Classification Of Lymphoid Malignancies Research Articles

Uncommon Variants of Mature T-Cell Lymphomas (MTCLs): Imaging and Histopathologic and Clinical Features with Updates from the Fourth Edition of the World Health Organization (WHO) Classification of Lymphoid Neoplasms.

Simple SummaryFamiliarity with the updated fourth edition WHO classification of lymphoid malignancies released in 2016, and the new terminology introduced, is crucial for oncologists, pathologists and radiologists. It is mandatory to be aware of rare variants of T-cell lymphomas, specifically mature T-cell lymphomas, including clinicopathologic keys and the most common imaging features and sites of involvement for each subtype. Even though some of these disorders may have perceptible clinical and imaging features, they may overlap with more common disorders, causing delay in diagnosis and treatment. Understanding the appropriate clinical setting and imaging findings will help radiologists to include these disorders in their differential diagnosis. Imaging plays a pivotal role in subclassifying these subtypes of MTCLs, affecting prognosis and treatment implications. Many of these disorders if diagnosed early can be potentially treatable, and early, aggressive intervention may be lifesaving.Understanding the pathogenesis and molecular biology of malignant lymphomas is challenging, given the complex nature and incongruity of these disorders. The classification of lymphoma is continually evolving to account for advances in clinical, pathological, molecular biology and cytogenetic aspects, which impact our understanding of these disorders. The latest fourth edition of the WHO classification of lymphoid malignancies was released in 2016 to account for these changes. Additionally, unlike B-cell lymphomas (BCL), T-cell lymphomas (TCL) are uncommon, and may be sporadically experienced in clinical practice. These disorders are rare, thus early diagnosis is challenging for both physicians and radiologists, owing to the overlap in clinical and imaging features with other, more common disorders. We aim to discuss some rare variants of T-cell lymphomas, including clinicopathologic and imaging features, as well as to give a glimpse of the updates contained within the new 2016 WHO classification.

A Phase 1a/1b Trial of ST-001, a Fenretinide Phospholipid Suspension for 4-Hour Intravenous Infusion in Relapsed/Refractory T-Cell Non-Hodgkin's Lymphoma

A phase 1a/1b trial is planned for specific types of T-cell non-Hodgkin's lymphoma (T-NHL) using a new formulation of fenretinide for intravenous (IV) administration (ST-001, IND# 135475). Despite documented anticancer properties, clinical development of fenretinide has been hampered by poor bioavailability of the oral preparations and poor water solubility for IV infusion although some progress has been made. A phase 1 clinical trial of a 20% soy oil-in-water emulsion containing 2mg/mL of fenretinide, administered via 24-hour daily infusions x5 q3wks, demonstrated activity in mycosis fungoides /Sézary syndrome (MF/SS) and in angioimmunoblastic T-cell lymphoma (AITL) (Mohrbacher et al 2017). However, all doses exhibiting disease activity were associated with grade 4 hypertriglyceridemia. ST-001 from SciTech Development, LLC is a second generation, triglyceride-free, phospholipid-based nano-dispersion formulation of higher potency fenretinide (12.5mg/mL) suitable for IV infusion. The SciTech Delivery Vehicle (SDV) is composed of 4 clinically acceptable phospholipids (DPPC, DOPC, DMPC, and DMPG) which, in the presence of fenretinide, form lamellar bilayer structures <200nm in diameter. Pharmacokinetic (PK) studies showed that IV administration of ST-001 in the Sprague-Dawley rat model achieved fenretinide blood levels required for in vitro cytotoxicity to human cancer cell lines (including T- and B-NHL). The planned US multicenter phase 1a trial utilizes an Accelerated Titration (Simon) 4B design, with 100% dose escalation in single-patient cohorts until first instance of grade 3 or higher toxicity is encountered, at which point the trial reverts to a 'standard', 3 patient-cohort approach and 40% dose escalation. To maximize each patient's chance to be treated at a potentially active dose, intrapatient dose escalation is allowed for patients who remain on study and have no evidence of toxicity once the safety of the next dose level is established in a drug-naïve patient. The primary study objective is determining the maximum tolerated dose (MTD) of ST-001 in adult patients with T-NHL. Secondary objectives are to describe the toxicity profile of ST-001, observe and record anti-tumor activity of ST-001 in patients with T-NHL, describe the PK of ST-001 when given at the specified dose/schedule in this study, and evaluate potential mechanisms of action of ST-001 using pharmacodynamic (PD) biomarkers. Eligible patients will be 18 years or older with histologically confirmed diagnosis of MF/SS (stages IB-IV according to TNMB system), or Ann Arbor stage II-IV non-cutaneous peripheral T-cell NHL (PTCL), AITL, or follicular T-NHL (FTCL) as defined in the 2016 WHO classification of lymphoid malignancies. Patients must have received at least 2 prior systemic therapies, have good performance status, and acceptable organ function. The drug will be administered IV over 4 hours daily for 5 consecutive days as outpatient starting at a dose of 1.25mg/m2/day. Treatment will be repeated every 3 weeks for up to 8 cycles. Once MTD is determined, an expanded cohort (phase 1b) will be conducted at MTD for diseases that demonstrate efficacy signals in phase 1a; however, patients must have at least one measurable disease site to be eligible for 1b. Up to 44 patients are projected to be enrolled (24 for phase 1a, and 20 for 1b). All patients who receive at least one dose of ST-001 will be evaluated for safety and toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Patients with at least one measurable site of disease and have received at least one full cycle (5-day infusion) of ST-001 are eligible for response evaluation. Descriptive statistics will be used for PK analysis to characterize the range, median and mean of calculated values of clearance, volume of distribution, and half-lives of distribution and elimination phases across all evaluable patients. PD analysis will use each patient's baseline value as the control and normalize PD values as % change from baseline. Effect of ST-001 on specific immune functions including cytokines and immune effector cell function will be evaluated at baseline and after therapy. It is anticipated that ST-001 will demonstrate activity in T-NHL in the absence of excipients that contribute to triglyceride elevations. Disclosures Kuzel: SciTech Development, LLC: Membership on an entity's Board of Directors or advisory committees. Parchment:SciTech Development, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Epstein Barr Virus Associated B-Cell Lymphomas and Iatrogenic Lymphoproliferative Disorders.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting up to 90% of the population. EBV was first identified as an oncogenic virus in a Burkitt lymphoma cell line, though subsequently has been found to drive a variety of malignancies, including diffuse large B-cell lymphoma (DLBCL) and other lymphoma subtypes. EBV has a tropism for B-lymphocytes and has the unique ability to exist in a latent state, evading the host immune response. In cases of impaired cell mediated immunity, as in patients with advanced age or iatrogenic immune suppression, the virus is able to proliferate in an unregulated fashion, expressing viral antigens that predispose to transformation. EBV-positive DLBCL not otherwise specified, which has been included as a revised provisional entity in the 2016 WHO classification of lymphoid malignancies, is thought to commonly occur in older patients with immunosenescence. Similarly, it is well-established that iatrogenic immune suppression, occurring in both transplant and non-transplant settings, can predispose to EBV-driven lymphoproliferative disorders. EBV-positive lymphoproliferative disorders are heterogeneous, with variable clinical features and prognoses depending on the context in which they arise. While DLBCL is the most common subtype, other histologic variants, including Burkitt lymphoma, NK/T-cell lymphoma, and Hodgkin lymphoma can occur. Research aimed at understanding the underlying biology and disease prevention strategies in EBV-associated lymphoproliferative diseases are ongoing. Additionally, personalized treatment approaches, such as immunotherapy and adoptive T-cell therapies, have yielded encouraging results, though randomized trials are needed to further define optimal management.

Understanding the New WHO Classification of Lymphoid Malignancies: Why It's Important and How It Will Affect Practice.

Improved delineation of lymphoid malignancy biology has prompted refinement of the 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid tumors with a new framework introduced in 2016. This knowledge has provided valuable insights regarding management. Early clonal proliferations have been set apart given their limited potential for malignant dissemination. Increasing knowledge of molecular drivers of aggressive lymphomas has allowed subclassification and opportunity for clinical investigations to personalize therapy. New insights into T-cell pathophysiology has allowed grouping based on shared molecular and cellular features. This article will summarize the key changes in terms of diagnosis and histopathologic definitions, the impact of these changes on clinical management, and the challenges of future research in this field.

Understanding the New WHO Classification of Lymphoid Malignancies: Why It's Important and How It Will Affect Practice

Understanding the New WHO Classification of Lymphoid Malignancies: Why It's Important and How It Will Affect Practice

Immunohistochemical markers in lymphoid malignancies: Protein correlates of molecular alterations.

Histomorphology, immunohistochemistry (IHC), and genetics are essential tools for the evaluation and classification of lymphoid malignancies. Advances in diagnostic techniques include the development of immunohistochemical assays that can serve as surrogates for genetic tests. We review the performance of a select subset of assays that detect the aberrant expression of onco-proteins secondary to chromosomal translocations (MYC; BCL2), somatic mutations (BRAF V600E; NOTCH1), and gene copy number gains (CD274 (encoding PD-L1); PDCD1LG2 (encoding PD-L2)) in fixed tissue biopsy sections. We discuss the limitations of IHC, but also its primary advantage over genetics; specifically, its ability to assess the final, common phenotypic consequences of a multitude of genetic and non-genetic events that influence protein expression. The information provided by IHC and genetic testing are thus intimately related; surgical pathologists will increasingly need to interpret and integrate the results of both to provide a comprehensive assessment of tumor biology and guide therapy.

Does Upfront Therapy with Fludarabine Increase the Risk of Histological Transformation In Patients with Follicular Lymphoma?

AbstractAbstract 4885 Introduction:Fludarabine has been reported to increase the incidence of relapse and histological transformation in chronic lymphocytic leukemia (Thornton PD, Leukemia research, 2005) and Waldenstrom macroglobulinemia (Leleu X, J Clincal Oncology, 2009). The purpose of our study was to investigate the role of Fludarabine and the risk of transformation and relapse in follicular lymphoma (FL). Patients and Methods:This is a retrospective single institution study. We included 50 patients consecutively diagnosed with FL Grade I and II based on WHO classification of lymphoid malignancies. Grade III patients were excluded from the study. Median follow up is 2.86 years. Patients were grouped according to the initial therapy chosen by their treating physicians: Group 1(n=14) included patients on observation and radiation therapy, Group 2 (n=6) included patients on Fludarabine based regimens, Group 3(n=13) included CVP-R and other rituximab regimens and Group 4(n=17) included R-CHOP. Data collected included time to the onset of biopsy proven transformation, time to relapse, mortality and overall survival. Level of significance was set at <0.05. Results:Median age of the patients was 56.5 and it was not significantly different for the various groups. High risk FLIPI score was seen in 66% of patients treated with Fludarabine regimens as compared to 61% of R-CHOP treated patients. Overall, relapse occurred in 38% patients and transformation occurred in 16% patients during the follow up period. Fludarabine treated patients had the highest relapse rate: 50% (p=0.03). R-CHOP group has lowest relapse rate: 11%. Transformation rate was highest in the Fludarabine group: 33%, as compared to 13% to 17% in other groups (p=0.10). Mortality rate was 7% in group 1, 16% in group 2, 23% for group 3 and 5% in group 4 (p=0.44). Time to relapse/progression in group 1 was 2.9 years; in group 2 was 2.1 years; in group 3 was 2.7 years and in group 4 was 5.8 years. Conclusions:In our study, Fludarabine treated patients appear to be at higher risk for relapse and transformation compared to patients treated with R-CHOP. The differences can not be explained on the basis of known prognostic factors such as age or FLIPI score. The retrospective nature of the study and the small numbers of patients preclude more definitive conclusions. Further research is needed with large number of patients. Disclosures:No relevant conflicts of interest to declare.

Clinicopathological differences between EBV-positive and EBV-negative diffuse large B-cell lymphoma.

8083 Background: Epstein Barr virus-positive diffuse large B-cell lymphoma (EBV-positive DLBCL) of the elderly is a new entity considered in the new WHO classification of lymphoid malignancies. EBV-positive DLBCL is a very aggressive entity with a short survival. Few data comparing the clinicopathological features between EBV-positive and EBV-negative DLBCL are available. Our study attempts to compare these characteristics and also identify prognostic factors. Methods: Between January 2002 and December 2009, 102 patients diagnosed with DLBCL were included in the analysis; 21 cases were EBV-positive and 81 cases were EBV-negative. Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the immunohistochemical expression of bcl-6, CD10, CD30 and MUM-1. Samples from patients were also analyzed for the presence of EBV-encoded RNA (EBER). Descriptive statistics were used to assess categorical and continuous variables. Survival curves for OS were estimated using the Kaplan-Meier method and compared using the log-rank test. For the multivariate analysis, the Cox proportional-hazard regression test was used. Results: Mean age for EBV-positive and EBV-negative patients was 73 and 65years, respectively (p=0.043). Sex, LDH levels, performance status, clinical stage, response to initial treatment and extranodal involvement were not significantly different between groups. The EBV status demonstrated a substantially poorer overall survival 3 months (95% CI, 0.0–2.6 months) and 15.5 months (1.0–43.0 months) in EBV-positive and EBV-negative, respectively (p=0.022). At the multivariate level, EBV status was an independent factor compared with the International Prognostic Index (IPI) score (p=0.001) with a 2.4-fold (95% CI, 1.2–4.8) risk for death for EBV-positive cases. In the EBV-positive group, a non-germinal center profile, the Oyama score and the IPI score were associated with survival. In the multivariate analysis only IPI score was significant (p=0.0045). Conclusions: EBV- positive DLBCL correlated with advanced age and a poor survival in comparison with EBV-negative DLBCL. The IPI score was a better prognostic tool than the Oyama score in EBV-positive patients. No significant financial relationships to disclose.

From the Guest Editor

Hodgkin’s lymphoma was once a uniformly fatal disease. However, today at least 80% to 85% of all patients are cured. No stage of disease is beyond cure. Patients may even be cured after they have relapsed. Indeed, anecdotal data make it difficult to ever throw in the towel in managing patients with Hodgkin’s lymphoma. When one sees a patient who has been in her fifth complete remission for 26 years, it makes one reluctant to ever say “never.” Even when the physician has exhausted the conventional curative approaches, palliative therapy may also produce long periods of symptom-free survival. The paradoxical outcome from this success is that it makes the death of a patient with Hodgkin’s lymphoma much more difficult to bear. For many advanced cancers, death is the expected outcome and when it comes, it is painful to be sure, but the physician has been preparing himself or herself, the patient, and the patient’s family for the event. When a patient with Hodgkin’s lymphoma dies, it is often an even more devastating blow because the course of treatment was embarked upon with such high hopes. Despite the enormous progress that has been made in successfully treating patients with Hodgkin’s lymphoma, our knowledge about the disease is far from comprehensive. Furthermore, even the information we know about Hodgkin’s lymphoma and its treatment is not agreed upon. Controversy surrounds the decision on the best treatment approach. In this issue of The Cancer Journal, I have been fortunate to collect the thoughts of many of the leading figures in Hodgkin’s lymphoma in the world. Their contributions here will bring the reader up to date on the facts and opinions of many experienced thought leaders. What causes Hodgkin’s lymphoma? We don’t know. However, in these pages, Neil Caporaso and his colleagues from the National Cancer Institute (NCI) discuss what has been revealed from studies of the epidemiology of the disease. Genetic factors contribute to the disease, but we do not know precisely what genes are involved or how they lead to the tumor. A higher incidence occurs in westernized populations including those who emigrate from low-incidence sites to the United States. Efforts to find an infectious etiologic agent have been largely unsuccessful, though a role for Epstein-Barr virus has been implicated in some cases. How does Hodgkin’s lymphoma present and progress? Fortunately, we have Joseph Connors, a master clinician and clinical researcher at the British Columbia Cancer Agency, to draw on his own vast experience and the world literature on the clinical manifestations and natural history of Hodgkin’s lymphoma. The disease has a predilection for lymph nodes. If only a single site is involved, it is usually the left supraclavicular node region. The disease marches progressively from one lymph node-bearing group to the next. When it spreads to the abdomen, usually the spleen is the first site involved. Because the spleen lacks afferent lymphatics, this may argue for hematogenous spread with selective growth in the fertile soil of the spleen. Fever, weight loss, and night sweats reflect systemic effects from tumor-induced cytokines. The disease may also be associated with important alterations in other organs including nephrotic syndrome and neurologic symptoms. What is Hodgkin’s lymphoma? As discussed in detail by the NCI’s Franziska Eberle, Haresh Mani, and Elaine Jaffe, Hodgkin’s lymphoma currently seems to be at least 2 diseases, as reflected in the World Health Organisation classification of lymphoid malignancies: the more common classic Hodgkin’s lymphoma and the much less common nodular lymphocyte predominant Hodgkin’s lymphoma. However, more recent evidence suggests that classic Hodgkin’s lymphoma may be a heterogeneous category with at least 2 diseases, nodular sclerosis representing 1 subset and mixed cellularity and lymphocyte depleted types forming a continuum on the other. Reliably distinguishing these entities is the first step toward sorting out their pathogenesis and perhaps defining new therapeutic targets for the subset of patients not cured by existing approaches. The staging of the extent of disease has undergone changes through the years as therapy has produced better results and nearly all patients receive some systemic therapy. Thus, removed from

Application of Immunohistochemistry in the Diagnosis of Non-Hodgkin and Hodgkin Lymphoma

Beginning with the immunologic classifications of Lukes and Collins and Kiel and culminating in the Revised European-American Lymphoma and World Health Organization classifications, the diagnosis of lymphoid tumors relies heavily on the determination of cell lineage, maturation, and function, based on antigen expression in addition to morphology and clinical features. Technologic advances in immunology, antibody production, genetic analysis, cloning, and the identification of new genes and proteins by microarray and proteomics have provided pathologists with many antibodies to use in routine diagnosis. To provide guidance to the practicing pathologist in the appropriate selection of an antibody panel for the diagnosis of lymphoma based on morphology and relevant clinical data and to avoid pitfalls in the interpretation of immunohistochemical data. Attention is given to some of the newer antibodies, particularly against transcription factors, that are diagnostically and prognostically useful. The information presented in this article is based on review of the literature using the OVID database (Ovid MEDLINE 1950 to present with daily update) and 20 years of experience in diagnostic hematopathology. Immunophenotyping is required for the diagnosis and classification of lymphoid malignancies. Many paraffin-reactive antibodies are available to the pathologist but most are not specific. To avoid diagnostic pitfalls, interpretation of marker studies must be based on a panel and knowledge of a particular antigen's expression in normal, reactive, and neoplastic conditions.

Multiple Parameter Flow Cytometric Immunophenotyping Is Helpful in the Diagnosis of Patients with Chronic Lymphoproliferative Diseases.

The new WHO classification of lymphoid malignancies can become a big challenge to pathologists, owing to technical limitations of conventional pathologic diagnosis and immunohistochemistry. Multiple parameter analysis by flow cytometry (FCM) could provide a potent tool in improving the diagnostic status of chronic lymphoproliferative diseases(CLPDs). To evaluate its role in improving the accuracy and efficacy of diagnosis, we studied the immunophenotype by FCM in a total of 214 samples, including lymph nodes, peripheral blood, bone marrow and cerebrospinal fluid samples, in 186 patients with suspected mature B or T cell neoplasmas. A total of 102 male and 84 female patients were included in this study. The medium age was 49 years old, ranging from 3 to 82. Samples were prepared in routine fashion for morphology, pathology and immunohistochemistry, as LCA, L26, UCHL-1, CD5, Cyclin D1, CD10, Bcl-2, CD20, CD3, TdT and CD79α stains were performed by traditional APAAP method. A diagnosis was made according to the new WHO classification for lymphoid malignancies. Meanwhile, suspended single cells were also prepared by direct immunophenotyping with fluorescent conjugated antibody to CD3, CD5, CD7, CD19, CD20, CD56, CD57, CD38, CD138, CD22 on cell surface and CD3, CD22, Kappa, Lambda in cytoplasm. Immunophenotype of the gated lymphocytes were analyzed with multiple parameter cytometric analysis to come to a diagnosis. The accuracy and efficacy of the diagnosis was compared between methods of conventional and conventional combined with FCM immunophenotyping. Nine out of 38 lymph nodes failing to get a correct diagnosis by conventional methods were accurately diagnosed when FCM immunophenotyping was performed (P< 0.01), but there still remained 3 cases that did not get a clear pathological diagnosis. A total of 102 out of 104 peripheral blood or bone marrow samples were diagnosed according to the new WHO classification by flow cytometric immunophenotype analysis, compared to 90 out of 104 samples by conventional immnohistochemistry (P< 0.01). There remained 2 cases without clear diagnosis, including a patient with CD5 positive B cells. He was finally diagnosed as splenic marginal zone lymphoma, after cyclinD1 immunochemistry and FISH detection of translocation between chromosome 11 and 14 were performed to exclude mantle cell lymphoma. Multiple parameter phenotype analysis in cerebrospinal fluid by FCM was also informative for the diagnosis of the infiltration of leukemia or lymphoma cells in central nervous system. A patient with Burkit lymphoma was diagnosed as diffused infiltration of lymphoma cell in center nerves system after cerebrospinal fluid examination. The same patient was considered brain infection by CT scanning before FCM immunophenotype analysis was conducted. We concluded that multiple parameter phenotypic analysis by FCM can be used in the diagnosis, differentiated diagnosis and detection of minimal residue diseases in CLPDs. It provides a useful tool to improve the accuracy and efficacy of diagnosis in lymphoid malignancies.

Molecular Signatures of Lymphoma

Hematologic malignancies have historically been characterized by morphologic, immunophenotypic, molecular, and genetic features. However, morphologically identical tumors can have clearly distinct clinical outcomes, suggesting underlying biological heterogeneity. Recent advances in microarray technology have helped the classification of lymphoid malignancies evolve to a new refined level. In addition to the discovery of new disease subclasses defined by unique molecular profiles, gene expression patterns can be correlated with specific genetic abnormalities and prognoses. Furthermore, the discovery of new disease subtypes has provided further insight into lymphoma biology and pathogenesis. Unique gene signatures can highlight key deregulated pathways that are active in molecular disease categories, and in some cases these findings have elucidated new targets for novel therapeutic approaches. This review summarizes the current status of molecular profiling in non-Hodgkin lymphomas. In this review, we have endeavored to include data from multiple investigator groups and tried to cover the breadth of lymphoid tumors, excluding acute and chronic leukemias.

Who is WHO and what was REAL?

The principles of the new WHO classification of haematopoietic and lymphoid tumours are based on those defined in the Revised European American classification of Lymphoid neoplasms (REAL), published by the International Lymphoma Study Group (ILSG) in 1994. Thus, the new WHO classification may be considered an updated version of the REAL classification rather than of the old WHO classification published in 1976. Disease entities are defined on the basis of morphological, phenotypic, genotypic, and clinical data. The relative impact of these characteristics varies among different diseases and there is "no gold standard". Thus, the strict hierarchy among diagnostic criteria, headed by morphology and followed by immunohistochemistry and genetics, has been discontinued. The WHO classification not only encompasses lymphoid tumours but extends to myeloid, mast cell and histiocytic/dendritic cell malignancies. Neoplasms are primarily stratified according to their tumour cell lineage. For each neoplasm a cell of origin is postulated. The classification of lymphoid malignancies recognises three major categories, B-cell neoplasms, T-/NK-cell neoplasms, and Hodgkin lymphomas. B-cell and T-cell lymphomas are further divided into precursor neoplasms and mature neoplasms, the latter being subdivided according to their clinical manifestation into disseminated/leukaemic, extranodal and nodal malignancies. In contrast to previous classifications, the neoplasms are grouped neither according to their histological grade (Kiel classification) nor according to their clinical aggressiveness (International Working Formulation). However, the histological grade is considered a prognostic factor which enters into the description of each disease entity. Hodgkin's disease, now more appropriately termed Hodgkin lymphoma, comprises nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphomas of nodular sclerosis, mixed cellularity, lymphocyte-depleted and lymphocyte-rich subtype. For practical purposes this minireview disregards the description of myeloid, macrophage/histiocytic, dendritic cell and mast cell disorders. Furthermore, the present paper is restricted to those lymphoid tumours that are not already identically described in the REAL classification, in order to focus on what is really new in the WHO classification.

A SOUTHWEST ONCOLOGY GROUP PERSPECTIVE ON THE REVISED EUROPEAN-AMERICAN LYMPHOMA CLASSIFICATION

In recent years several new morphologic entities and a new classification system, Revised European-American Lymphoma Classification (REAL), have been proposed which affect the nomenclature and classification of lymphoid malignancies. This article reviews some of the features of the more common new entities, places these entities in immunologic context, explores the clinical utility of these entities, and provides a working clinical organization to the names.