1186/1756-0500-7-293
PMCID: PMC4025537  PMID: 24885770
Neoplasms; Lymph nodes; Lymphatic metastasis; Spontaneous neoplasm regression; Cellular immunity
6.  Characteristics of Cutaneous Lymphomas in Korea According to the New WHO-EORTC Classification: Report of a Nationwide Study 
Korean Journal of Pathology  2014;48(2):126-132.
Background
Previously, cutaneous lymphomas were classified according to either the European Organization for the Research and Treatment of Cancer (EORTC) or the World Health Organization (WHO) classification paradigms. The aim of this study was to determine the relative frequency of Korean cutaneous lymphoma according to the new WHO-EORTC classification system.
Methods
A total of 517 patients were recruited during a recent 5 year-period (2006-2010) from 21 institutes and classified according to the WHO-EORTC criteria.
Results
The patients included 298 males and 219 females, and the mean age at diagnosis was 49 years. The lesions preferentially affected the trunk area (40.2%). The most frequent subtypes in order of decreasing prevalence were mycosis fungoides (22.2%), peripheral T-cell lymphoma (17.2%), CD30+ T-cell lymphoproliferative disorder (13.7%), and extranodal natural killer/T (NK/T) cell lymphoma, nasal type (12.0%). Diffuse large B-cell lymphoma accounted for 11.2% of cases, half of which were secondary cutaneous involvement; other types of B-cell lymphoma accounted for less than 1% of cases.
Conclusions
In comparison with data from Western countries, this study revealed relatively lower rates of mycosis fungoides and B-cell lymphoma in Korean patients, as well as higher rates of subcutaneous panniculitis-like T-cell lymphoma and NK/T cell lymphoma.
doi:10.4132/KoreanJPathol.2014.48.2.126
PMCID: PMC4026803  PMID: 24868225
Cutaneous lymphoma; World Health Organization; EORTC; Classification
7.  NTRK1 Fusion in Glioblastoma Multiforme 
PLoS ONE  2014;9(3):e91940.
Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor, yet with no targeted therapy with substantial survival benefit. Recent studies on solid tumors showed that fusion genes often play driver roles and are promising targets for pharmaceutical intervention. To survey potential fusion genes in GBMs, we analysed RNA-Seq data from 162 GBM patients available through The Cancer Genome Atlas (TCGA), and found that 3′ exons of neurotrophic tyrosine kinase receptor type 1 (NTRK1, encoding TrkA) are fused to 5′ exons of the genes that are highly expressed in neuronal tissues, neurofascin (NFASC) and brevican (BCAN). The fusions preserved both the transmembrane and kinase domains of NTRK1 in frame. NTRK1 is a mediator of the pro-survival signaling of nerve growth factor (NGF) and is a known oncogene, found commonly altered in human cancer. While GBMs largely lacked NTRK1 expression, the fusion-positive GBMs expressed fusion transcripts in high abundance, and showed elevated NTRK1-pathway activity. Lentiviral transduction of the NFASC-NTRK1 fusion gene in NIH 3T3 cells increased proliferation in vitro, colony formation in soft agar, and tumor formation in mice, suggesting the possibility that the fusion contributed to the initiation or maintenance of the fusion-positive GBMs, and therefore may be a rational drug target.
doi:10.1371/journal.pone.0091940
PMCID: PMC3960150  PMID: 24647444
8.  Targeted Inhibition of FAK, PYK2 and BCL-XL Synergistically Enhances Apoptosis in Ovarian Clear Cell Carcinoma Cell Lines 
PLoS ONE  2014;9(2):e88587.
Ovarian clear cell carcinoma (OCCC) displays a higher resistance to first line chemotherapy, requiring the development of new therapeutics. We previously identified a frequent chromosomal gain at 8q24 that harbors the focal-adhesion kinase (FAK) gene; the potential of this gene as a therapeutic target remains to be evaluated in OCCCs. We first examined the dependence of OCCCs on FAK and the PI3K/AKT signaling pathway. FAK was overexpressed in 20% of 67 OCCC samples, and this overexpression was correlated with its copy number gain. FAK copy number gains and mutations in PIK3CA accounted for about 40% of OCCC samples, suggesting that the FAK/PI3K/AKT axis is an attractive candidate for targeted therapeutics. We, therefore, treated ovarian cancer cell lines, including OCCC subtypes, with the FAK inhibitors PF-562,271 (PF271), and PF-573,228 (PF228). Ovarian cancer cells were more sensitive to PF271 than PF228. We then searched for single agents that exhibited a synergistic effect on cell death in combination with PF271. We found that co-treatment of PF271 with ABT-737, a BCL-2/BCL-XL antagonist, was profoundly effective at inducing apoptosis. RMGI and OVISE cells were more sensitive to ABT-737 than OVMANA and SKOV3 cells, which have PIK3CA mutations. Mechanistically, PF271 treatment resulted in the transient down-regulation of the anti-apoptotic protein MCL1 via the PI3K/AKT pathway. Therefore, PF271/ABT-737 treatment led to the inhibition of the anti-apoptotic proteins MCL1 and BCL-XL/BCL-2. We suggest that pharmacological inhibition of BCL-XL and FAK/PYK2 can be a potential therapeutic strategy for the treatment of OCCC.
doi:10.1371/journal.pone.0088587
PMCID: PMC3921183  PMID: 24523919
9.  Mutation analysis of NF-κB signal pathway-related genes in ocular MALT lymphoma 
Constitutive nuclear factor-kappa B (NF-κB) activation has been reported in ocular adnexal lymphoma (OAL). TNFAIP3/A20 is a “global” inhibitor of NF-κB pathway. We have shown that OAL has preferential loss of the 6q23.3 region where TNFAIP3/A20 exist, which is suggested to involve in lymphomagenesis of OAL. The mechanisms causing NF-κB activity in OAL remain elusive. Recently, NF-κB canonical pathway genes including CARD11, CD79B and MYD88 were shown to be frequently mutated in diffuse large B-cell lymphomas. In this study, we analyzed the mutation status of these genes by direct sequencing in 24 OAL cases including 9 cases with loss of 6q23.3 previously identified by array comparative genomic hybridization. We showed that genetic alterations of these genes were not found in OAL, a finding differing from that of most B-cell lymphomas. Genetic or epigenetic alterations in other genes are likely to be relevant in pathogenesis of OAL case without A20 loss.
PMCID: PMC3396059  PMID: 22808296
Ocular adnexal lymphoma; TNFAIP3 (A20) deletion; NF-κB related gene mutation
10.  Nasal Chondromesenchymal Hamartoma: CT and MR Imaging Findings 
Korean Journal of Radiology  2009;10(4):416-419.
We report CT and MR imaging findings for a case of nasal chondromesenchymal hamartoma occurring in a 19-month-old boy. A nasal chondromesenchymal hamartoma is a rare benign pediatric hamartoma that can simulate malignancy. Although rare, knowledge of this entity is essential to avoid potentially harmful therapies.
doi:10.3348/kjr.2009.10.4.416
PMCID: PMC2702054  PMID: 19568473
Nose, neoplasms; Paranasal sinus, neoplasms; Paranasal sinus, CT; Paranasal sinus, MR
11.  Multidetector CT and MR Imaging of Cardiac Tumors 
Korean Journal of Radiology  2009;10(2):164-175.
The purpose of this article is to provide a current review of the spectrum of multidetector CT (MDCT) and MRI findings for a variety of cardiac neoplasms. In the diagnosis of cardiac tumors, the use of MDCT and MRI can help differentiate benign from malignant masses. Especially, the use of MDCT is advantageous in providing anatomical information and MRI is useful for tissue characterization of cardiac masses. Knowledge of the characteristic MRI findings of benign cardiac tumors or thrombi can be helpful to avoid unnecessary surgical procedures. Presurgical assessment of malignant cardiac tumors with the use of MDCT and MRI may allow determination of the resectability of tumors and planning for the reconstruction of cardiac chambers.
doi:10.3348/kjr.2009.10.2.164
PMCID: PMC2651440  PMID: 19270863
Cardiac tumor; Magnetic resonance (MR); Multidetector CT
12.  Systemic EBV+ T-cell lymphoma in elderly patients: comparison with children and young adult patients 
Virchows Archiv  2008;453(2):155-163.
Fulminant Epstein–Barr virus (EBV+) T-cell lymphoma in immunocompetent elderly patients is rare and its character has not been well defined. This study analyzed the clinicopathological features of five elderly patients (group A: 50–84 years) and compared them with those of eight children and young adult patients with systemic T-cell lymphomas (group B: 10–34 years). Group A more commonly presented with generalized lymphadenopathy (n = 3) than did group B (n = 1). Chronic active EBV infection (n = 3) and hydroa vacciniforme-like eruptions (n = 1) were seen in group B, while group A showed no evidence of chronic EBV infection, but did show chronic hepatitis B or C virus infections (n = 3). The histological and immunophenotypical findings were similar. All patients died within 1 to 14 months of diagnosis. These findings suggest that EBV+ T-cell lymphoma in elderly patients is a unique disease with an underlying derangement of T-cell immunity and failure to eradicate infected virus. Additional factors related to senility may play a role in the disruption of homeostasis between the virus and the host’s immune system.
doi:10.1007/s00428-008-0640-7
PMCID: PMC2516298  PMID: 18636273
Epstein–Barr virus; Lymphoma; T-cell
13.  Sentinel Lymph Node Radiolocalization with 99mTc Filtered Tin Colloid in Clinically Node-Negative Squamous Cell Carcinomas of the Oral Cavity 
Journal of Korean Medical Science  2006;21(5):865-870.
The objective of this study was to evaluate the feasibility of sentinel lymph node biopsy by using a radiotracer lymphatic mapping technique in patients with squamous cell carcinoma of the oral cavity, and the diagnostic value of this technique. We studied twenty patients with previously untreated squamous cell carcinomas of the oral cavity and N0 necks. After the peritumoral injection of 99mTc filtered tin colloid preop-eratively, lymphoscintigraphy and intraoperative mapping using a gamma detector were performed to localize sentinel nodes. An open biopsy of the sentinel node was followed by complete neck dissection. We identified the sentinel nodes in 19 of 20 patients (95.0%) by lymphoscintigraphy and in all (100%) by intraoperative gamma detector. In all cases, the status of the sentinel node accurately predicted the pathologic status of the neck with the false negative rate being 0%. The negative predictive value for the absence of cervical metastases was 100%. In conclusion, our radio-localization technique of sentinel nodes using 99mTc filtered tin colloid in N0 squamous cell carcinomas of the oral cavity is technically feasible and appears to accurately predict the presence of the occult metastatic disease.
doi:10.3346/jkms.2006.21.5.865
PMCID: PMC2721997  PMID: 17043421
Sentinel Lymph Node Biopsy; Lymphatic Metastasis; Mouth Neoplasms; Radionuclide Imaging
14.  A case of coexistent angiosarcoma and follicular carcinoma of the thyroid. 
Journal of Korean Medical Science  2003;18(6):908-913.
Angiosarcoma of the thyroid has long been a controversial entity, and it is histologically defined as cleft-like anastosmosing spaces lined by large, atypical cells of endothelial lineage. However, clear-cut separation between the angiosarcoma and anaplastic carcinoma of the thyroid is difficult because they yield nearly the same clinical prognosis and overlapping histologic findings. We report a case of thyroid neoplasm composed of minimally invasive well differentiated follicular carcinoma and angiosarcoma with intervening transitional area. Immunohistochemically, the angiosarcomatous portion showed focal immunoreactivity for endothelial markers such as CD31, CD34, Ulex europaeus 1 lectin, factor VIII-related antigen, and immunonegativity for epithelial markers including pancytokeratin, epithelial membrane antigen and thyroglobulin, whereas the reverse was demonstrated in the minimally invasive follicular carcinomatous portion. The follicular carcinoma portion was positive for thyroid transcription factor-1 (TTF-1). Each component showed ultrastructural findings of epithelial and endothelial differentiation, respectively. The present case was unique in that angiosarcoma of the thyroid was confirmed by immunohistochemistry and electron microscopy, as well as light microscopy, and also coexisted with a minimally invasive well differentiated follicular carcinoma in the same mass. This combination has never been described in the literature. Although restricted to a single case, the present case further supports that angiosarcoma is a true existent entity rather than a variant of anaplastic carcinoma.
PMCID: PMC3055138  PMID: 14676455
15.  Stereotactic Core-Needle Biopsy of Non-Mass Calcifications: Outcome and Accuracy at Long-Term Follow-Up 
Korean Journal of Radiology  2003;4(4):217-223.
Objective
To determine, by means of long-term follow-up evaluation, the outcome and accuracy of stereotactic core-needle biopsy (SCNB) of non-mass calcifications observed at mammography, and to analyze the factors contributing to false-negative findings.
Materials and Methods
Using a 14-gauge needle, SCNB was performed in cases involving 271 non-mass calcified lesions observed at mammography in 267 patients aged 23-72 (mean, 47) years. We compared the SCNB results with those of long-term follow-up which included surgery, mammography performed for at least six months, and reference to Korean Cancer Registry listings. We investigated the retrieval rate for calcifications observed at specimen mammography and histologic evaluation, and determined the incidence rate of cancer, sensitivity, and the underestimation rate for SCNB. False-negative cases were evaluated in terms of their mammographic findings, the effect of the operators' experience, and the retrieval rate for calcifications.
Results
For specimen mammography and histologic evaluation of SCNB, the retrieval rate for calcifications was, respectively, 84% and 77%. At SCNB, 54 of 271 lesions (19.9%) were malignant [carcinoma in situ, 45/54 (83%)], 16 were borderline, and 201 were benign. SCNB showed that the incidence of cancer was 5.0% (6/120) in the benign mammographic category and 31.8% (48/151) in the malignant category. The findings revealed by immediate surgery and by long-term follow-up showed, respectively, that the sensitivity of SCNB was 90% and 82%. For borderline lesions, the underestimation rate was 10%. For false-negative cases, which were more frequent among the first ten cases we studied (p = 0.01), the most frequent mammographic finding was clustered amorphous calcifications. For true-negative and false-negative cases, the retrieval rate for calcifications was similar at specimen mammography (83% and 67%, respectively; p = 0.14) and histologic evaluation (79% and 75%, respectively; p = 0.47).
Conclusion
In this study group, most diagnosed cancers were in-situ lesions, and long-term follow-up showed that the sensitivity of SCNB was 82%. False-negative findings were frequent during the operators' learning period.
doi:10.3348/kjr.2003.4.4.217
PMCID: PMC2698099  PMID: 14726638
Breast, biopsy; Breast neoplasms, diagnosis; Stereotaxis
16.  Foreign Body Granulomas of the Breast Presenting as Bilateral Spiculated Masses 
Korean Journal of Radiology  2001;2(2):113-116.
In Asia, mammography following the injection of foreign materials into the breasts for cosmetic augmentation is frequently seen and diagnosis based on the typical radiologic findings is straightforward.
We report the unusual radiologic findings in two patients with foreign body granulomas caused by injected foreign materials and discovered incidentally during screening work up. The mammographic findings were bilateral, hyperdense, spiculated masses, with occasional microcalcification, and at sonography, markedly hypoechoic, spiculated solid masses, located near the pectoralis muscle and partly extending into it, were observed. These radiologic findings mimicked malignancy.
doi:10.3348/kjr.2001.2.2.113
PMCID: PMC2718101  PMID: 11752980
Breast, abnormalities; Breast radiography

Results 1-16 (16)