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1.  Prognostic Markers in Peripheral T-Cell Lymphoma 
Based on their own experience and knowledge of the literature, the authors review the pathobiological characteristics of peripheral T-cell lymphomas (PTCLs), focusing on the available prognostic indicators. The International Prognostic Index (IPI), which is based on age, performance status, lactate dehydrogenase [LDH], stage, and extranodal involvement, appears to be efficient as a prognostic index for PTCLs, at least in part and especially for certain PTCL subtypes. However, it is not so satisfactory for the two commonest PTCLs, PTCL not otherwise specified (PTCL/NOS) and angioimmunoblastic T-cell lymphoma (AITL), for which novel scores, possibly based on the biologic features of the tumors, have been explored. An Italian cooperative group proposed a revision of the IPI for PTCL unspecified (PTCL-U), the Prognostic Index for PTCL-U (PIT), which includes age, performance status, LDH, and bone marrow involvement. The PIT apparently offered some advantages, but they were not confirmed in subsequent studies. A clinical-biological score (the Bologna score) was then proposed, including tumor proliferation and clinical features (age, LDH, and performance status). This score appears promising and offers the intriguing advantage of integrating biological and clinical elements, but independent validation on a large series is still warranted. More recently, gene expression profiling has been used to identify novel molecular prognostic factors. In particular, inactivation of the NFκB pathway, high expression of proliferation-associated genes, and cytotoxic molecular phenotype seem to be associated with a worse outcome. So far, however, none of these indicators has been validated in an independent series. Finally, various reports have dealt specifically with the prognostication of NK-derived tumors, including nasal and nasal-type lymphomas. Both the IPI and dedicated models have turned out to be of prognostic relevance for these tumors. In conclusion, although the IPI is somewhat effective for PTCL prognostication, novel scores that are more refined and possibly disease-specific are warranted. The validation process for several models, including clinical-pathological and molecular models, is now ongoing.
doi:10.1007/s11899-010-0062-x
PMCID: PMC2948168  PMID: 20690003
Peripheral T-cell lymphoma; PTCL; Prognostication; Gene expression profile; International prognostic index; Bologna score
2.  Serum C-Reactive Protein (CRP) as a Simple and Independent Prognostic Factor in Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type 
PLoS ONE  2013;8(5):e64158.
Background
C-reactive protein (CRP) is a biomarker of the inflammatory response, and it shows significant prognostic value for several types of solid tumors. The prognostic significance of CRP for lymphoma has not been fully examined. We evaluated the prognostic role of baseline serum CRP levels in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL).
Methods
We retrospectively analyzed 185 patients with newly diagnosed ENKTL. The prognostic value of the serum CRP level was evaluated for the low-CRP group (CRP≤10 mg/L) versus the high-CRP group (CRP>10 mg/L). The prognostic value of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) were evaluated and compared with the newly developed prognostic model.
Results
Patients in the high-CRP group tended to display increased adverse clinical characteristics, lower rates of complete remission (P<0.001), inferior progression-free survival (PFS, P = 0.001), and inferior overall survival (OS, P<0.001). Multivariate analysis demonstrated that elevated serum CRP levels, age >60 years, hypoalbuminemia, and elevated lactate dehydrogenase levels were independent adverse predictors of OS. Based on these four independent predictors, we constructed a new prognostic model that identified 4 groups with varying OS: group 1, no adverse factors; group 2, 1 factor; group 3, 2 factors; and group 4, 3 or 4 factors (P<0.001). The novel prognostic model was found to be superior to both the IPI in discriminating patients with different outcomes in the IPI low-risk group and the KPI in distinguishing between the low- and intermediate-low-risk groups, the intermediate-low- and high-intermediate-risk groups, and the high-intermediate- and high-risk groups.
Conclusions
Our results suggest that pretreatment serum CRP levels represent an independent predictor of clinical outcome for patients with ENKTL. The prognostic value of the new prognostic model is superior to both IPI and KPI.
doi:10.1371/journal.pone.0064158
PMCID: PMC3665788  PMID: 23724031
3.  Primary Systemic Anaplastic Large Cell Lymphoma in a Single Korean Institution: Clinical Characteristics and Treatment Outcome 
Journal of Korean Medical Science  2006;21(4):633-638.
Despite advances in the characterization of anaplastic large cell lymphoma (ALCL), little data is available on Asian patients. We report here upon single Korean institution's experience regarding the clinical characteristics and outcomes of ALCL. We performed a retrospective study of 32 adults with ALCL. Most of the patients received anthracycline-based chemotherapy. Ann Arbor stage III-IV, B symptoms, high-intermediate/high International Prognostic Index (IPI), and extranodal disease at diagnosis were present in 56%, 44%, 41%, and 63%, respectively. Compared with Western studies, the male/female ratio (4.3) was markedly higher and skin (9%) and bone involvement (9%) were less frequent. The staining results for anaplastic lymphoma kinase were positive in 6 (33%) of 18 cases available. The complete response (CR) rate was 62% (95% CI, 44-80%). With a median follow-up of 51.0 months, 5 yr overall survival was 40±11%. The 3 yr relapse-free survival for the 18 patients who achieved CR was 74±12%. Age, performance status, lactate dehydrogenase, extranodal disease sites number, and IPI were correlated with treatment response and survival. Our data suggest that Korean ALCL patients appear to have a higher male/female ratio, less frequent skin/bone involvement, and lower CR rate compared with those of Western studies.
doi:10.3346/jkms.2006.21.4.633
PMCID: PMC2729883  PMID: 16891805
Lymphoma, Large Cell, Ki-1; CD30-Positive Anaplastic Large-Cell Lymphoma; anaplastic lymphoma kinase; Drug Therapy
4.  A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome 
Annals of Oncology  2011;22(7):1608-1613.
Background: The prognosis for patients with most forms of T-cell lymphoma is poor. Allogeneic hematopoietic stem-cell transplantation (HSCT) may improve the outcome.
Patients and methods: This study examines the outcome of 52 patients who underwent ablative or nonablative allogeneic HSCT for peripheral T-cell lymphoma (PTCL) or advanced mycosis fungoides/Sezary syndrome over a 12-year period at a single institution. We divided the patients into those with predominantly nodal histologies: peripheral T-cell not otherwise specified (PTCL NOS), angioimmunoblastic (AITL), or anaplastic large cell lymphoma, T/null type (systemic) (ALCL), and predominantly extranodal histologies: natural killer (NK)/T cell, enteropathy type, hepatosplenic, subcutaneous panniculitic, mycosis fungoides, or T cell or NK cell other.
Results: Median follow-up of survivors is 49 months. Non-relapse mortality and relapse at 3 years was 27% and 43%, respectively. The incidence of grade II–IV acute graft-versus-host disease (GVHD) was 21%. The incidence of extensive chronic GVHD at 2 years was 27%. The 3-year progression-free survival was 30%: 45% in patients with predominantly nodal histologies (PTCL NOS, AITL, and ALCL) and 6% in patients with predominantly extranodal histologies (P = 0.016). Overall survival at 3 years was 41% for all patients.
Conclusion: Allogeneic HSCT can produce long-term remissions in relapsed/refractory T-cell lymphoma, especially those with nodal histologies.
doi:10.1093/annonc/mdq698
PMCID: PMC3121969  PMID: 21252059
allogeneic transplant; CTCL; GVHD; mycosis fungoides; NK lymphoma; T-cell lymphoma
5.  18F-fluorodeoxyglucose positron emission tomography in the staging and prognosis of T cell lymphoma 
Leukemia & lymphoma  2013;54(10):2163-2167.
We previously reported that 18F-fluorodeoxyglucose positron emission tomography scan (FDG-PET) is almost universally positive in patients with T cell lymphoma. In the present analysis we examined the impact of FDG-PET on the initial staging of peripheral T cell lymphomas (PTCLs), and the prognostic value of interim FDG-PET. This retrospective analysis identified patients with mature T or natural killer (NK) lymphomas who had PET scans as part of initial staging or staging at relapse [(n = 95) (staging cohort)] in the PTCL database at Memorial Sloan-Kettering Cancer Center. A subset of these patients had repeat PET for interim restaging during initial therapy with curative intent [(n = 50) (interim restaging cohort)]. The frequency of specific T cell histologies included in this analysis were: PTCL not otherwise specified (NOS) (n = 35); angioimmunoblastic T cell lymphoma (AITL) (n = 17); anaplastic large cell lymphoma (ALCL), ALK-1+ (n = 11) and ALK-1− (n = 12); adult T cell lymphoma/leukemia (ATLL) (n = 7); NK/T cell lymphoma (NKTCL) (n = 10); and enteropathy-associated T cell lymphoma (EATL) (n = 3). In the staging cohort, 77 patients were newly diagnosed, and 18 had relapsed disease. Pretreatment FDG-PET was positive in 96% of patients. PET identified additional disease sites in 47/95 patients (50%) when added to conventional staging. Most frequently identified additional sites were: other nodal (n = 24); bone (n = 10); skin (n = 8); nasopharynx (n = 4); spleen (n = 3); and lung (n = 2). However, FDG-PET modified computed tomography (CT)-based staging in only 5/95 patients (5.2%): two patients were upstaged and three patients were downstaged. FDG-PET-based staging did not alter planned treatment for any patient. Interim restaging with PET was performed after a median of 4 cycles of chemotherapy. In this cohort, treatment regimens included cyclophosphamide, doxorubicin, vincristine and prednisone CHOP (n = 19); CHOP/ifosfamide, carboplatin and etoposide (ICE) (n = 26); and other (n = 7). Subsequently, 29 patients were consolidated with either autologous (n = 22) or allogeneic (n = 7) stem cell transplant. After a median follow-up of 3.4 years for surviving patients, those with negative interim PET had superior progression-free survival (PFS) compared to patients with positive interim PET (p = 0.03). There were no differences in overall survival (OS). In PTCL, FDG-PET commonly identifies additional sites of disease but infrequently impacts CT-based staging and does not influence therapy. Interim FDG-PET may predict for PFS. FDG-PET should be integrated into prospective trials to confirm these findings.
doi:10.3109/10428194.2013.767901
PMCID: PMC3915724  PMID: 23369041
Lymphoma and Hodgkin disease; FDG-PET; T cell lymphoma; prognosis; staging
6.  Expression of HAT1 and HDAC1, 2, 3 in Diffuse Large B-Cell Lymphomas, Peripheral T-Cell Lymphomas, and NK/T-Cell Lymphomas 
Korean Journal of Pathology  2012;46(2):142-150.
Background
It has generally been proven that histone acetylation and deacetylation are involved in the malignant transformation. To date, however, this has rarely been studied in cases of malignant lymphoma.
Methods
We studied nine cases of reactive lymphoid hyperplasia, 78 cases of diffuse large B-cell lymphoma (DLBCL), 13 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 cases of extranodal NK/T-cell lymphoma, nasal type (NKTCL). Thus, we attempted to elucidate the associations of the degree of the expression of histone acetyltransferase 1 (HAT1), histone deacetylase (HDAC) 1, HDAC2, and HDAC3 with the clinical behaviors of above malignant lymphomas using the immunohistochemistry and a western blot analysis.
Results
The degree of the expression of HAT1 was higher in cases of DLBCL, PTCL-NOS or NKTCL as compared with reactive lymphoid hyperplasia (p<0.05). The degree of the expression of HAT1 was correlated with that of HDAC1 in cases of DLBCL or NKTCL (p<0.05). The degree of the expression of HAT1 and HDAC1 was correlated with a poor survival in cases of DLBCL or PTCL-NOS (p>0.05).
Conclusions
HAT1, HDAC1, and HDAC2 play a critical role in the development of malignant lymphomas. Both HAT1 and HDAC1 might be indicators for a poor prognosis in cases of DLBCL as cooperating factors.
doi:10.4132/KoreanJPathol.2012.46.2.142
PMCID: PMC3479788  PMID: 23109994
Acetylation; Deacetylation; Histone deacetylase inhibitors; Lymphoma
7.  Identification and Characterization of Peripheral T-Cell Lymphoma-Associated SEREX Antigens 
PLoS ONE  2011;6(8):e23916.
Peripheral T-cell lymphomas (PTCL) are generally less common and pursue a more aggressive clinical course than B-cell lymphomas, with the T-cell phenotype itself being a poor prognostic factor in adult non-Hodgkin lymphoma (NHL). With notable exceptions such as ALK+ anaplastic large cell lymphoma (ALCL, ALK+), the molecular abnormalities in PTCL remain poorly characterised. We had previously identified circulating antibodies to ALK in patients with ALCL, ALK+. Thus, as a strategy to identify potential antigens associated with the pathogenesis of PTCL, not otherwise specified (PTCL, NOS), we screened a testis cDNA library with sera from four PTCL, NOS patients using the SEREX (serological analysis of recombinant cDNA expression libraries) technique. We identified nine PTCL, NOS-associated antigens whose immunological reactivity was further investigated using sera from 52 B- and T-cell lymphoma patients and 17 normal controls. The centrosomal protein CEP250 was specifically recognised by patients sera and showed increased protein expression in cell lines derived from T-cell versus B-cell malignancies. TCEB3, BECN1, and two previously uncharacterised proteins, c14orf93 and ZBTB44, were preferentially recognised by patients' sera. Transcripts for all nine genes were identified in 39 cancer cell lines and the five genes encoding preferentially lymphoma-recognised antigens were widely expressed in normal tissues and mononuclear cell subsets. In summary, this study identifies novel molecules that are immunologically recognised in vivo by patients with PTCL, NOS. Future studies are needed to determine whether these tumor antigens play a role in the pathogenesis of PTCL.
doi:10.1371/journal.pone.0023916
PMCID: PMC3161784  PMID: 21887344
8.  Clinical analysis and prognostic significance of hepatitis B virus infections for diffuse large B-cell lymphoma with or without rituximab therapy 
The aim of this study was to analyze the clinical features of hepatitis B surface antigen (HBsAg)-positive and negative diffuse large B-cell lymphomas (DLBCLs) and to compare the outcomes and serum hepatitis B virus (HBV)-DNA loads of patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimens with rituximab (RCHOP) or without. A total of 451 DLBCL patients, of which 90 were HBsAg-positive and 361 were HBsAg-negative, were retrospectively reviewed. We compared onset age, gender, Ann Arbor stage, international prognostic index (IPI), lactate dehydrogenase (LDH) and β2-microglobulin (β2-M) levels, as well as overall survival (OS) rates and HBV-DNA loads under CHOP or RCHOP regimens. The OS rate of the HBsAg-positive DLBCL patients was significantly lower than that of HBsAg-negative DLBCL patients and the HBsAg-positive DLBCL patients had an earlier median onset age. HBsAg-positive DLBCL patients had poorer OS rates compared with HBsAg-negative patients (62.2% HBsAg-positive vs. 76.2% HBsAg-negative, P=0.018). HBsAg-positive DLBCL patients with HBV-DNA loads >103 cps/ml during chemotherapy had significantly lower OS rates than those with lower HBV-DNA loads (48.4% HBV-DNA elevated vs. 71.2% HBV-DNA normal, P=0.037). HBsAg-positive DLBCL patients treated with RCHOP had a significantly higher OS rate (79.6%) compared with the 41 CHOP-treated patients (43.9%; P<0.001). HBsAg-positive DLBCL patients with an earlier median onset age and elevated HBV-DNA during chemotherapy had poorer prognoses. HBsAg and HBV-DNA during chemotherapy may be used as prognostic indicators for patients with DLBCL. Rituximab improves the outcome of HBsAg-positive DLBCL patients when administered in combination with anti-viral lamivudine.
doi:10.3892/etm.2013.1079
PMCID: PMC3735511  PMID: 23935730
diffuse large B-cell lymphoma; hepatitis B virus; serum hepatitis B virus-DNA load; rituximab; lamivudine
9.  Clinicopathologic Characteristics of T-cell Non-Hodgkin's Lymphoma: A Single Institution Experience 
Background/Aims
Although the incidence of T-cell non-Hodgkin's lymphoma (NHL) is higher in Far East Asia than in Western countries, its incidence and clinical course in Korea are not well-defined. Therefore, we assessed the relative frequency and clinical features of T-cell NHL in Korea.
Methods
We performed a retrospetcive analysis of 586 patients with NHL.
Results
101 (17.2%) had T-cell NHL. The most frequent subtypes of T-cell NHL were extranodal NK/T-cell lymphoma, nasal type (NASAL), peripheral T-cell lymphoma, unspecified type (PTCL-U), and anaplastic large cell lymphoma, T/null cell, primary systemic type (ALCL). The seven pathological subtypes could be classified into three prognostic subgroups. When patients with the three most frequent subtypes were grouped together, their survival was reflected in the International Prognostic Index (IPI) scores. Univariate analysis of IPI elements and other clinical features showed that clinical stage and extranodal sites were significant predictors of survival. Cox multivariate analysis showed that the number of extranodal sites was the only independent prognostic indicator.
Conclusions
The relative frequency of T-cell NHL seems to be decreasing in Korea, although NASAL remains frequent. Korean patients with ALCL appear to have an unfavorable prognosis. Large-scale studies are warranted for Korean patients with T-cell NHL.
doi:10.3904/kjim.2009.24.2.128
PMCID: PMC2698621  PMID: 19543491
Lymphoma; T-cell; Peripheral
10.  Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis 
Mature natural killer (NK) cell neoplasms are classified by the World Health Organization into NK/T cell lymphoma, nasal type (NKTCL), aggressive NK-cell leukemia (ANKCL) and chronic lymphoproliferative disorders of NK-cells, the latter being considered provisionally. NKTCL and ANKCL are rare diseases, with higher prevalence in Asia, Central and South America. Most NKTCL present extranodal, as a destructive tumor affecting the nose and upper aerodigestive tract (nasal NKTCL) or any organ or tissue (extranasal NKTCL) whereas ANKCL manifests as a systemic disease with multiorgan involvement and naturally evolutes to death in a few weeks. The histopathological hallmark of these aggressive NK-cell tumors is a polymorphic neoplastic infiltrate with angiocentricity, angiodestruction and tissue necrosis. The tumor cells have cytoplasmatic azurophilic granules and usually show a CD45+bright, CD2+, sCD3-, cytCD3epsilon+, CD56+bright, CD16−/+, cytotoxic granules molecules+ phenotype. T-cell receptor genes are in germ-line configuration. Epstein-Barr virus (EBV) -encoded membrane proteins and early region EBV RNA are usually detected on lymphoma cells, with a pattern suggestive of a latent viral infection type II. Complex chromosomal abnormalities are frequent and loss of chromosomes 6q, 11q, 13q, and 17p are recurrent aberrations. The rarity of the NK-cell tumors limits our ability to standardize the procedures for the diagnosis and clinical management and efforts should be made to encourage multi-institutional registries.
doi:10.1186/1750-1172-8-95
PMCID: PMC3770456  PMID: 23816348
NK-cell Neoplasms; NK/T-cell Lymphoma; Nasal-type; Aggressive NK-Cell Leukemia; CD56; Neoplasias de células NK; Linfomas de células NK; tipo nasal; Leucemia agressiva de células NK; CD56
11.  Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma 
BMC Cancer  2013;13:222.
Background
Extranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL.
Methods
Retrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis.
Results
The AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category.
Conclusion
The baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL.
doi:10.1186/1471-2407-13-222
PMCID: PMC3653743  PMID: 23638998
Absolute monocyte count; Extranodal natural killer/T-cell lymphoma; Prognosis; Tumor microenvironment
12.  Should Eligible Patients with T-Cell Lymphoma Receive High-Dose Therapy and Autologous Stem Cell Transplant in the Upfront Setting? 
Current oncology reports  2010;12(6):374-382.
Peripheral T-cell lymphomas (PTCL) are rare and aggressive subtypes of non-Hodgkin’s lymphoma. Compared to B cell lymphomas, the immunologic phenotype of PTCL portends a poorer prognosis, with the exception of anaplastic large cell lymphoma bearing the anaplastic lymphoma kinase protein. Patients with PTCL tend to present clinically in advanced disease states, show lower response rates to chemotherapy, and suffer from more frequent relapses and shorter remissions. The rarity of these lymphomas has made it difficult to carry out prospective, randomized trials delineating optimal treatments. Conventional and intensified chemotherapy have led to reasonable responses, but in many studies, frequent relapses. Consequently, high-dose chemotherapy and autologous stem cell transplantation (ASCT) have been actively studied in both the relapsed and upfront setting. In addition, the impact of disease status at transplantation is being investigated, though the optimal disease state at transplant is still a matter of debate, as is the timing of transplant. This article seeks to review the literature on the role of ASCT in PTCL, as well as to clarify what may be the optimal disease state in which to offer patients with PTCL autologous transplantation, if at all.
doi:10.1007/s11912-010-0125-0
PMCID: PMC4075438  PMID: 20737300
Peripheral T-cell lymphoma; Non-Hodgkin’s lymphoma; Autologous stem cell transplantation; Aggressive lymphoma; Upfront setting; Complete remission; High-dose therapy
13.  CHO(E)P-14 followed by alemtuzumab consolidation in untreated peripheral T cell lymphomas: final analysis of a prospective phase II trial 
Annals of Hematology  2013;92:1521-1528.
The rate of long-term remissions after treatment of peripheral T cell lymphomas (PTCL) with standard CHOP-like protocols is unsatisfactory. A prospective multicenter phase II trial was initiated in untreated patients with PTCL of all International Prognostic Index-risk groups, evaluating alemtuzumab consolidation in patients with complete or good partial remission after CHO(E)P-14 induction. Twenty-nine (70.7 %) of the 41 enrolled patients received alemtuzumab consolidation (133 mg in total). The main grades 3–4 toxicities during alemtuzumab therapy were infections and neutropenia with one potentially treatment-related death. Complete responses were seen in 58.5 %, partial responses in 2.4 % and 29.3 % had progressive disease. After a median observation time of 46 months, 19 patients have died, 16 of them due to lymphoma and/or salvage therapy complications. Event-free and overall survival at 3 years in the whole intent to treat population are 32.3 and 62.5 %, respectively, and 42.4 and 75.1 % in the patients who received alemtuzumab. In conclusion, application of a short course of alemtuzumab after CHO(E)P-14 induction is feasible although complicated by severe infections. A current phase III trial, applying alemtuzumab as part of the initial chemotherapy protocol to avoid early progression, will further clarify its significance for the therapeutic outcome.
doi:10.1007/s00277-013-1880-4
PMCID: PMC3790248  PMID: 23978945
Alemtuzumab; Phase II trial; T cell lymphoma
14.  Pitfalls in diagnostic hematopathology – Part II 
The overlapping features of malignant lymphomas create a diagnostic “grey zone” , and lead to the invention of “grey zone lymphomas”. There are several major grey zone lymphomas: 1) Lymphomas with overlapping features of Hodgkin lymphoma and large B-cell lymphoma; 2) Lymphomas with overlapping features of Burkitt lymphoma and diffuse large B-cell lymphoma; 3) Lymphomas with overlapping features of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte rich large B-cell lymphoma; 4) Lymphomas with overlapping features of Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL) and peripheral T-cell lymphoma (PTCL); 5) T-cell classical Hodgkin lymphoma and ALCL-HL. The second review of this series will be dedicated to discussion of the “grey zone” features of the lymphomas and how to narrow down the “grey zone” between those lymphomas.
PMCID: PMC2776261  PMID: 19918327
DLBCL; Hodgkin lymphoma; Burkitt lymphoma; grey zone lymphoma; diagnostic pitfalls
15.  Modified Number of Extranodal Involved Sites as a Prognosticator in R-CHOP-Treated Patients with Disseminated Diffuse Large B-Cell Lymphoma 
Background/Aims
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP) has improved survival in patients with diffuse large B-cell lymphoma (DLBCL) and weakened the prognostic power of the international prognostic index (IPI). We evaluated the efficacy of the IPI and revised IPI (R-IPI) in patients with DLBCL who were treated with R-CHOP, focusing on extranodal site number (ENS) because extranodal involvement occurs frequently in Koreans.
Methods
A total of 126 R-CHOP-treated patients with stage III/IV DLBCL were analyzed. We performed a retrospective analysis of the clinicopathologic factors and verified the predictive power of the standard IPI and R-IPI. Various numbers of extranodal sites were analyzed for further stratification, and we set the extranodal site-modified IPI (E-IPI) as the IPI when the number of extranodal sites was stratified as < 3 vs. ≥ 3.
Results
A univariate analysis showed that ENS was associated with complete response (CR, p = 0.04), event-free survival (EFS, p = 0.01), and overall survival (OS, p < 0.001) when the ENS cut-off was set at ≥ 3. A multivariate analysis revealed that an ENS ≥ 3 remained associated with EFS (p < 0.01; hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.29 to 5.26) and OS (p < 0.01; HR, 3.52; 95% CI, 1.68 to 7.35). The IPI was effective for determining prognosis in terms of OS (p = 0.04) but not EFS (p = 0.17). The R-IPI was effective in terms of both variables (p = 0.02 and 0.04, respectively), as was the E-IPI (p = 0.01 and 0.001, respectively).
Conclusions
An ENS < 3 vs. ≥ 3, rather than the original < 2 vs. ≥ 2, was the most significant prognostic factor for EFS and OS. All three indices were predictive, but only the E-IPI identified the high-risk group of R-CHOP-treated Korean patients with disseminated DLBCL.
doi:10.3904/kjim.2010.25.3.301
PMCID: PMC2932944  PMID: 20830228
Prognosis; Lymphoma, large B-cell, diffuse; Rituximab; Extranodal
16.  Malignant lymphoma of the testis: a study of 12 cases 
Introduction:
Testicular lymphoma is a rare and deadly disease representing 1% to 2% of all non-Hodgkin lymphomas (NHLs) and approximately 5% of all testicular neoplasms. Our objective is this study was to identify the presenting signs and symptoms, treatment and outcome of patients with testicular lymphoma diagnosed at our institution from 1992 to 2005, and to identify any differences in survival based on Ann Arbor Stage and International Prognostic Index (IPI).
Methods:
A retrospective chart review was performed to identify demographic characteristics, presenting signs and symptoms, treatment and outcomes. Survival was assessed using Kaplan-Meier survival curves and log-rank testing.
Results:
Thirteen cases were identified; 1 of these cases was ultimately excluded due to a diagnosis of lymphoma a year before he presented with testicular involvement. Of the remaining 12 cases, the mean age was 65 years. Most patients presented with testicular and scrotal swelling or mass. B symptoms (weight loss, fever, night sweats) were present in 1 case. Of the 12 cases, 7 cases were stage I, 1 stage II and 4 stage IV. International Prognostic Index was low risk (≤1) in 7 cases and high risk (>1) in 4 cases. Orchiectomy was performed in all cases. Three patients received no further treatment. Of the remaining 9 patients, overall 7 received systemic chemotherapy, and 7 radiation therapy (prophylactic in 6). Three patients received intrathecal chemotheraphy prophylaxis. Seven patients achieved complete remission. Four patients (57%) relapsed following complete remission. Median time to relapse was 32 months (range 11 to 73 months). Six patients died. Median survival was 29 months, and was significantly different between early versus advanced stage (stage I/II disease: 71 months; stage IV: 5 months p = 0.007).
Conclusion:
Testicular lymphoma is a rare and deadly form of extra-nodal lymphoma. Survival was significantly different in early stage I/II and IPI low-risk versus advanced stage IV and IPI high-risk disease. Randomized, prospective treatment trials may help to establish better treatment strategies.
PMCID: PMC2758504  PMID: 19829735
17.  Reassessment of the prognostic value of the International Prognostic Index and the revised International Prognostic Index in patients with diffuse large B-cell lymphoma: A multicentre study 
The International Prognostic Index (IPI) is a widely accepted model that is used to predict the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) who are treated using chemotherapy. However, the prognostic value of the IPI has been a focal point of debate in the immunochemotherapy era. The aim of this study was to reassess the value of the IPI and revised IPI (R-IPI) in a Chinese population. A multicentre retrospective analysis of DLBCL patients who were treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like chemotherapy alone or chemotherapy plus rituximab (R-CHOP-like) was performed. The prognostic values of IPI and R-IPI at the time of diagnosis with respect to overall survival (OS) and progression-free survival (PFS) were evaluated. Among the 438 patients in the study, 241 received a CHOP-like regimen and 197 patients received an R-CHOP-like regimen. Although the IPI remained predictive for the CHOP-like group, it failed to distinguish between the various prognostic categories in the R-CHOP-like group. Notably, redistribution of the IPI factors into R-IPI factors identified three discrete prognostic groups with significantly different outcomes in both the CHOP-like and R-CHOP-like groups. In the R-CHOP-like group, these three risk groups, very good, good and poor, had distinctly different 3-year PFS rates of 96, 84.3 and 67.5% (P=0.001), and 3-year OS rates of 96, 87.6 and 71.1% (P=0.003), respectively. Our study demonstrates the power of the R-IPI as a simplified and more clinically relevant predictor of disease outcome than the standard IPI in DLBCL populations in the rituximab era. Therefore, the R-IPI merits further study in a larger population-based prospective study.
doi:10.3892/etm.2012.607
PMCID: PMC3503699  PMID: 23181121
International Prognostic Index; diffuse large B-cell lymphoma; rituximab
18.  Long-Term Results Of Autologous Hematopoietic Cell Transplantation For Peripheral T Cell Lymphoma: The Stanford Experience 
The peripheral T cell lymphomas (PTCL) carry a worse prognosis compared to B cell non-Hodgkin lymphoma. There is no uniform standard therapy for PTCL, and autologous hematopoietic cell transplant (AHCT) is often offered as consolidation in first remission or at relapse because of the poor outcomes with conventional therapy. We conducted a retrospective review of patients who underwent AHCT for PTCL from 1989 to 2006. Fifty-three cases were identified consisting of systemic anaplastic large cell (n = 18), PTCL unspecified (n = 17), angioimmunoblastic (n = 9), nasal type extranodal NK/T (n = 7), hepatosplenic (n = 2), and adult T cell leukemia/lymphoma (n = 1). Fifteen patients were transplanted in first complete or partial response (CR1/PR1), 32 in second or beyond CR or PR (CR2/PR2+), and 11 with primary refractory disease (REF). With a median follow-up was 5 years (range: 1.0–11.5), the 5-year progression-free survival (PFS) and overall survival (OS) were 25% and 48%, respectively. Disease status at AHCT had a significant impact on PFS and OS. The 5-year PFS for patients in CR1/PR1, CR2/PR2+, and REF was 51%, 12%, and 0%, respectively, and the corresponding figures for OS were 76%, 40%, and 30%, respectively. The pretransplant factors that impacted survival were disease status and the number of prior regimens. Histology, age, sex, stage, B symptoms, bone marrow involvement, and duration of first response did not significantly affect PFS or OS. Based on these results, AHCT as consolidation therapy in first complete or partial response may offer a durable survival benefit. However, AHCT with conventional salvage chemotherapy has minimal durable benefit in patients with relapsed or refractory PTCL, and thus novel strategies and/or allogeneic HCT should be more aggressively explored in lieu of AHCT for relapsed/ refractory PTCL.
doi:10.1016/j.bbmt.2008.04.004
PMCID: PMC2980839  PMID: 18541192
Lymphoma; Autologous transplantation; Peripheral T cell lymphoma
19.  Clinical analysis and prognostic significance of lymphoma-associated hemophagocytosis in peripheral T cell lymphoma 
Annals of Hematology  2012;92(4):481-486.
This study aims to retrospectively analyze the clinical characteristics, treatments, and prognosis of aggressive peripheral T cell lymphoma (PTCL) patients with a lymphoma-associated hemophagocytosis syndrome (LAHS). We compared the clinical features and the overall survival (OS) rates of 159 PTCL patients with and without LAHS as well as the treatment outcomes of these patients with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or intensive chemotherapy regimens. We observed that in 23 % (36/159) patients PTCL was associated with LAHS. Different subtypes of PTCL in LAHS patients were diagnosed and peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) was the main subtype (78 %). The median survival rates of the LAHS and non-LAHS groups were 3 and 16 months, respectively. The elevated rates of serum β2-microglobulin, ferritin, fasting triglycerides, and hypofibrinogen levels were higher in the LAHS group, so were bone marrow involvement, liver dysfunction, hepatosplenomegaly, and B symptoms. Three patients who were treated with a plasma exchange had a longer survival time. There was no statistically significant difference in the OS rates between the intensive chemotherapy and CHOP regimen groups (P > 0.05). PTCL patients with LAHS had a poorer prognosis. Awareness of the clinical symptoms and laboratory findings are crucial in order to diagnose LAHS in an early stage and repeated biopsies of multiple bone marrows from different locations in those patients without enlargement of superficial lymph nodes are necessary to improve the diagnosis. Intensive chemotherapy due to its severe toxicity was not obviously advantageous for the OS rate compared to the CHOP regimen.
doi:10.1007/s00277-012-1644-6
PMCID: PMC3590418  PMID: 23238896
Aggressive peripheral T cell lymphoma (PTCL); Lymphoma-associated hemophagocytosis syndrome (LAHS); Hemophagocytic lymphohistiocytosis (HLH); Intensive chemotherapy
20.  A Systematic Review and Meta-Analysis of Front-line Anthracycline-Based Chemotherapy Regimens for Peripheral T-Cell Lymphoma 
ISRN Hematology  2011;2011:623924.
Anthracycline-based chemotherapy remains standard treatment for peripheral T-cell lymphoma (PTCL) although its benefits have been questioned. We performed systematic literature review and meta-analyses examining the complete response (CR) and overall survival (OS) rates for patients with PTCL. The CR rate for PTCL patients ranged from 35.9% (95% CI 23.4–50.7%) for enteropathy-type T-cell lymphoma (ETTL) to 65.8% (95% CI 54.0–75.9%) for anaplastic large cell lymphoma (ALCL). The 5-year OS was 38.5% (95% CI 35.5–41.6%) for all PTCL patients and ranged from 20.3% (95% CI 12.5–31.2%) for ETTL to 56.5% (95% CI 42.8–69.2%) for ALCL. These data suggest that there is marked heterogeneity across PTCL subtypes in the benefits of anthracycline-based chemotherapy. While anthracyclines produce CR in half of PTCL patients, this yields reasonable 5-year OS for patients with ALCL but not for those with PTCL-NOS or ETTL. Novel agents and regimens are needed to improve outcomes for these patients.
doi:10.5402/2011/623924
PMCID: PMC3197255  PMID: 22084700
21.  Clinicopathologic Characteristics of Angioimmunoblastic T-Cell Lymphoma: Analysis of the International Peripheral T-Cell Lymphoma Project 
Journal of Clinical Oncology  2012;31(2):240-246.
Purpose
The International Peripheral T-Cell Lymphoma Project was undertaken to better understand the subtypes of T-cell and natural killer (NK) –cell lymphomas.
Patients and Methods
Angioimmunoblastic T-cell lymphoma (AITL) was diagnosed according to the 2001 WHO criteria by a central review process consisting of panels of expert hematopathologists. Clinical, pathologic, immunophenotyping, treatment, and survival data were correlated.
Results
Of 1,314 patients, 243 (18.5%) were diagnosed with AITL. At presentation, generalized lymphadenopathy was noted in 76% of patients, and 89% had stages III to IV disease. Skin rash was observed in 21% of patients. Hemolytic anemia and hypergammoglobulinemia occurred in 13% and 30% of patients, respectively. Five-year overall and failure-free survivals were 33% and 18%, respectively. At presentation, prognostic models were evaluated, including the standard International Prognostic Index, which comprised the following factors: age ≥ 60 years, stages III to IV disease, lactic dehydrogenase (LDH) > normal, extranodal sites (ENSs) > one, and performance status (PS) ≥ 2; the Prognostic Index for Peripheral T-Cell Lymphoma, comprising: age ≥ 60 years, PS ≥ 2, LDH > normal, and bone marrow involvement; and the alternative Prognostic Index for AITL (PIAI), comprising: age > 60 years, PS ≥ 2, ENSs > one, B symptoms, and platelet count < 150 × 109/L. The simplified PIAI had a low-risk group (zero to one factors), with 5-year survival of 44%, and a high-risk group (two to five factors), with 5-year survival of 24% (P = .0065).
Conclusion
AITL is a rare clinicopathologic entity characterized by an aggressive course and dismal outcome with current therapies.
doi:10.1200/JCO.2011.37.3647
PMCID: PMC3532394  PMID: 22869878
22.  Variable CD52 Expression in Mature T Cell and NK Cell Malignancies: Implications for Alemtuzumab Therapy 
British journal of haematology  2009;145(2):173-179.
Summary
The anti-CD52 antibody alemtuzumab has been explored as a novel targeted therapy in T-cell malignancies. To assess the suitability of alemtuzumab therapy we carried out a comprehensive study of CD52 expression using flow cytometry (FC) in 78 untreated patients diagnosed with mature T/NK cell neoplasms, including 34 adult T-cell leukemia /lymphomas (ATLL), two anaplastic large cell lymphomas (ALCL), three angioimmunoblastic T-cell lymphomas (AITL), 16 cutaneous T-cell lymphomas (CTCL), four extra-nodal T/NK cell lymphomas (ENT/NKCL), four hepatosplenic T-cell lymphomas (HSTCL), 13 peripheral T-cell lymphomas, unspecified (PTCL-NOS), and two T-prolymphocytic leukemia (T-PLL). The level of CD52 expression was quantitated using QuantiBRITE standard beads. The level of CD52 expression varied widely within each diagnostic category. All AITL, HSTCL, and T-PLL cases were CD52 positive and the frequency of CD52 expression was high in PTCL-NOS (92.3%), ATLL (94.1%) and CTCL (87.5%), implying a rational role for alemtuzumab in the treatment of these diseases; however, CD52 expression was low in ALCL (50%) and ENT/NKCL (25%). FC testing for cell surface expression of CD52 is indicated in patients with T/NK cell malignancies being considered for alemtuzumab therapy. Further studies are necessary to determine if the level of CD52 expression correlates with response to therapy.
doi:10.1111/j.1365-2141.2009.07606.x
PMCID: PMC3487105  PMID: 19236377
Alemtuzumab; CD52; flow cytometry; NK cell lymphoma; T cell lymphoma
23.  Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type 
Blood  2009;115(6):1226-1237.
Biopsies and cell lines of NK/T-cell lymphoma, nasal-type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared to PTCL, NOS, NKTCL had higher transcript levels for NK-cell markers and cytotoxic molecules, especially granzyme H, a novel sensitive biomarker of NKTCL. Compared to normal NK cells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, EBV-induced genes and PDGFRA. Notably, PDGFRα and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL-cell line was sensitive to imatinib. Deregulation of the AKT, JAK-STAT and NF-κB pathways suggested by bioinformatical analysis, was corroborated by nuclear expression of phosphorylated AKT, STAT3 and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 (1q44), IL6R (1q21.3), CCL2 (17q12), TNFRSF21 (6p12.3)). Several features of NKTCL uncovered by this analysis (overexpression of VEGFA and its receptor KDR by the tumor cells, overexpression of MET-HGF) suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets.
doi:10.1182/blood-2009-05-221275
PMCID: PMC2826234  PMID: 19965620
24.  Comparison of Conventional Prognostic Indices in Patients Older than 60 Years with Diffuse Large B-Cell Lymphoma Treated with R-CHOP in the US Intergroup Study (ECOG 4494, CALGB 9793): Consideration of Age Greater than 70 Years in an Elderly Prognostic Index (E-IPI) 
British journal of haematology  2010;151(2):143-151.
Summary
To assess if immunochemotherapy influenced the prognostic value of IPI in elderly diffuse large B-cell lymphoma (DLBCL) patients, we evaluated the performance of the standard International Prognostic Index (IPI) and following modifications: age adjusted (AA)-IPI, revised (R)-IPI, and an elderly IPI with age cut-off 70 years (E-IPI) in patients >60 years treated with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). In 267 patients, by IPI/AA-IPI 60% were high-intermediate, 53% high and 12% low risk. With R-IPI, 60% were poor risk and none very good risk. Using E-IPI, 45% were high-intermediate/high risk and 27% low risk. No differences in outcome were seen in the low/low-intermediate groups with IPI/AA-IPI. For E-IPI, failure-free survival (FFS) and overall survival (OS) were significantly different for low/low-intermediate groups. No differences were detected in the four indices with model fit/discrimination measures; however, E-IPI ranked highest. For elderly R-CHOP treated patients, distribution of IPI/AA-IPI skewed toward high/high-intermediate risk with no differences in FFS/OS between low/low-intermediate risk. In contrast, with E-IPI, more are classified as low risk with significant differences in FFS/OS for low-intermediate compared to low risk. The R-IPI does not identify a very good risk group, thus minimizing its utility in this population. The prognostic discrimination provided by the E-IPI for low and low-intermediate elderly DLBCL patients needs validation by other datasets.
doi:10.1111/j.1365-2141.2010.08331.x
PMCID: PMC3615251  PMID: 20735398
immunochemotherapy; prognostic; elderly; NHL; CHOP
25.  Enhanced Autophagy and Reduced Expression of Cathepsin D Are Related to Autophagic Cell Death in Epstein-Barr Virus-Associated Nasal Natural Killer/T-Cell Lymphomas: An Immunohistochemical Analysis of Beclin-1, LC3, Mitochondria (AE-1), and Cathepsin D in Nasopharyngeal Lymphomas 
Acta Histochemica et Cytochemica  2011;44(3):119-131.
This study investigated autophagy in 37 cases of nasopharyngeal lymphomas including 23 nasal natural killer (NK)/T-cell lymphomas (NKTCL), 3 cytotoxic T-cell lymphomas (cytotoxic-TML) and 9 B-cell lymphomas (BML) by means of antigen-retrieval immunohistochemistry of beclin-1, LC3, mitochondria (AE-1) and cathepsin D. Peculiar necrosis was noted in EBV+ lymphomas comprising 21 NKTCL, 2 cytotoxic-TML and 1 BML. Lymphomas without peculiar necrosis showed high expression of beclin-1, macrogranular cytoplasmal stain of LC3 with sporadic nuclear stain, a hallmark of autophagic cell death (ACD), some aggregated mitochondria and high expression of cathepsin D, suggesting a state of growth with enhanced autophagy with sporadic ACD. EBV+ NKTCL with the peculiar necrosis, showed significantly low level of macrogranular staining of LC3, aggregated mitochondria and low expression of cathepsin D in the cellular areas when degenerative lymphoma cells showed decreased beclin-1, significantly advanced LC3-labeled autophagy, residual aggregated mitochondria and significantly reduced expression of cathepsin D, suggesting advanced autophagy with regional ACD. Consequently it was suggested that enhanced autophagy and reduced expression of lysosomal enzymes induced regional ACD under EBV infection in NKTCL.
doi:10.1267/ahc.10024
PMCID: PMC3130144  PMID: 21753858
nasopharyngeal lymphoma; NKT-cell lymphoma nasal type; Epstein-Barr virus (EBV); autophagy; autophagic cell death; antigen retrieval immunohistochemistry (beclin-1; LC3; mitochondria (AE-1) and cathepsin D)

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