Revised European-American Lymphoma Research Articles

Clinicopathogenetic Significance of Chromosomal Abnormalities in Patients With Blastic Peripheral B-Cell Lymphoma

AbstractSo far, reproducible histomorphologic and immunological criteria to distinguish clinicopathologic subtypes of blastic peripheral B-cell non-Hodgkin’s lymphoma (BBCL), especially centroblastic (cb) and immunoblastic (ib) lymphomas, for daily diagnostic use are still lacking. Therefore, we correlated the cytogenetic findings in 126 patients with BBCL with histopathologic diagnoses. Subclassification of cb and ib lymphomas relied on the criteria defined in the updated Kiel classification; these subtypes are also listed in the Revised European-American Lymphoma (REAL) classification and in a preliminary report on the newly established World Health Organization classification, to investigate their clinical significance. Moreover, we performed a multivariate analysis to compare the prognostic significance of cytogenetic findings with the International Index. There were significant differences in the frequency of chromosome aberrations between different BBCL subtypes: t(8;14) was predominantly present in Burkitt’s lymphomas, t(14;18) in centroblastic lymphomas, deletions in 8q and 14q, changes of 4q and losses of chromosome 10 in immunoblastic lymphomas; t(11;14) was restricted to blastoid mantle cell lymphomas and associated with a poor prognosis. In cb lymphomas, deletions in 1q42-qter, duplications in 1q23-32, trisomy 5, and changes of 15q were identified as independent prognostic factors. In ib lymphomas, changes of 7q and 8q had stronger impact on survival than the International Index. These findings underline that Burkitt’s, cb, ib, and blastoid mantle-cell lymphoma are biologically distinct and clinically relevant entities and that cytogenetic findings can be helpful to subtype BBCL.

PS1096 INTERIM UPDATE FROM A MULTI‐CENTER STUDY OF PRALATREXATE IN ASIAN PATIENTS WITH RELAPSED OR REFRACTORY(R/R) PERIPHERAL T‐CELL LYMPHOMA (PTCL)

Background:Peripheral T‐cell lymphomas (PTCL) are a group of rare, aggressive and diverse lymphoproliferative disorder. When patients are in the relapsed/refractory setting, the survival is mostly less than 6 months. Pralatrexate, a folate analogue metabolic inhibitor, was the first monotherapy approved to treat R/R PTCL patients. As the subtypes difference between western and eastern countries, we would like to investigate the efficacy/safety of pralatrexate in Taiwanese patients.Aims:This single‐arm, multi‐center study aims to demonstrate the efficacy/ safety of pralatrexate in R/R PTCL patients. The patients who undergo Hematopoietic Stem Cell Transplantation (HSCT) or not after pralatrexate will be also investigated individually.Methods:Eligibility criteria included age ≧ 20 with PTCL according to the NCCN diagnosis criteria, the Revised European American Lymphoma (REAL), and WHO disease classification with the following subtypes: Peripheral T‐cell lymphoma, NOS (PTCL‐NOS), Angioimmunoblastic T‐cell lymphoma (AITL), Extranodal NK/T‐cell lymphoma, nasal type (ENKL), Enteropathy‐type T‐cell lymphoma (EATL), Hepatosplenic T‐cell lymphoma (HSTCL), Subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) and Adult T‐cell lymphoma/leukemia (human T‐cell leukemia virus [HTLV] 1+) (ATLL). Patients were documented disease progression after prior treatment. Intravenous pralatrexate was administrated weekly for 6 weeks in 7‐week cycles up to 5 cycles with concurrent vitamin B12 and folic acid. Patients who complete at least 1 cycle of pralatrexate and have at least 1 post‐treatment tumor assessment are defined as evaluable patients. The primary end point is Objective Response Rate (ORR, CR + PR). Secondary end points include Progression‐Free Survival (PFS), Duration of response (DoR) and Overall Survival (OS).Results:Twenty‐two patients were evaluable for efficacy per protocol definition. The subtype distribution included PTCL‐NOS (n = 9, 40.9%), AITL (n = 5, 22.7%), ENKL (n = 5, 22.7%), EATL (n = 1, 4.5%), SPTCL (n = 1, 4.5%) and ATLL (n = 1, 4.5%). The ORR was 54.5% with CR 18.2% (n = 4) and PR 36.3% (n = 8). When divided into 2 groups based on if patients received HSCT after pralatrexate, the ORR in HSCT group (n = 5) was 60% with CR 20% (n = 1) and PR 40% (n = 2), while ORR in non‐HSCT group (n = 17) was 53% with CR 18% (n = 3) and PR 35% (n = 6). At the time of data cut‐off, median PFS was 5 months (95% C.I. 5.51, 12.93), median DOR was 5.4 months (95% C.I. 2.64, 13.10) and OS not reached yet. It's notably that, among 5 patients that received HSCT successfully after pralatrexate, 4 patients are ENKL and the other is PTCL‐NOS. Except one who experienced disease progression after HSCT, the others still remain in response. It indicated that pralatrexate may play a beneficial role in bridging to transplantation in PTCL patients, especially in ENKL. Safety population analysis (n = 27) showed the most common TEAEs (grades 3–4) were: anemia (33%), stomatitis (26%), peripheral edema (22%), thrombocytopenia (15%) and leukopenia (11%).Summary/Conclusion:This interim update of this multi‐center study demonstrated the efficacy of pralatrexate monotherapy in R/R PTCL is 54.5%. Interestingly, most ENKL patients received HSCT after obtaining good disease control with pralatrexate. In addition, it showed tolerable safety profile. This is the first data demonstrated benefits of pralatrexate in R/R PTCL patients with intention or no intention to receive transplantation.image

LEUKEMIC PHASE OF MALIGNANT LYMPHOMA IN CHILDREN

Leukemic phase of malignant lymphoma is a group of lymphoid malignancies typically localized in lymph node and present typical clinical features such as lymphadenopathy with irregular distribution. It can manifest as an extranodal disorder infiltrates the bloodstream (leukemic phase). Lymphomas are differentiated into Hodgkin and non-Hodgkin. The presentation of Reed-Sternberg (RS) cells in histological evaluation establishes Hodgkin lymphoma. A number of classification systems have been used before the publication of Revised European American Lymphoma (REAL) classification in 1994 which includes all lymphoid and lymphoma malignancies according to typical histology, morphology, immunophenotype, genetic, and clinical manifestation. A highly proliferative and fatal malignant lymphoma with leukemic phase case in 13 years and a one-month-old male was reported. The diagnosis was established based on marble-sized lymph nodes enlargement that increased in size, two weeks after initial identification on the neck, head, and inguinal regions and followed by lymphadenopathies in submental, right submandibular, preauricular and right inguinal region. No fever history of this patient or malignant history among his family was found. Laboratory findings included WBC of 26,050/µL, Hb 9.6 g/dL, and PLT 16,000/µL. Peripheral blood smear results indicated suspected leukemic phase of malignant lymphoma DD/ALL. Bone marrow aspiration showed leukemic-phase of malignant lymphoma with bone marrow infiltration. Cytological evaluation of Fine Needle Aspiration (FNA) identified atypical round nucleated cells with nucleus size mostly larger than the mature lymphocytes, minimum cytoplasm, diffuse erythrocyte as background, a conclusion was malignant lymphoma.

Midline Granuloma

Midline granulomaor nasal type extranodal T/NK-cell non-Hodgkin’s lymphoma often cause various problem. This tumor is a disorder of the center of the face with the characteristic of progressive destruction and ulceration, including the nose, paranasal sinuse, palate, eyes, and facial soft tissues. Etiology and pathophysiologyis unclear between inflammatory and tumor reactions. Midline granulomais included innasal granuloma disease based on biopsy examination, where as The Revised European American Lymphoma (REAL) / Wordl Health Organization (WHO) classifiesmidline granulomainextranodal T/NK-cellnon-Hodgkin’s lymphomabased on immunohistologic examination. Epstein-Barr Virus (EBV) infections 90-100% are involved in the tumor formation process. Difficult diagnosis and wide-ranging diagnosis, requiring complete anamnesis and examination, especially biopsy, imunohistology, and cytogenetics in obtaining necrosis features with vascular destruction and ulceration, inflammation with pleomorphic cell infiltrate, CD56+, CD3+, cytotoxict and EBV+ proteins. Management with radiotherapy, chemotherapy, bone marrow transplant, and immunotherapy. Complications can occur locally or systemically with spread to peripheral blood circulation, soft tissue, lung, liver, skin, gastrointestinal tract, testes, central nervous and bone marrow. Poor prognosis is less than 50%of patient who respond fully after chemotherapy and radio therapy. Pronosis can only be assessed by the International Prognostic Index (IPI).
 Midline diagnosis of granulomais difficult,management is often delayed, while its progressive nature leads to various complications, thus further aggravating the prognosis.

Guillain-Barré syndrome and severe infection following chemotherapy for peripheral T-cell lymphoma: A case report.

Guillain-Barré syndrome (GBS) is a rare complication of malignant lymphoma. The current study describes a case of GBS in a patient with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). A 47-year-old male was admitted to the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) with systemic multiple subcutaneous nodules and was diagnosed with stage IV high-grade PTCL-NOS (according to the Revised European American Lymphoma Classification). During chemotherapy, severe infection and progressive flaccid quadriparesis appeared, which eventually developed to respiratory muscles paralysis. The clinical course and neurological examination were consistent with GBS. Following mechanical ventilation and intravenous immunoglobulin administration, the neurological symptoms were in remission after one month. Three months later, the patient achieved complete remission without any treatment during this period. We hypothesized that immune reconstruction may have a significant role in this phenomenon.

NK/T Cell Lymphoma, Nasal Type

NK/T cell lymphoma of the nasal type is an aggressive lymphoma commonly presenting as a destructive process of the facial midline, often demonstrating clinical and histologic features of necrosis and angioinvasion. It was initially categorized as an angiocentric lymphoma in the Revised European-American Lymphoma (REAL) classification. It has been recategorized as extranodal NK/T cell lymphoma in the World Health Organization classification of lymphoid neoplasms. Historically these tumors were considered part of “midline lethal granuloma.” This entity frequently arises in extranodal regions, especially the nasal or paranasal sinuses.

Histidine based adsorbents for selective removal of monoclonal immunoglobulin IgM antibodies from Waldenstrom's macroglobulinemia patient sera: A preliminary study

Waldenstrom's macroglobulinemia (WM) is considered by the Revised European American Lymphoma (REAL) and World Health Organization (WHO) as a clinical lympho plasmacytic syndrome associated with high monoclonal (IgM) secretion. The hyper viscosity syndrome is associated with several clinical disorders of monoclonal IgM. Patients with clinical symptoms of hyper viscosity should be treated with plasma pheresis, which is limited by its non-selective removal of all plasma components. These limitations have steered efforts to find a more specific removal according to clinical needs and avoiding plasma components replacement. Removal by specific adsorption is the most powerful selective apheresis technique. The active adsorbed ligand is covalently bound to an insoluble matrix through which plasma is passed. Amino acids have been introduced as ligands in clinical apheresis for the removal of auto antibodies associated with autoimmune diseases. The present preliminary study describes the binding of monoclonal IgM antibodies from sera of patients with WM, on histidine immobilized to activated sepharose. The advantages of efficient binding and elution, suggest histidine adsorbents as prospective clinical means suitable for the removal of monoclonal IgM from sera of patients diagnosed with WM. The advantages of efficient adsorption and elution, non toxicity of histidine, good selectivity, good stability, as well as their low cost strongly suggest histidine adsorbents as prospective clinical means suitable for the removal of monoclonal IgM from sera of patients diagnosed with WM.

Lymphoma classification: the quiet after the storm

The classification of malignant lymphomas remained controversial for over 30 years. The first scheme was proposed by Rappaport in the '60th and was based on incorrect histogenetic concepts. To overcome these limitations, several groups formulated new proposals in '70th. Among these two merited attention: the Lukes and Collins and the Kiel Classifications. They were based on the assumption that each lymphoma category might be related to a precise differentiation step of the lymphoid system, thus excluding any correlation with histiocytes, present on the Rappaport scheme. The Kiel Classification became very popular in Europe, while the one of Luke and Collins did not meet success in the United States (U.S.). In 1978, the National Cancer Institute proposed an international trial to compare the classifications used in Europe and U.S. The result was the genesis of the Working formulation, the tool for lymphoma classification in the U.S. up to the early '90th, but which was conversely rejected in Europe. In order to get over this lack of transatlantic communication, in 1994 the Revised European-American Lymphoma (REAL) Classification was proposed by the International Lymphoma Study Group. Its goal was to list "real" entities, each defined by the presence of homogeneous morphologic, phenotypic, cytogenetic, molecular, and clinical criteria, along with the possible recognition of its normal counterpart. The REAL Classification became the model for the WHO Classification of all haematopoietic tumours published in 2001. The present review aims to analyse future perspectives after the fourth edition of the WHO Classification released in 2008.

Autologous Peripheral Blood Stem Cell Transplantation in Children with Refractory or Relapsed Lymphoma: Results of Children’s Oncology Group Study A5962

This prospective study was designed to determine the safety and efficacy of cyclophosphamide, BCNU, and etoposide (CBV) conditioning and autologous peripheral blood stem cell transplant (PBSCT) in children with relapsed or refractory Hodgkin and non-Hodgkin lymphoma (HL and NHL). Patients achieving complete remission (CR) or partial remission (PR) after 2 to 4 courses of reinduction underwent a granulocyte-colony stimulating factor (G-CSF) mobilized PBSC apheresis with a target collection dose of 5 × 10⁶ CD34(+)/kg. Those eligible to proceed received autologous PBSCT after CBV (7200 mg/m², 450-300 mg/m², 2400 mg/m²). Forty-three of 69 patients (30/39 HL, 13/30 NHL) achieved a CR/PR after reinduction. Thirty-eight patients (28 HL, 10 NHL) underwent PBSCT. All initial 6 patients who received BCNU at 450 mg/m² experienced grade III or IV pulmonary toxicity compared to none of the subsequent 32 receiving 300 mg/m² (P < .0001). The probability of overall survival (OS) at 3 years for all patients is 51% and for transplanted patients is 64%. The 3-year event-free survival (EFS) is 38% (45% for HL; 30% NHL). The 3-year EFS in transplanted patients is 66% (65% HL; 70% NHL). Initial duration of remission of ≥12 versus <12 months was associated with a significant increase in OS (3 years OS 70% versus 34%) (P = .003). BCNU at 300 mg/m(2) in a CBV regimen prior to PBSCT is well tolerated in relapsed or refractory pediatric lymphoma patients. A short duration (<12 months) of initial remission is associated with a poorer prognosis. Last, a high percentage of patients achieving a CR/PR after reinduction therapy can be salvaged with CBV and autologlous PBSCT.

A phase II, single-arm, open-label study of pralatrexate in patients with aggressive relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL): Study PDX-015.

e18568 Background: Pralatrexate, a targeted antifolate approved for the treatment of recurrent/refractory peripheral T-cell lymphoma, has demonstrated activity in B-cell lymphomas in preclinical models and early clinical trials. Complete tumor regression was observed in pralatrexate-treated mice bearing diffuse large B-cell lymphoma and follicular B-cell xenografts. Partial responses have been observed in patients with B-cell lymphoma in a completed phase I-II study of single-agent pralatrexate and in an ongoing phase I-II study of pralatrexate + gemcitabine. Based on this encouraging research, a phase II trial of PDX-015 has been designed to evaluate pralatrexate in relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) with a primary objective of efficacy. Methods: Patient eligibility includes: (a) histologically/cytologically confirmed, measurable, aggressive B-cell NHL, using the Revised European American Lymphoma World Health Organization disease classification; (b) progressive or persistent disease after at least 1 prior treatment; (c) Eastern Cooperative Oncology Group Performance Status ≤ 2; (d) adequate hematological, hepatic, and renal function; and (e) ≥18 years of age. Pralatrexate is administered with vitamin supplementation at an initial dose of 30 mg/m2/week for 3 weeks in a 4- week cycle. Vitamin supplementation consists of folic acid 1 mg orally daily and vitamin B12 1 mg intramuscularly every 8 to 10 weeks. This study is a 2-stage design, in which ≥1 of the first 13 evaluable patients must respond for a total of 27 evaluable patients to be enrolled. The primary end point is objective response rate per International Workshop Criteria. Secondary objectives include safety, tolerability, and pharmacokinetic profile of pralatrexate in this patient population. Enrollment is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Allos Therapeutics Allos Therapeutics Allos Therapeutics

Histopathologic classification of 171 cases of canine and feline non-Hodgkin lymphoma according to the WHO

A retrospective collection of 171 lymphoid neoplasms (123 dogs and 48 cats) was classified according to the Revised European-American Lymphoma (REAL) classification, adopted in 2002 by the World Health Organization (WHO), to evaluate the WHO system for categorization of canine and feline neoplasms. Microscopic examination was performed after standard hematoxylin-eosin staining and immunohistochemical labelling for B (CD79a) or T (CD3) cell phenotypes. B-cell lymphomas were prevalent in dogs and T-cell lymphomas in cats. B-Large cell lymphoma (B-LCL) frequently showed plasmacytoid differentiation; notably, two canine plasma cell tumours (PCT) expressed both CD79 and CD3. There were difficulties in differentiating B-lymphoblastic lymphoma (B-LBL) from Burkitt-type lymphoma. Furthermore, intestinal T-cell lymphoma (ITCL) exhibited a huge morphologic variability. Finally, multicentric mature small and thymic T-cell lymphomas were diagnosed, although these categories are not codified by the WHO classification.

Enzastaurin in Patients with Non-Hodgkin Lymphomas: A Multicenter, Open-Label, Screening Study.

Abstract 3719Poster Board III-655 BackgroundEnzastaurin, an oral serine/threonine kinase inhibitor, targets the PKCβ and PI3K/AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-induced angiogenesis. At a clinically achievable concentration, enzastaurin suppressed growth and induced apoptosis in B-cell lymphoma (BCL) cell lines and induced apoptosis through AKT signaling in cutaneous T-cell lymphoma (CTCL) cell lines. Enzastaurin has demonstrated clinical activity in patients with relapsed/refractory diffuse large B-cell lymphoma. A screening study was initiated to evaluate the activity (response) of enzastaurin in relapsed peripheral TCL (PTCL), CTCL, and indolent and aggressive BCLs (IBCL and ABCL). Secondary objectives included determination of progression-free survival (PFS) and safety. MethodsIn this open-label, three (parallel) arm, non-comparative screening study, patients with relapsed TCL or BCL received 250 mg oral enzastaurin, twice daily (1125-mg loading dose on day 1), in 28-day cycles, for up to 2 years. TCL cohort consisted of patients who had histologically/cytologically confirmed PTCL and or histologically confirmed stage IB-IVB CTCL (including mycosis fungoides or Sézary syndrome). IBCL cohort had patients with stage II-IV, histologically confirmed small lymphocytic lymphoma (SLL) and grade 1/2 follicular lymphoma (FL) or marginal zone lymphoma (MZ: splenic, extranodal, or nodal). ABCL cohort included patients who had histologically confirmed grade 3a/b FL or aggressive lymphoma with prior clinical history of indolent lymphoma. Patients must have failed ≥1 prior systemic treatment (1 for TCL and IBCL; 2 for ABCL). Response was assessed using the modified Severity-Weighted Assessment Tool (mSWAT) in CTCL patients and the International Workshop criteria in all other patients. Safety was assessed using the Common Terminology Criteria for Adverse Events, version 3.0. ResultsA total of 58 patients were enrolled into the study: 24 in the TCL cohort, 19 in the IBCL cohort and 15 in the ABCL cohort. Patient characteristics and efficacy results at the interim analysis are summarized in the table. None of the patients had a complete response. Partial responses were observed in 1 patient each with CTCL, SLL, grade 1/2 FL, and grade 3a/3b FL. Eleven patients are ongoing treatment for >6 cycles (8 patients ≥12 cycles). Three patients (5%) discontinued due to drug-related toxicities: 1 due to grade (G) 3 hallucination, 1 due to G1 erectile dysfunction, and 1 due to G3 pruritus. One patient had drug-related G3 diarrhea and jaundice and G4 edema. Other 'G3 toxicities, regardless of causality, reported in >1 patient were: anemia (n=4), thrombocytopenia (n=2), and sepsis (n=3) in TCL patients; anemia (n=4) in IBCL patients; and pneumonia (n=2) in ABCL patients. There were no drug-related deaths. ConclusionsThese preliminary results indicate that enzastaurin appears to have activity and is well tolerated in patients with indolent lymphomas, grade 3a/3b FL, and CTCL.TCLIBCL*ABCL*PTCL† (N=13)CTCL‡ (N=11)SLL (N=7)FL grade 1/2 (N=8)MZ (N=4)FL grade 3a/b (N=5)IBCL (N=10)Median age, years55.552.072.074.062.060.060.3Female/Male4/98/31/63/51/30/57/3ECOG PS 0/1/24/7/25/4/23/4/06/2/00/2/24/1/05/3/2PR0111010RR, %09.114.312.5020.00SD4565416PD/UNK6/34/10/01/10/02/13/1Median PFS‡, days57Not determined308Not determined15911868Abbreviations: ECOG PS=Eastern Cooperative Oncology Group performance status; RR=response rate; SD=stable disease, PD=progressive disease; UNK=unknown; PFS=progression-free survival.‡ Median PFS at interim analysis*WHO criteria.†Revised European American Lymphoma (REAL) classification.‡AJCC TNM staging. Disclosures:Eliadis:HOCA Employee: Employment, Membership on an entity's Board of Directors or advisory committees. Crespo-Solis:Eli Lilly and Company: Honoraria. Pereira:Fundacao Faculdade de Medicina da Universidade de Sao Paulo: Employment. Roberson:Eli Lilly and Company: Employment. Hamid:Eli Lilly and Company: Employment. Smith:Eli Lilly and Company: Employment.

Frequencies of non-Hodgkin’s lymphoma subtypes in Kuwait: comparisons between different ethnic groups

There is a wide variation in the prevalence of various subtypes of non-Hodgkin's lymphoma worldwide. The aim of this study was to determine the relative frequency of different subtypes of non-Hodgkin's lymphoma in Kuwait based on the Revised European-American Lymphoma (REAL) classification. From 1998 to 2006, 738 subjects were included that were registered with non-Hodgkin's lymphoma in the population-based cancer registry at the Kuwait Cancer Control Center. Expert pathologists reviewed histological slides from all subjects. We performed detailed immunohistochemical studies and classified subjects based on the REAL classification. The prevalence of different types of non-Hodgkin's lymphoma was determined based on age, sex, site of disease, and ethnicity. Ethnicity groups comprised Kuwaiti Arabs, non Kuwaiti Arabs, Asians, and others. The prevalence of B- and T-cell lymphomas was 81.8% and 14.2%, respectively. The most common age group was 41-60 years old. The three most common subtypes in Kuwaiti Arabs were diffuse large B-cell lymphoma (46.5%), follicular lymphoma (15.5%), and mycosis fungoides (9.3%). In non-Kuwaiti Arabs, the most common subtypes were diffuse large B-cell lymphoma (48%), B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia (15.8%), and follicular lymphoma (12.7%). Overall, non-Kuwaiti Arabs exhibited the highest prevalence (59%), and 54% of all cases had extranodal presentation. Compared to the Western world, Kuwait had a lower prevalence of follicular lymphoma, a higher prevalence of diffuse large B-cell lymphoma and extranodal presentation, and a high frequency of mycosis fungoides. Compared to other parts of Asia, Kuwait had a lower frequency of peripheral T-cell lymphomas.

Peripheral T-Cell Lymphomas: An Historical Perspective

Peripheral T-cell lymphomas (PTCL) remain largely unexplored due to disease rarity and biological heterogeneity as well as relatively recent recognition in modern classification systems. Before 1970, classifications of non-Hodgkin’s lymphomas (NHL) were based on morphology. The discovery of distinct T-, B- and natural killer (NK)–cell lineages led to two immunologically based classification systems proposed in 1974: the European Kiel and the North American Lukes-Collins. In 1982, the Working Formulation (WF), based on clinical and morphologic criteria, was developed in the United States. The updated Kiel classification separated B- and Tcell lymphomas but still failed to address some disease types. The addition of molecular genetic features/criteria and increasing immunophenotypic subclassification allowed for more diagnostic standardization and reproducibility. The International Lymphoma Study Group (ILSG) integrated morphologic, phenotypic, molecular and clinical information in the 1994 REAL (Revised European American Lymphoma) classification. The T-cell lymphomas were grouped into “precursor” neoplasms versus “peripheral” or post-thymic T-cell and NK neoplasms, the so-called “PTCLs.” The World Health Organization (WHO) subsequently made the following modifications: PTCLs were subdivided into predominantly leukemic, extranodal and nodal types; cutaneous and systemic anaplastic large cell lymphomas (ALCL) were separated; terminology was updated for some diseases; and subcutaneous panniculitis-type and hepatosplenic γδ T-cell lymphomas were recognized as distinct entities. Almost a decade later, the recently published fourth edition of the WHO classification has refined the classification further, including defining ALK-negative ALCL as a provisional entity, confining subcutaneous panniculitislike T-cell lymphoma to cases with an αβ phenotype and combining the γδ cases with primary cutaneous γδ PTCL. Two other provisional categories have been established under the category of primary cutaneous peripheral T-cell lymphomas: primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma and CD8-positive cytotoxic T-cell lymphoma. Several important advances in the pathobiology of PTCL have been made. Unlike mature B-cell lymphomas, there are virtually no recurrent translocations characterizing the PTCLs. The one exception is a proportion of ALCL cases in which a non-random t(2;5)(p23;q35) translocation produces a novel fusion protein composed of the nucleophosmin (NPM) and anaplastic lymphoma (ALK) coding regions. The use of more detailed cytogenetic analysis with comparative genomic hybridization and gene expression profiling now provide evidence for recurrent genetic changes in other PTCL subtypes. Several PTCL subtypes have viral associations that may be involved in disease pathogenesis. In 1982, HTLV1 was found to be the etiologic agent of adult T-cell leukemia and lymphoma. In 1988, T-cell lymphomas were described in patients with chronic Epstein-Barr virus (EBV) infections, and EBV was subsequently found to be associated with extranodal NK/T-cell lymphoma, nasal type and angioimmunoblastic T-cell lymphoma. With the development of molecular techniques in the 1990s, the importance of the γδ T-cell receptor rearrangement and impact on prognosis is apparent. For example, in the updated WHO classification primary cutaneous γδ T-cell lymphoma is recognized by an aggressive course and considered a new provisional entity. Although significant progress has been made in defining specific disease categories within the diverse group of PTCLs and establishing the prognostic significance, advances in therapy have been much slower. In the last several years, attention has turned to testing new chemotherapy combinations, targeted agents and high-dose chemotherapy approaches specifically in PTCL. The hope for the future is that treatment can be tailored better for PTCL and outcomes will more approximate what is observed in aggressive B-cell NHL.

Proposed classification of lymphoid neoplasms for epidemiologic research from the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph)

AbstractRecent evidence suggests that there is etiologic heterogeneity among the various subtypes of lymphoid neoplasms. However, epidemiologic analyses by disease subtype have proven challenging due to the numerous clinical and pathologic schemes used to classify lymphomas and lymphoid leukemias over the last several decades. On behalf of the International Lymphoma Epidemiology Consortium (InterLymph) Pathology Working Group, we present a proposed nested classification of lymphoid neoplasms to facilitate the analysis of lymphoid neoplasm subtypes in epidemiologic research. The proposed classification is based on the World Health Organization classification of lymphoid neoplasms and the International Classification of Diseases–Oncology, Third Edition (ICD-O-3). We also provide a translation into the proposed classification from previous classifications, including the Working Formulation, Revised European-American Lymphoma (REAL) classification, and ICD-O-2. We recommend that epidemiologic studies include analyses by lymphoma subtype to the most detailed extent allowable by sample size. The standardization of groupings for epidemiologic research of lymphoma subtypes is essential for comparing subtype-specific reports in the literature, harmonizing cases within a single study diagnosed using different systems, as well as combining data from multiple studies for the purpose of pooled analysis or meta-analysis, and will probably prove to be critical for elucidating etiologies of the various lymphoid neoplasms.

Review of the literature on benzene exposure and leukemia subtypes

The epidemiologic literature on benzene exposure and leukemia in the MEDLINE and TOXNET databases was examined through October 2004 using the keywords “benzene”, “leukemia” and “adverse health effects”. This search was complemented by reviewing the reference lists from extant literature reviews and criteria documents on benzene. Published studies were characterized according to the type of industry studied and design, exposure assessment, disease classification, and control for confounding variables. Study design consisted of either cohort studies or case-control studies, which were further categorized into population-based and nested case-control studies. Disease classification considered the source of diagnostic information, whether there was clinical confirmation from medical records or histopathological, morphological and/or cytogenetic reviews, and as to whether the International Classification of Diseases (ICD) or the French–American–British (FAB) schemes were used (no studies used the Revised European–American Lymphoma (REAL) classification scheme). Nine cohort and 13 case-control studies met inclusion criteria for this review. High and significant acute myeloid leukemia risks with positive dose response relationships were identified across study designs, particularly in the “well-conducted” cohort studies and especially in more highly exposed workers in rubber, shoe, and paint industries. Risks for chronic lymphocytic leukemia (CLL) tended to show elevations in nested case-control studies, with possible dose response relationships in at least two of the three studies. However, cohort studies on CLL show no such risks. Data for chronic myeloid leukemia and acute lymphocytic leukemia are sparse and inconclusive.

Association of celiac disease and intestinal lymphomas and other cancers

Celiac disease (CD) is associated with intestinal lymphoma and other forms of cancer, especially adenocarcinoma of the small intestine, of the pharynx, and of the esophagus. Enteropathy-associated T-cell lymphoma (EATL) is a rare form of high-grade, T-cell non-Hodgkin lymphoma (NHL) of the upper small intestine that is specifically associated with CD. This NHL subtype arises in patients with either previously or concomitantly diagnosed CD. In a subgroup of patients, there is progressive deterioration of a refractory form of CD. EATL derives from a clonal proliferation of intraepithelial lymphocytes and is often disseminated at diagnosis. Extraintestinal presentations are not uncommon in the liver/spleen, thyroid, skin, nasal sinus, and brain. The outlook of EATL is poor. Recent studies indicated that (1) CD is associated with a significantly increased risk for NHL, especially of the T-cell type and primarily localized in the gut (EATL); (2) the CD-lymphoma association is less common than previously thought, with a relative risk close to 3; (3) CD screening is not required in patients with NHL of any primary site at the onset, unless suggested by specific findings (T-cell origin and/or primary gut localization). The risk of NHL associated with clinically milder (or silent) forms could be lower than in typical cases of CD. Several follow-up studies suggest that the GFD protects from cancer development, especially if started during the first years of life. Strict adherence to the GFD seems to be the only possibility of preventing a subset of rare but very aggressive forms of cancer.

A case of primary gastric Burkitt-like lymphoma in the early stage diagnosed by endoscopic mucosal resection

Dear Editor: Burkitt-like lymphoma (BLL) is a rare and rapidly progressive type of lymphoma that usually occurs in young males. In the Revised European– American Lymphoma (REAL) classification, BLLs are described as diffuse B-cell lymphomas with a high proliferative rate and molecular biological characteristics considered to be borderline between those of classic Burkitt lymphoma (BL) and those of diffuse large B-cell lymphoma (DLBCL). Although the gastrointestinal tract is one of the most common regions for extranodal malignant lymphomas, primary gastrointestinal lymphomas are rare. BL and BLL occur in various gastrointestinal sites, and 30–80% of patients have involvement of the small bowel or colon and rectum, especially the ileocecal region. Involvement of the stomach occurs in only 10% of the patients, and almost all of the cases were detected in the late stage as a bulky mass located in the abdomen or other gastrointestinal sites. Here we report a case of primary gastric BLL in the early stage. To the best of our knowledge, this is the first report of a case of BLL presenting with a submucosal tumor (SMT) that was diagnosed by endoscopic mucosal resection (EMR). In June 2003, a 52-year-old Japanese man underwent upper gastrointestinal endoscopy and a SMT measuring 20 mm was detected in the gastric antrum. Endoscopic pictures with indigocarmine spraying dye clearly revealed the surface of the SMT. It was extensible, nodular, and glossy with telangiectasia, and no ulcer was seen on the surface. The tumor was elastic and immovable, and four biopsy specimens showed inflammatory cell (neutrophil and plasma cell) invasion with infection by Helicobacter pylori. Endoscopic ultrasonography (EUS) (20 MHz) was performed to examine the inner parts of the SMT. The tumor was found to be a homogeneous hypoechoic lesion and to be located in the submucosal layer. A computed tomography (CT) scan showed neither bulky mass nor lymph node metastasis. On scintigraphy, there was no accumulation of gallium except in the stomach. No abnormality was detected in other portions of the alimentary tract by small-bowel examination and colonoscopy. Since the proper muscular layer of the tumor was thought to be intact, we thought that this tumor was resectable, and EMR was performed for diagnosis. Pathologically, the cut end of the resected specimen was negative. The tumor cells showed a very high mitotic rate and a nuclear variability in the submucosal layer. A starry-sky appearance and mediumsized lymphoid cells showing a jigsaw puzzle effect of cytoplasmic borders were seen in the tumor tissues. Immunohistochemically, tumor cells were positive for L-26 and K. Nosho (*) . M. Shitani . F. Takahashi . Y. Ikeda . A. Goto . H. Yamamoto . Y. Arimura . T. Ishida . T. Endo . K. Imai First Department of Internal Medicine, Sapporo Medical University, S.-1, W.-16, Chuo-ku, Sapporo, 060-8543, Japan e-mail: nosho@sapmed.ac.jp Tel.: +81-11-6112111 Fax: +81-11-6112282

Pathology review for paediatric non-Hodgkin's lymphoma patients in Japan: a report from the Japan association of childhood leukaemia study (JACLS)

A central pathology review system with an immunophenotyping laboratory was established in Japan to support the clinical trial, the Japan Association of Childhood Leukaemia Study (JACLS) NHL-98, for patients with paediatric non-Hodgkin's lymphoma (NHL). Pathology samples from 155 clinically-suspected NHL cases were evaluated centrally initially using the Revised European-American Lymphoma (REAL) classification in a rapid review (within 2 weeks after surgery/biopsy) and then later at the consensus review (once a year). The samples were subsequently re-classified according to the new World Health Organisation (WHO) classification. After the pathology review, 96 (62%) patients were eligible for the study, and 58 of them (60%) had extra-nodal primaries. These NHL cases included B-cell lymphomas (precursor B-cell, 11; Burkitt, 18; diffuse large B-cell, 18; not otherwise specified, 3) and T/Natural Killer (NK)-cell lymphomas (precursor T-cell, 23; anaplastic large cell, 20; others, 3). There was excellent concordance in making the diagnoses (95/96, 99%) and typing (93/96, 97%) of NHL between the rapid and consensus reviews. Five cases, initially diagnosed as diffuse large B-cell lymphoma by the review, were re-classified as Burkitt lymphoma according to the immunocytochemical criteria by the WHO classification. A total of 59 (38%) cases were excluded from the study: they were Hodgkin lymphoma (7), leukaemias (11), reactive lymphoid hyperplasia (20), necrotizing lymphadenitis (7), no consensus diagnosis (1), insufficient materials (2), and others (11). This is the first report of the central pathology review from the paediatric NHL group study in Japan. Because various diseases, either neoplastic or reactive, mimicked NHL, clinically and histopathologically, the central pathology review system was critical and essential for patient enrollment and protocol assignment in our clinical trial. Through the two-step review system, highly reliable data were generated to support this study.

Immunophenotypic and Molecular Studies in the Diagnosis and Classification of Malignant Lymphoma

Immunophenotypic and molecular studies play an increasingly important role in the diagnosis and classification of lymphoid neoplasms. These studies are not yet a substitute for expert histopathologic evaluation, but are a valuable adjunct to the examination of the hematoxylin and eosin-stained slide. Major applications include determination of lineage, determination of B and T cell monoclonality, detection of oncoprotein expression, and detection of oncogene rearrangements and chromosomal translocations. The recognition of the lymphomas as distinct biologic entities with specific immunophenotypic and genotypic features, as embodied in the Revised European-American Lymphoma (REAL) and World Health Organization (WHO) classifications, is a key to the future development and application of targeted biologic and molecular therapies. In the future, application of gene expression array analysis to the lymphoid neoplasms will permit classification of the lymphomas at a molecular level.