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author:("Ko, Young-yeh")
1.  Clonal relationships in recurrent B-cell lymphomas 
Oncotarget  2016;7(11):12359-12371.
Immunoglobulin (Ig) gene rearrangements remain largely unmodified during the clonal expansion of neoplastic cells. We investigated the clonal relationships between lymphoma components at diagnosis and at relapse by analyzing Ig gene rearrangements. A BIOMED-2 multiplex polymerase chain reaction (PCR) assay was performed in 27 patients using formalin-fixed paraffin embedded tissues, with subsequent cloning and sequencing of the amplified Ig genes in 17 patients. All 27 cases of primary and corresponding relapsed tumors showed monoclonal rearrangements of the Ig genes by BIOMED-2 PCR. Whereas IgVH or IgVK fragment lengths were identical in 8/27 pairs (30%), fragment lengths differed in 19/27 pairs (70%). In 17 cases analyzed by sequencing, an identical VDJ gene rearrangement was confirmed in 4/4 pairs (100%) with the same fragment lengths and in 10/13 pairs (77%) with different fragment lengths. Four of 17 primary lymphomas had multiple VDJ rearrangements, and three of them showed an unrelated relapse. Unrelated relapse was observed in 1/8 mantle cell lymphomas, 1/5 diffuse large B-cell lymphomas, and a large B cell lymphoma developed in a patient with a small lymphocytic lymphoma. Unrelated relapses developed after a longer disease-free interval and tended to show poorer outcome compared with related relapse. In summary, relapse of a lymphoma from an unrelated clone is uncommon, but can occur in B-cell lymphomas. Clonal relationships should be determined by sequencing of the Ig genes, and not just by comparing the PCR product size.
doi:10.18632/oncotarget.7132
PMCID: PMC4914290  PMID: 26848863
recurrent B-cell lymphomas; clonality; immunoglobulin gene rearrangements; BIOMED-2 multiplex polymerase chain reaction
2.  Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type 
Oncotarget  2015;6(19):17764-17776.
Extranodal NK/T-cell lymphoma nasal type (ENKL) is a rare type of non-Hodgkin lymphoma that more frequently occurs in East Asia and Latin America. Even though its molecular background has been discussed in the last few years, the current knowledge does not explain the disease pathogenesis in most cases of ENKL. Here, we performed multiple types of next-generation sequencing on 34 ENKL samples, including whole-exome sequencing (9 cancer tissues and 4 cancer cell lines), targeted sequencing (21 cancer tissues), and RNA sequencing (3 cancer tissues and 4 cancer cell lines). Mutations were found most frequently in 3 genes, STAT3, BCOR, and MLL2 (which were present in 9, 7, and 6 cancer samples, respectively), whereas there were only 2 cases of JAK3 mutation. In total, JAK/STAT pathway- and histone modification-related genes accounted for 55.9% and 38.2% of cancer samples, respectively, and their involvement in ENKL pathogenesis was also supported by gene expression analysis. In addition, we provided 177 genes upregulated only in cancer tissues, which appear to be linked with angiocentric and angiodestructive growth of ENKL. In this study, we propose several novel driver genes of ENKL, and show that these genes and their functional groups may be future therapeutic targets of this disease.
PMCID: PMC4627344  PMID: 25980440
extranodal NK/T-cell lymphoma nasal type; next-generation sequencing; JAK-STAT pathway; chromatin modification; somatic mutation
3.  Clinical outcomes of radiation therapy for early-stage gastric mucosa-associated lymphoid tissue lymphoma 
AIM: To evaluate the clinical outcomes of radiation therapy (RT) for early-stage gastric mucosa-associated lymphoid tissue lymphoma (MALToma).
METHODS: The records of 64 patients treated between 1998 and 2011 were analyzed retrospectively. For Helicobacter pylori (H. pylori)-positive patients (n = 31), chemotherapy or H. pylori eradication therapy was the initial treatment. In patients with failure after H. pylori eradication, RT was performed. For H. pylori-negative patients (n = 33), chemotherapy or RT was the first-line treatment. The median RT dose was 36 Gy. The target volume included the entire stomach and the perigastric lymph node area.
RESULTS: All of the patients completed RT without interruption and showed complete remission on endoscopic biopsy after treatment. Over a median follow-up period of 39 mo, the 5-year local control rate was 89%. Salvage therapy was successful in all relapsed patients. Secondary malignancies developed in three patients. The 5-year overall survival rate was 94%. No patient presented symptoms of moderate-to-severe treatment-related toxicities during or after RT.
CONCLUSION: Radiotherapy results in favorable clinical outcomes in patients with early-stage gastric MALToma who experience failure of H. pylori eradication therapy and those who are H. pylori negative.
doi:10.3748/wjg.v19.i36.6062
PMCID: PMC3785628  PMID: 24106407
Gastric mucosa-associated lymphoid tissue lymphoma; Radiation therapy; Treatment response
4.  EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood 
Korean Journal of Pathology  2013;47(2):137-147.
Background
Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality.
Methods
Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed.
Results
STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis.
Conclusions
EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment.
doi:10.4132/KoreanJPathol.2013.47.2.137
PMCID: PMC3647126  PMID: 23667373
Epstein-Barr virus infections; Lymphoma, T-cell; Killer cells, natural; Lymphoproliferative disorders; Clonality
5.  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
6.  MET Expression in Sporadic Renal Cell Carcinomas 
Journal of Korean Medical Science  2006;21(4):672-677.
Although germline mutations of met proto-oncogene on human chromosome 7q31-34 have been known as useful molecular markers of hereditary papillary renal cell carcinoma (RCC), the expression of MET, a product of met proto-oncogene, has not been fully studied in sporadic RCC, along with its clinical significance. We investigated the expression of MET by immunohistochemistry in 182 cases of renal neoplasm encompassing 145 RCC, 25 urothelial carcinomas of renal pelvis, and 12 oncocytomas. MET was diffusely and strongly expressed in 90% of papillary RCC, all collecting duct carcinomas, and 92% of urothelial carcinomas of renal pelvis. On the contrary, clear cell RCC, chromophobe RCC, and oncocytomas were negative or focally positive for MET expression. In clear cell RCC, MET expression was positively correlated with high nuclear grade, presence of infiltrative growth, tumoral necrosis, papillary architecture, sarcomatoid component, tumoral involvement of the renal pelvis or ureter, involvement of the calyx, and lymphatic invasion. In conclusion, diffuse and strong expression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubular or papillary growth. In case of MET expression observed in clear cell RCC, it might correlate with those clinicopathological parameters implying aggressive behavior.
doi:10.3346/jkms.2006.21.4.672
PMCID: PMC2729889  PMID: 16891811
Proto-Oncogene Proteins c-met; Carcinoma, Renal Cell; Kidney Neoplasms; Kidney; Immunohistochemistry
7.  Bone Marrow is Involved in Less than 10% of Patients with Nasal-Type NK/T Cell Lymphoma at Initial Diagnosis 
Journal of Korean Medical Science  2004;19(2):229-233.
To evaluate the frequency of bone marrow involvement by nasal-type NK/T cell lymphoma, we retrospectively studied biopsy specimens from 40 patients by EBV in situ hybridization (ISH). Three patients had marrow involvement at initial diagnosis (7.5%). In one patient (1/40, 2.5%), the disease in bone marrow was recognized by routine morphological assessment, while two other patients had minimal involvement of lymphoma cells which was recognized only by EBV in situ hybridization (2/40, 5%). Two patients had a disseminated disease at diagnosis and died 6 days and 214 days after diagnosis. One patient had diffuse colonic lesion and died 82 days later. In conclusion, marrow involvement in nasal NK/T cell lymphoma is infrequent at initial diagnosis, and EBV ISH is a useful technique for identifying the minor subgroup of patients which have easily overlooked neoplastic involvement.
doi:10.3346/jkms.2004.19.2.229
PMCID: PMC2822304  PMID: 15082896
Killer Cell, Natural; Lymphoma; Herpesvirus 4, Human; In Situ Hybridization; Bone Marrow
8.  Long Non-coding RNA HOTAIR Expression in Diffuse Large B-Cell Lymphoma: In Relation to Polycomb Repressive Complex Pathway Proteins and H3K27 Trimethylation 
Background
A long non-coding RNA hox transcript antisense intergenic RNA (HOTAIR) is involved in epigenetic regulation through chromatin remodeling by recruiting polycomb repressive complex 2 (PRC2) proteins (EZH2, SUZ12, and EED) that induce histone H3 trimethylation at lysine 27 (H3K27me3). Deregulation of c-MYC and interaction between c-MYC and EZH2 are well known in lymphomagenesis; however, little is known about the expression status of HOTAIR in diffuse large B-cell lymphomas (DLBCLs).
Methods
The expression status of PRC2 (EZH2, SUZ12, and EED), H3K27me3, c-MYC, and BCL2 was analyzed using immunohistochemistry (n = 231), and HOTAIR was investigated by a quantification real-time polymerase chain reaction method (n = 164) in DLBCLs.
Results
The present study confirmed the positive correlation among PRC2 proteins, H3K27me3, and c-MYC in DLBCLs. Expression level of HOTAIR was also positively correlated to EZH2 (p < .05, respectively). Between c-MYC and HOTAIR, and between c- MYC/BCL2 co-expression and HOTAIR, however, negative correlation was observed in DLBCLs (p < .05, respectively). High level of H3K27me3 was determined as an independent prognostic marker in poor overall survival (hazard ratio, 2.0; p = .023) of DLBCL patients. High expression of HOTAIR, however, was associated with favorable overall survival (p = .004) in the univariate analysis, but the impact was not significant in the multivariate analysis. The favorable outcome of DLBCL with HOTAIR high expression levels may be related to the negative correlation with c- MYC expression or c-MYC/BCL2 co-expression.
Conclusions
HOTAIR expression could be one of possible mechanisms for inducing H3K27me3 via EZH2-related PRC2 activation, and induced H3K27me3 may be strongly related to aggressive DLBCLs which show poor patient outcome.
doi:10.4132/jptm.2016.06.06
PMCID: PMC5042898  PMID: 27550047
Lymphoma, large B-cell, diffuse; HOTAIR; hox transcript antisense intergenic RNA; Polycomb repressive complex2; Histone H3trimethylation at lysine 27
9.  Treatment outcomes and clinical relevance of the Follicular Lymphoma International Prognostic Index in Korean follicular lymphoma patients treated with chemotherapy 
Background/Aims:
The Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI2 are well-known prognostic models for patients with follicular lymphoma (FL). However, their prognostic relevance has not been examined before in Korean patients with FL.
Methods:
We reviewed clinical and laboratory information from our database of patients between 1995 and 2012. In total, 125 patients were stratified in three categories according to FLIPI or FLIPI2 scores: low-, intermediate-, and high-risk groups. We compared FLIPI and FLIPI2 in terms of progression-free survival (PFS) and overall survival (OS).
Results:
Among the 125 patients, the prognostic value of FLIPI and FLIPI2 was evaluated in 73 patients who fulfilled the criteria of both prognostic models. Risk stratification by FLIPI and FLIPI2 showed significant differences in unfavorable parameters among each risk group, particularly between low- and intermediate-risk groups. The high-risk group b was significantly associated with poor PFS on both FLIPI and FLIPI2 (p < 0.05). However, the OS was significantly different only in the risk groups determined by FLIPI2 (p = 0.042). In a subgroup analysis of patients who received rituximab-containing chemotherapy, the risk stratification of both prognostic models showed a significant impact on PFS, especially in the low-risk group.
Conclusions:
FLIPI and FLIPI2 are appropriate prognostic models in Korean FL patients, especially for discriminating low-risk patients from intermediate- and high-risk groups.
doi:10.3904/kjim.2014.222
PMCID: PMC4855088  PMID: 26898595
Follicular lymphoma; Prognosis; Index
10.  Association Between PD-L1 and HPV Status and the Prognostic Value of PD-L1 in Oropharyngeal Squamous Cell Carcinoma 
Purpose
Oropharyngeal squamous cell carcinoma (OSCC) has been recognized as an immunosuppressive disease. Various mechanisms have been proposed for immune escape, including dysregulation of immune checkpoints such as the PD-1:PD-L1 pathway. We investigated the expression of programmed cell death-ligand 1 (PD-L1) in HPV-negative and HPV-positive OSCC to determine its prevalence and prognostic relevance.
Materials and Methods
Using immunohistochemistry, 133 cases of OSCC were evaluated for expression of PD-L1. Formalin-fixed paraffin-embedded tumor samples were stained with monoclonal antibody (clone 5H1) to PD-L1. PD-L1 positivity was defined as membrane staining in ≥20% of tumor cells. Correlations between PD-L1 expression and HPV status and survival parameters were analyzed.
Results
Of the 133 patients, 68% showed PD-L1 expression, and 67% of patients were positive for p16 expression by immunohistochemistry. No significant difference in PD-L1 expression was observed between HPV(-) and HPV(+) tumors (61% vs. 71%, p=0.274). No significant difference in age, gender, smoking history, location of tumor origin, or stage was observed according to PD-L1 status. With a median follow-up period of 44 months, older age (≥65) (p=0.017) and T3-4 stage (p<0.001) were associated with poor overall survival (OS), whereas PD-L1 expression did not affect OS in univariate and multivariate analysis.
Conclusion
PD-L1 expression was observed in the majority of OSCC patients regardless of HPV status. Further large prospective studies are required to determine the role of PD-L1 expression as a prognostic or predictive biomarker, and clinical studies of immune checkpoint inhibitors in OCSS are warranted regardless of HPV status.
doi:10.4143/crt.2015.249
PMCID: PMC4843713  PMID: 26511814
Programmed death ligand-1 (PD-L1); Human papillomavirus (HPV); Oropharyngeal Neoplasms; Immune checkpoint inhibitor; Immune therapy
11.  Cross-sectional Study of Patients with Diffuse Large B-Cell Lymphoma: Assessing the Effect of Host Status, Tumor Burden, and Inflammatory Activity on Venous Thromboembolism 
Purpose
The risk factors for venous thromboembolism (VTE) in diffuse large B-cell lymphoma (DLBCL) are not clear although thrombosis can be associated with host status, tumor burden, and inflammatory activity. We assessed the effect of those factors on VTE in a cross-sectional study of patients enrolled in a prospective cohort study.
Materials and Methods
We analyzed the occurrence of VTE in 322 patients with newly diagnosed DLBCL who received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) between 2008 and 2011. Serum levels of inflammatory cytokines were measured from serum samples archived at diagnosis.
Results
With a median follow-up duration of 41.9 months, VTE was documented in 34 patients (10.6%). A comparison of baseline characteristics indicated the group with VTE had higher percentage of old age, stage III/IV and extranodal involvements than the group without VTE (p < 0.05). Thus, the International Prognostic Index was significantly associated with VTE, but the Khorana score was not. A univariate competing risk factor analysis for VTE revealed that increased levels of inflammatory cytokines such as interleukin (IL)-6 and IL-10 were also associated with VTE (p < 0.05) in addition to host and tumor burden. However, a multivariate analysis showed that two host factors including age (≥ 60 years) and poor performance were independent risk factors for VTE.
Conclusion
Among potential risk factors for VTE including tumor burden and inflammatory activity, age and performance status had a strong impact on the occurrence of VTE in patients with DLBCL who received R-CHOP.
doi:10.4143/crt.2014.266
PMCID: PMC4720058  PMID: 25761485
Diffuse large B-cell lymphoma; Venous thromboembolism; Risk factors; Chemotherapy
12.  Prediction of Lymph Node Metastasis by Tumor Dimension Versus Tumor Biological Properties in Head and Neck Squamous Cell Carcinomas 
Purpose
Lymph node metastasis (LNM) is a strong prognostic factor in many solid cancers, including head and neck squamous cell carcinomas (HNSCC), and LNM can be dependent upon primary tumor biology, as well as tumor dimension. Here, we investigate the relative risk of LNM in accordance to tumor dimension and biology in HNSCC subsites.
Materials and Methods
Medical data of 295 HNSCC patients who had undergone the initial curative surgery (oral tongue 174, oropharynx 75, hypopharynx 46) were analyzed to identify the significant predictive factor for LNM. Tumor volume and thickness were set as tumor dimensional variables, and biological variables included lymphovascular, perineural invasion, and tumor differentiation. Statistical analyses were conducted to assess the predictability of LNM from variables, and subgroup analyses according to the tumor subsites. In addition, we evaluated the impacts of tumor dimension and biological variables on the treatment outcomes and survival in HNSCC subsites.
Results
The overall tumor dimension and biological variables had a similar impact on the prediction of LNM in HNSCC (area under the curve, 0.7682 and 0.7717). The prediction sensitivity of LNM in oral tongue cancer was mainly dependent on tumor dimension, while LNM in oroand hypo-pharynx cancers was more influenced by biological factors. Survival analyses also confirmed that biological factor was more powerful in estimating disease-free survival of hypopharyngeal cancer patients, while tumor dimension was more significant in that of oral cancer patients.
Conclusion
Tumor dimension and biology have a significant, tumor subsite-dependent impact on the occurrence of LNM and disease-free survival in HNSCC.
doi:10.4143/crt.2014.332
PMCID: PMC4720059  PMID: 25761475
Lymphatic metastasis; Head and neck neoplasms; Tumor burden; Tumor biological markers; Neoplasm metastasis
13.  High-throughput profiling identifies clinically actionable mutations in salivary duct carcinoma 
Background
Salivary duct carcinoma (SDC) is a highly aggressive subtype of salivary gland cancers and there is no established standard therapy for this disease. Thus, development of molecular markers for SDC will be important to guide the diagnosis and therapy of this aggressive tumor.
Methods
We performed next-generation sequencing using the Ion Torrent AmpliSeq cancer panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes, and we analyzed copy number variations (CNVs) of 21 genes by NanoString nCounter for 37 patients with SDC. Fluorescent in situ hybridization was also conducted to confirm ERBB2 gene amplification. Clinical records and tumor histopathology of the patients were retrospectively reviewed.
Results
Genetic alterations were detected in 29 of 37 (78.3%) tumors, including mutations in PIK3CA (N = 9, 24.3%), ERBB2 (N = 4, 10.8%), and EGFR (N = 4, 10.8%). To our knowledge, this is the first time that ERBB2 mutations have been reported in this tumor type. Both PIK3CA and ERBB2 mutation status were associated with poor overall survival, but without statistical significance. ERBB2 amplification was strong and common in SDC and almost all cases also exhibited EGFR and ERBB3 amplifications.
Conclusions
This study reports the largest and most comprehensive analysis of DNA aberrations in SDC. Our results show that PIK3CA and/or ERBB2 alterations in the development of SDC might be a useful diagnostic tool and could serve as a potential therapeutic target.
doi:10.1186/s12967-014-0299-6
PMCID: PMC4216375  PMID: 25343854
Salivary duct carcinoma; Next-generation sequencing; Molecular markers; PIK3CA; ERBB2; EGFR
14.  Brentuximab vedotin for relapsed or refractory CD30+ Hodgkin lymphoma: a multicenter analysis from Asia 
OncoTargets and therapy  2014;7:1717-1722.
Introduction
Brentuximab vedotin (SGN-35), an anti-cluster of differentiation (CD)-30 antibody conjugated to the anti-tubulin agent monomethyl auristatin E, has demonstrated promising efficacy and tolerability in relapsed and heavily treated Hodgkin lymphoma (HL). In this study, we report the Asian experience with brentuximab vedotin in patients with relapsed or refractory CD30-positive (CD30+) HL.
Methods
This is an observational, multicenter, retrospective study. Between October 2011 and June 2013, a total of 22 patients were treated with brentuximab vedotin under a named patient program in Asia. Patients received a 30 min infusion of brentuximab vedotin at a dose of 1.8 mg/kg of body weight every 3 weeks.
Results
Four patients (18.2%) showed a complete response, and the overall response rate was 72.7%. The median duration of response was 4.4 months (range 1.0–17.4). The median progression-free survival was 5.7 months, and the median overall survival has not yet been reached. The 1-year expected survival rate was 67.2%. The most common grade 3/4 adverse events were neutropenia (n=7; 31.8%). No patients experienced grade 3/4 sensory neuropathy.
Conclusions
These results confirm that brentuximab vedotin as a single agent is also effective and well tolerated when used in Asian patients with relapsed and refractory CD30+ HL.
doi:10.2147/OTT.S67380
PMCID: PMC4196794  PMID: 25328405
Asian; efficacy; safety
15.  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
16.  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
17.  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
18.  The Prognostic Role of p16 Expression in Tonsil Cancer Treated by Either Surgery or Radiation 
Objectives
Although human papillomavirus (HPV) infection is considered as a favorable prognostic factor in oropharyngeal cancer, the prognosis of HPV-associated tonsil cancer has rarely been studied especially when surgery was the main treatment. In this study, the authors investigated the effect of p16 over-expression (HPV infection) on tonsil cancer prognosis according to the type of treatment, HPV presence by PCR, and expression of p53 and epidermal growth factor receptor (EGFR) by immunohistochemistry (IHC).
Methods
Medical records of 33 tonsil cancer patients were reviewed. Using formalin-fixed and paraffin-embedded tumor specimens, PCR-based genotyping of HPV and IHC of p16, p53 and EGFR were performed. The effects of HPV presence and the expression of IHC markers were analyzed on the recurrence-free survival. Five-year disease-free survival (DFS) rates were evaluated according to p16 expression status.
Results
An over-expression of p16 was observed in 27 (81.9%) out of 33 cases. Surgery-based treatment was provided for 21 (63.6%) patients. There was no association between p16 immunoreactivity and HPV presence, nor with p53 and EGFR expression. Regardless of main treatment modalities, five-year DFS did not differ by p16 expression status (P=0.051). However, over-expression of p16 was associated with a lower recurrence in multivariable analyses (P=0.046).
Conclusion
Regardless of main treatment modalities, an over-expression of p16 (HPV infection) is associated with a lower recurrence in tonsil cancers. However it is not associated with simple HPV presence or p53 and EGFR over-expression.
doi:10.3342/ceo.2012.5.4.207
PMCID: PMC3506771  PMID: 23205225
Human papillomavirus; Oropharyngeal neoplasms; Therapeutics; Immunohistochemistry; Prognosis; p16 (INK4A)
19.  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
20.  Primary CNS lymphoma other than DLBCL: a descriptive analysis of clinical features and treatment outcomes 
Annals of Hematology  2011;90(12):1391-1398.
Diffuse large B-cell lymphoma (DLBCL) constitutes most primary central nervous system (CNS) lymphoma (PCNSL), whereas T-cell, low-grade and Burkitt’s lymphomas (BL) are rarely encountered. Due to the paucity of cases, little is known about the clinical features and treatment outcomes of PCNSL other than DLBCL. The objective of this study was to describe the clinical characteristics and outcomes for patients with PCNSL other than DLBCL. Fifteen patients, newly diagnosed with PCNSLs other than DLBCL between 2000 and 2010, were included. The male to female ratio was 0.67:1 with a median age of diagnosis of 31 years (range 18–59). Pathologic distributions were as follows: peripheral T-cell lymphoma (PTCL; n = 7), marginal zone B-cell lymphoma (MZBCL; n = 1), lymphoplasmacytic lymphoma (LPL; n = 2), Burkitt’s lymphoma (n = 1), other unspecified (T-cell lineage, n = 2; B-cell lineage, n = 2). Thirteen patients (87%) showed Eastern Cooperative Oncology Group performance score (ECOG PS) 1–2. The remaining two were one PTCL patient and one Burkitt’s lymphoma patient. Of the nine patients with T-cell lymphoma, five (56%) had multifocal lesions, and one (20%) with LPL of the five patients with B-cell lymphoma showed a single lesion. Leptomeningeal lymphomatosis was identified in two patients (one with Burkitt’s lymphoma and one with unspecified B-cell lymphoma). Two patients (22%) with T-cell lymphoma died 7.7 and 23.3 months later, respectively, due to disease progression, despite HD-MTX-based therapy. Six patients with T-cell lymphoma (6/9, 66.7%) and four patients with low-grade B-cell lymphoma (4/5, 80%) achieved complete response and have survived without relapse (Table 3). One patient with Burkitt’s lymphoma showed poor clinical features with ECOG PS 3, deep structure, multifocal, and leptomeningeal lymphomatosis, and died 7.6 months after the initiation of treatment. In comparison with previously reported DLBCLs (median OS 6.4 years, 95% CI 3.7–9.1 years), T-cell lymphoma showed equivocal or favorable clinical outcomes and low-grade B-cell lymphomas, such as MZBCL and LPL, had a good prognosis. However, primary CNS Burkitt’s lymphoma presented poor clinical outcomes and showed a comparatively aggressive clinical course. In conclusion, primary CNS lymphoma other than DLBCL occurred more in younger patients and showed a generally good prognosis, except for Burkitt’s lymphoma. Further research on treatment strategies for Burkitt’s lymphoma is needed.
doi:10.1007/s00277-011-1225-0
PMCID: PMC3210363  PMID: 21479535
Primary CNS lymphoma; Diffuse large B-cell lymphoma
21.  The Clinical Usefulness of 18F-FDG PET/CT for the Evaluation of Lymph Node Metastasis in Periorbital Malignancies 
Korean Journal of Radiology  2009;10(1):1-7.
Objective
The aim of this study was to assess the clinical role of 18F-FDG PET/CT for the evaluation of lymph node metastasis in periorbital malignancies, compared with CT alone.
Materials and Methods
We analyzed eighteen PET/CT and CT scans in 15 patients with biopsy-proven periorbital malignancies. We compared the diagnostic capabilities of PET/CT and CT with regard to nodal metastasis by level-by-level analysis and by N staging prediction. The reference standards were surgical pathology (n = 7) from dissected lymph node specimens and the results from radiological follow-up (n = 11, mean 20.5 months; range 10-52 months). Moreover, any changes in patient care as prompted by PET/CT were recorded and compared with treatment planning for CT alone.
Results
PET/CT had a sensitivity of 100%, while CT had a sensitivity of 57% (p = 0.03) for nodal metastasis by level-by-level analysis. PET/CT had a specificity of 97%, positive predictive value of 93%, negative predictive value of 100%, and diagnostic accuracy of 98%, while the CT values for these same parameters were 97%, 89%, 82%, and 84%, respectively. PET/CT correctly predicted N staging with an accuracy of 100%, while CT was only 83% accurate (p = 0.01). Regarding the impact on patient care, the extent of surgery for regional lymph nodes and the treatment decision were modified by PET/CT in 39% of patients.
Conclusion
PET/CT could provide useful information in the management of regional lymph node metastases in patients with periorbital malignancies.
doi:10.3348/kjr.2009.10.1.1
PMCID: PMC2647179  PMID: 19182496
18F-FDG; PET/CT; Computed tomography (CT) scans; Lymphatic Metastasis; Eyelid Neoplasm
22.  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
23.  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
24.  De novo CD5 Positive Diffuse Large B-cell Lymphomas with Bone Marrow Involvement in Korean 
Journal of Korean Medical Science  2004;19(6):815-819.
In CD5 positive (CD5+) mature B-cell lymphomas, newly recognized CD5+ diffuse large B-cell lymphoma (DLBCL) has been characterized by aggressive features. We studied twenty-five cases with CD5+ lymphomas involving bone marrow. Eleven cases were diagnosed as chronic lymphocytic leukemia, six cases were diagnosed as mantle cell lymphoma (MCL), and three cases with morphologic characteristics of MCL and without both the cyclin D1 expression and IGH/CCND1 rearrangement were unclassifiable. The remaining five cases, showing large to medium-sized lym-phoid cells with prominent nucleoli and a moderate amount of cytoplasm, were diagnosed as DLBCL. Five DLBCL cases were positive for CD5, CD20, surface immuno-globulin, but negative for CD23. Patients with CD5+ DLBCL showed a high age of onset (median, 68 yr) and two patients expired one month after the diagnosis. Since CD5+ DLBCL forms a distinct subgroup of DLBCL, a study of CD5 expression in DLBCL would be helpful to predict prognosis and to determine future therapeutic strategy. To the best of our knowledge, this is the first report on de novo CD5+ DLBCL in Koreans.
doi:10.3346/jkms.2004.19.6.815
PMCID: PMC2816303  PMID: 15608391
Antigens, CD5; Leukemia, Lymphocytic, Chronic; Lymphoma, Mantle-Cell; Lymphoma, Large-Cell, Diffuse
25.  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

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