Young Hyeh Ko

Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is often challenging to diagnose and classify. Gene expression profiling was performed on 144 cases of PTCL and natural killer cell lymphoma and robust molecular classifiers were constructed for angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma. PTCL-unclassifiable was molecularly heterogeneous, but we were able to identify a molecular subgroup with features of cytotoxic T lymphocytes and a poor survival compared with the remaining PTCL-not otherwise specified cases. Many of the pathologic features and substantial components of the molecular signature of AITL are contributed by the follicular dendritic cells, B-cell, and other stromal components. The expression of Th17-associated molecules in ALK(+) ALCL was noted and may represent aberrant activation of Th17-cell differentiation by abnormal cytokine secretion. Adult T-cell leukemia/lymphoma has a homogeneous molecular signature demonstrating high expression of human T-lymphotropic virus type 1-induced genes. These classifiers reflect the biology of the tumor cells as well as their microenvironment. We also constructed a molecular prognosticator for AITL that appears to be largely related to the microenvironmental signature, and the high expression of 2 immunosuppressive signatures are associated with poor outcome. Oncogenic pathways and tumor-host interactions also were identified, and these findings may lead to better therapies and outcome in the future.

Phase II Trial of Concurrent Radiation and Weekly Cisplatin Followed by VIPD Chemotherapy in Newly Diagnosed, Stage IE to IIE, Nasal, Extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma Study

PURPOSE On the basis of the benefits of frontline radiation in early-stage, extranodal, natural killer (NK)/T-cell lymphoma (ENKTL), we conducted a phase II trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of etoposide, ifosfamide, cisplatin, and dexamethasone (VIPD). PATIENTS AND METHODS Thirty patients with newly diagnosed, stages IE to IIE, nasal ENKTL received CCRT (ie radiation 40 to 52.8 Gy and cisplatin 30 mg/m(2) weekly). Three cycles of VIPD (etoposide 100 mg/m(2) days 1 through 3, ifosfamide 1,200 mg/m(2) days 1 through 3, cisplatin 33 mg/m(2) days 1 through 3, and dexamethasone 40 mg days 1 through 4) were scheduled after CCRT. RESULTS All patients completed CCRT, which resulted in 100% response that included 22 complete responses (CRs) and eight partial responses (PRs). The CR rate after CCRT was 73.3% (ie, 22 of 30 responses; 95% CI, 57.46 to 89.13). Twenty-six of 30 patients completed the planned three cycles of VIPD, whereas four patients did not because they withdrew (n = 2) or because they had an infection (n = 2). The overall response rate and the CR rate were 83.3% (ie; 25 of 30 responses; 95% CI, 65.28 to 94.36) and 80.0% (ie, 24 of 30 responses; 95% CI, 65.69 to 94.31), respectively. Only one patient experienced grade 3 toxicity during CCRT (nausea), whereas 12 of 29 patients experienced grade 4 neutropenia. The estimated 3-year, progression-free and overall survival rates were 85.19% (95% CI, 72.48 to 97.90) and 86.28% (95% CI, 73.97 to 98.59), respectively. CONCLUSION Patients with newly diagnosed, stages IE to IIE, nasal ENKTL are best treated with frontline CCRT.

A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma

The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly17Val) using exome and transcriptome sequencing of samples from individuals with AITL. Further examination of the RHOA mutation encoding p.Gly17Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma. We demonstrate that the RHOA mutation encoding p.Gly17Val, which was found in 53.3% (24 of 45) of the AITL cases examined, is oncogenic in nature using multiple molecular assays. Molecular modeling and docking simulations provided a structural basis for the loss of GTPase activity in the RHOA Gly17Val mutant. Our experimental data and modeling results suggest that the RHOA mutation encoding p.Gly17Val is a driver mutation in AITL. On the basis of these data and through integrated pathway analysis, we build a comprehensive signaling network for AITL oncogenesis.

Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in children and young adults: overlap with chronic active EBV infection and infantile fulminant EBV T-LPD.

EBV‐associated T/natural killer (NK)‐cell lymphoproliferative disorder (EBV‐T/NK LPD) of children and young adults is generally referred to with the blanket nosological term of severe chronic active EBV infection (CAEBV). This disease is rare, associated with high morbidity and mortality, and appears to be more prevalent in East Asian countries. But because there is no grading or categorization system for CAEBV, pathologists and clinicians often disagree regarding diagnosis and therapy. EBV‐T/NK LPD includes polyclonal, oligoclonal, and monoclonal proliferation of cytotoxic T and/or NK cells. Moreover, a unique disease previously described as infantile fulminant EBV‐associated T‐LPD has been identified and overlaps with EBV‐T/NK LPD. In the present review a clinicopathological categorization of EBV‐T/NK LPD is proposed, based on pathological evaluation and molecular data, as follows: (i) category A1, polymorphic LPD without clonal proliferation of EBV‐infected cells; (ii) category A2, polymorphic LPD with clonality; (iii) category A3, monomorphic LPD (T‐cell or NK cell lymphoma/leukemia) with clonality; and (iv) category B, monomorphic LPD (T‐cell lymphoma) with clonality and fulminant course. Categories A1, A2, and A3 possibly constitute a continuous spectrum and together are equivalent to CAEBV. Category B is the exact equivalent of infantile fulminant EBV‐associated T‐LPD. It is expected that this categorization system will provide a guide for the better understanding of this disorder. This proposal was approved at the third meeting of the Asian Hematopathology Association (Nagoya, 2006).

Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses.

Oligo-array comparative genomic hybridization (CGH) and gene-expression profiling of natural killer (NK)-cell neoplasms were used in an effort to delineate the molecular pathogenesis involved. Oligo-array CGH identified two 6q21 regions that were most frequently deleted (14 of 39 or 36%). One of these regions included POPDC3, PREP, PRDM1, ATG5, and AIM1, whereas the other included LACE1 and FOXO3. All genes located in these regions, except for POPDC3 and AIM1, were down-regulated in neoplastic samples, as determined by gene-expression analysis, and were therefore considered to be candidate tumor-suppressor genes. A20 and HACE1, the well-known tumor-suppressor genes located on 6q21-23, were included as candidate genes because they also demonstrated frequent genomic deletions and down-regulated expression. The Tet-Off NK cell line NKL was subsequently established for functional analyses. Seven candidate genes were transduced into Tet-Off NKL and forced re-expression was induced. Re-expression of FOXO3 and PRDM1 suppressed NKL proliferation, but this was not the case after re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10. Furthermore, genomic analyses detected nonsense mutations of PRDM1 that led to functional inactivation in one cell line and one clinical sample. PRDM1 and FOXO3 are considered to play an important role in the pathogenesis of NK-cell neoplasms.

Autologous Hematopoietic Stem Cell Transplantation in Extranodal Natural Killer/T Cell Lymphoma: A Multinational, Multicenter, Matched Controlled Study

Extranodal natural killer (NK)/T cell lymphoma, nasal type, is a recently recognized distinct entity and the most common type of non-B cell extranodal lymphoma in Asia. This retrospective analysis studied the potential survival benefits of hematopoeitic stem cell transplantation (HSCT) compared with a historical control group. A total of 47 patients from 3 previously published series of HSCT were matched according to NK/T cell lymphoma International Prognostic Index (NKIPI) risk groups and disease status at transplantation with 107 patients from a historical control group for analysis. After a median follow-up of 116.5 months, the median survival time was not determined for the HSCT group, but it was 43.5 months for the control group (95% confidence interval [CI] = 6.7 to 80.3 months; P = .127, log-rank test). In patients who were in complete remission (CR) at the time of HSCT or at surveillance after remission, disease-specific survival rates were significantly higher in the HSCT group compared with the control group (disease-specific 5-year survival rate, 87.3% for HSCT vs 67.8% for non-HSCT; P = .027). In contrast, in subgroup analysis on non-CR patients at the time of HSCT or non-HSCT treatment, disease-specific survival rates were not significantly prolonged in the HSCT group compared with the control group (1-year survival rate, 66.7% for HSCT vs 28.6% for non-HSCT; P = .141). The impact of HSCT on the survival of all patients was significantly retained at the multivariate level with a 2.1-fold (95% CI =1.2- to 3.7-fold) reduced risk of death (P = .006). HSCT seems to confer a survival benefit in patients who attained CR on postremission consolidation therapy. These findings suggest that, in particular, patients in CR with high NKIPI risk scores at diagnosis should receive full consideration for HSCT.

Angioimmunoblastic Lymphoma (aild-type T-cell Lymphoma) With Hyperplastic Germinal Centers

Angioimmunoblastic T-cell lymphoma (or angioimmunoblastic lymphadenopathy with dysgammaglobulinemia [AILD]) was originally considered to be an abnormal immune reaction in which reactive follicles with germinal centers (GCs) are usually absent. When hyperplastic GCs are present along with an angioimmunoblastic reaction, the lesion has been interpreted as a benign hyperimmune reaction. We report seven patients with angioimmunoblastic T-cell lymphoma (AITL) who initially had hyperplastic GCs, shown to be malignant lymphoma by further studies and clinical follow-up. Clonal T-cell populations were observed in all specimens evaluated, and sequential biopsies showed histologic progression to typical AITL in two patients. Clinical presentation was characterized by generalized lymphadenopathy of acute onset, constitutional symptoms, hepatosplenomegaly, skin rash, and polyclonal hypergammaglobulinemia in five patients; regional adenopathy preceded generalized adenopathy in two patients. Five patients had rapid progression of disease, and three patients whose treatment was delayed due to inadequate evidence to diagnose lymphoma died of infection. The initial biopsy findings of each patient were similar and showed angioimmunoblastic proliferation, hyperplastic GCs with ill-defined borders, and interfollicular tingible-body macrophages. These GCs differed from occasional residual follicles of typical AITL in that the GCs were enlarged and hyperplasia of follicular dendritic cells was not seen. Diagnostic clear cells were not observed. Apoptotic bodies were markedly increased and bcl-2+ lymphocytes were sparse compared with typical AITL. Results of in situ hybridization for Epstein-Barr virus were positive in each case. We conclude that hyperplastic germinal centers with ill-defined borders and frequent interfollicular tingible-body macrophages occur in a histologic variant of AITL that is necessary to recognize for early diagnosis and treatment.

Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma.

BACKGROUND The Bcl-6 gene product, a nuclear phosphoprotein, is expressed independently of Bcl-6 gene rearrangement. In lymph nodes, expression of Bcl-6 protein is restricted to germinal center (GC) B-cells and 10% to 15% of CD3/CD4+ intrafollicular T cells. Interfollicular cells are negative for Bcl-6 protein, except for rare CD3+/CD4+ T cells. Recently, we reported cases of angioimmunoblastic T-cell lymphoma (AITL) with hyperplastic GCs (AITL/GC), and observed that borders of enlarged GCs were ill defined, with features suggestive of an outward migration of GC cells to surrounding interfollicular zones. This prompted a study of follicular borders with Bcl-6 staining in reactive follicular hyperplasias and follicular lymphomas to compare with AITL/GC. MATERIALS AND METHODS Formalin-fixed paraffin sections were used for immunostaining of Bcl-6. Six cases of AITL/GC, 12 nonspecific reactive follicular hyperplasia (FH), 7 HIV adenopathy, 10 follicular lymphoma (FL), and 8 typical AITL (ie, AITL without GC) were studied. Double staining for Bcl-6/CD20, Bcl-6/CD3, and Bcl-6/CD57 was performed in selected cases. RESULTS In FH and HIV adenopathy, staining for Bcl-6 revealed densely populated GCs with well-defined and regular GC borders, whereas Bcl-6+ cells were rare in the interfollicular areas. An occasional GC with an ill-defined border was invariably surrounded by a broad mantle zone; those with indistinct mantle zones had well-defined, regular borders. In FL, follicles were densely populated, and their borders were irregular, with some Bcl-6+ cells in the interfollicular zones. In AITL/GC, GCs were less dense, GC borders were ill defined and irregular, and the number of interfollicular Bcl-6+ cells was markedly increased. Double staining revealed that these interfollicular Bcl-6+ cells in AITL/GC were Bcl6+/CD3+/CD20-/CD57- T cells. Moreover, CD3+ intrafollicular T cells were depleted in AITL/GC, whereas they were abundant in FH. Intrafollicular CD57+ cells did not stain for Bcl-6, and were also depleted in AITL/GC. In typical AITL, some neoplastic cells were positive for Bcl-6, showing variable degrees of staining. CONCLUSIONS (1) GCs of AITL/GC differed from those of other reactive follicular hyperplasias and follicular lymphomas, and staining for Bcl-6 was useful to discern them. (2) Intrafollicular CD3+ T cells, many of which were also positive for Bcl-6, were markedly depleted in AITL/GC, with increased interfollicular Bcl-6+/CD3+ cells, suggesting an outward migration of intrafollicular T cells in this condition. (3) Interfollicular Bcl-6+/CD3+ cells in AITL/GC were too numerous to be accounted for by migration alone, suggesting local proliferation. (4) Intrafollicular CD57+ cells were negative for Bcl-6, indicating heterogeneity of the intrafollicular T-cell population. (5) Some neoplastic cells in AITL stained for Bcl-6, suggesting up-regulation of Bcl-6 expression in this tumor.

Role of 18F-FDG PET/CT in Management of High-Grade Salivary Gland Malignancies

The role of 18F-FDG PET/CT for planning the treatment of high-grade salivary gland malignancies was investigated and was compared with that with using contrast-enhanced CT. Methods: The subjects chosen for the study had high-grade cancer of the salivary gland, as confirmed by surgical pathology. The diagnostic values from 37 CT and PET/CT scans of 33 subjects were compared. The ability to predict the extent of the disease was compared by performing a subsite-based analysis for the primary lesions and a level-by-level analysis for the neck node levels as well as for the final TNM staging. The surgical pathology (67.6%) and clinical follow-up examinations (32.4%) were used as the reference standards. Furthermore, the changes made in each subjects care, based on a PET/CT examination, were compared with the treatment received without using the PET/CT data. Results: Using a primary subsite-based analysis, the diagnostic accuracy for predicting the pathologic tumor extent was significantly higher for PET/CT (91.0%) compared with that using CT alone (70.1%, P < 0.001). For the neck nodes on a level-by-level analysis, the metastasis could be predicted more accurately on the basis of a PET/CT examination (97.6%) than with using only CT (86.0%, P = 0.01). PET/CT was also far superior to CT in terms of the TNM staging (83.7% vs. 62.1%, P = 0.03). For 43.2% of the subjects, changes in the clinical decision making were made as a result of the PET/CT scan data over what was previously determined by using the CT scans alone. Conclusion: PET/CT provides more accurate diagnostic information for the evaluation of high-grade salivary cancer than does CT and it has a major impact on making treatment decisions for patients with a high-grade salivary malignancy.

Multidetector CT and MR Imaging of Cardiac Tumors

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.