International Lymphoma Study Group Research Articles

BRACHIAL PLEXOPATHY AND CARDIAC TAMPONADE: AN UNCOMMON PRESENTATION OF DIFFUSE LARGE B-CELL MEDIASTINAL LYMPHOMA

TOPIC: Disorders of the Mediastinum TYPE: Medical Student/Resident Case Reports INTRODUCTION: Primary mediastinal large B-cell lymphoma (PMLBCL) is a unique type of B-cell lymphoma probably arising from a putative thymic medulla B-cell. PMLBCL comprises seven percent of diffuse large B cell lymphomas (2.4 percent of all non-Hodgkin lymphomas). There is a female predominance and a median age at diagnosis in the third to fourth decade. In some cases, the presentation can be an oncological emergency with locally invasive anterior mediastinal mass arising from thymus causing external pressure on the heart and the surrounding structures. PMLBCL presenting as brachial plexopathy with cardiac tamponade is an uncommon presentation. CASE PRESENTATION: 37-year-old female, who presented to the ED with a 3-week history of left- sided neck pain and progressive swelling with associated 2 weeks history of numbness in the left wrist, tingling sensation in her 4th and 5th finger with weakness on the same side. She endorsed exertional dyspnea and palpitation that worsened over the last 4 days prior to presentation.On examination she was noted to have left sided neck mass about 6 x 8cm, firm, nontender, non-mobile with extension below the clavicle. Tachycardic with Muffled heart sounds and grade 3/6 Systolic Ejection Murmur at right upper sternal border. Flexion deformity with reduced sensation of the left 4th and 5th finger. Chest X-ray shows cardiomegaly with widened mediastinum. Computed Tomography scan was suggestive of anterior mediastinal mass. Echocardiogram done showed large pericardial effusion with Echocardiographic findings consistent with tamponade physiology.She underwent pericardiocentesis with 700 cc of serosanguinous fluid drained and subsequently had CT guided biopsy of the anterior mediastinal mass. Biopsy report showed high grade B-cell lymphoma with Immunostain showing lymphoma cells positive for CD20, BCL6 and negative for BCL2, CD5. She was diagnosed to be High grade stage IIB, commenced on chemotherapy and completed 6 cycles of DA-EPOCH-R.Left hand weakness and neuropathy resolved following chemotherapy. Repeat CT chest and Echocardiogram showed near resolution of the anterior mediastinal mass and pericardial effusion respectively. DISCUSSION: The majority of patients with primary diffuse large B-cell mediastinal lymphoma are symptomaticat the time of diagnosis. Patients present with a locally invasive anterior mediastinal massoriginating in the thymus, with frequent airway compromise and superior vena cava (SVC)syndrome. Symptoms related to the compression or invasion of local structures (i.e., cough, dyspnea, dysphagia, hoarseness) are common, systemic B-symptoms occurs in about 47% ofpatients, brachial plexopathy is an uncommon presentation. CONCLUSIONS: PMBL is a tumor of young adults who present with a rapidly proliferating tumor. At diagnosis, the tumor is usually limited to the mediastinum, therefore high index of suspicion is required in making the diagnosis. REFERENCE #1: A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 1997 Jun1;89(11):3909-18. PMID: 9166827 REFERENCE #2: Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas:clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma ClassificationProject. J Clin Oncol. 1998 Aug;16(8):2780-95. doi: 10.1200/JCO.1998.16.8.2780. PMID:9704731. REFERENCE #3: van Besien K, Kelta M, Bahaguna P. Primary mediastinal B-cell lymphoma: a review ofpathology and management. J Clin Oncol. 2001 Mar 15;19(6):1855-64. doi:10.1200/JCO.2001.19.6.1855. PMID: 11251018. DISCLOSURES: No relevant relationships by Regine Afable, source=Web Response No relevant relationships by Ibrahim Omore, source=Web Response No relevant relationships by Farbod Raiszadeh, source=Web Response

Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies.

The cytotoxic T-cell and natural killer (NK)-cell lymphomas and related disorders are important but relatively rare lymphoid neoplasms that frequently are a challenge for practicing pathologists. This selective review, based on a meeting of the International Lymphoma Study Group, briefly reviews T-cell and NK-cell development and addresses questions related to the importance of precise cell lineage (αβ-type T cell, γδ T cell, or NK cell), the implications of Epstein-Barr virus infection, the significance of anatomic location including nodal disease, and the question of further categorization of enteropathy-associated T-cell lymphomas. Finally, developments subsequent to the 2008 World Health Organization Classification, including the recognition of indolent NK-cell and T-cell disorders of the gastrointestinal tract are presented.

Update on classification of lymphomas

Lymphomas constitute approximately 5% of all malignant neoplasms of the head and neck. They are divided into two major subtypes, Hodgkin's lymphomas and non-Hodgkin's lymphomas, depending on the presence or absence of Reed-Sternberg cells. Controversy in the classification of lymphomas dates back to the first attempts to formulate such classifications. Much of this controversy arose from the assumption that there must be a single guiding principle, a gold standard for classification. Earlier classifications of lymphomas were based on the morphology, treatment response, and survival and some were based on cell lineage and differentiation. The International Lymphoma Study Group (I.L.S.G.) developed a consensus list of lymphoid neoplasms, which was published in 1994 as the Revised European-American Classification of Lymphoid Neoplasms (REAL). The classification was based on the principle that a classification is a list of real disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features and there cannot be a single gold standard.

Lymphoma classification and the tools of our trade: an introduction to the 2012 USCAP Long Course

The 2012 USCAP Long Course ‘Malignant Lymphomas—Building on the Past, Moving to the Future’ began with an introduction to lymphoma classification over the last half century and a discussion of our current diagnostic armamentarium, together with a look toward the future. The Rappaport classification, originally published in 1956, was a morphologic classification with few categories. The early 1970s saw a great and tumultuous revolution in the field with the publication of two functional lymphoma classifications that related the malignant lymphomas to the cells of the normal immune system—the Lukes/Collins classification from the United States and the Kiel classification from Professor Lennert and the European Lymphoma Club. With discord abounding, the NCI working formulation, published in 1982, satisfied some but was a step back to a morphologic-based classification. In 1994, the International Lymphoma Study Group published the REAL classification, which reflected state-of-the-art practice for that time, and was shortly followed by preparations for the modern World Health Organization (WHO) classification published in 2001 and revised in 2008. The WHO classification, created by hematopathologists working with the advice and consent of clinical hematologist/oncologists, recognizes numerous distinct entities, defined based on their histopathological, immunophenotypical, molecular/cytogenetic and clinical features. The classification requires use of a multiparameter approach to lymphoma diagnosis although we still rely heavily on histopathology. Immunophenotypical studies, whether using paraffin section immunohistochemistry and/or flow cytometry, are also critical in almost all circumstances. Molecular/cytogenetic techniques that are constantly changing have an increasingly important role, even if not always required. The full impact of next-generation sequencing is yet to be felt but we are beginning to catch a glimpse of what is in our future. Finally, one must not forget the great importance of clinical data in arriving at a diagnosis that best serves the patient, our ultimate goal.

An Unusual Pulmonary Mass With Mediastinal Invasion and Multiple Intrapulmonary Nodules in a 52-Year-Old Man

An Unusual Pulmonary Mass With Mediastinal Invasion and Multiple Intrapulmonary Nodules in a 52-Year-Old Man

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.

Follicular lymphoma of the extrahepatic bile duct mimicking cholangiocarcinoma

We report a case of a 33-year old man who presented with symptoms and signs of an acute biliary tract obstruction with jaundice and abdominal pain. Diagnostic imaging studies revealed a biliary stricture of the hepatic confluence, and a mass at the hepatic hilum which obstructed the extrahepatic bile duct from the outside. At laparotomy, there was 3-cm-size nodule at the hilum which presented with a rubbery consistency. We performed extrahepatic bile duct resection and right and left hepaticojejunostomy. Histological examination of the resected specimen revealed follicular lymphoma, which consisted of medium cleaved follicle-like cells, grade 1 of 3 according to the revised European-American classification of lymphoid neoplasms proposed by International Lymphoma Study Group. Postoperative follow-up of more than 1 year has been completely uneventful, without any symptoms or signs of disease recurrence. This is the second case report of follicular lymphoma of the extrahepatic bile duct.

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.

Cranial Nerves Paralysis Revealing Two Cases of Histiocytic Sarcoma.

Pathological, immuno-chemical and cytogenetic studies have allowed in the two last decades to distinguished real histiocytic sarcoma (HS) from hemophagocytic activation syndrome secondary to lymphoma, Langerhans histiocytosis, benign histiocytic proliferation or dendritic cells tumor. Strict immunophenotypic criteria have been defined by the International Lymphoma Study Group (ILSG) in 2002. Published cases are rare as most cases have been reclassified into lymphoma. Clinical presentation is bad known. We report two cases with initial neurological involvement. Case 1: A 32-year-old black patient was admitted in hospital in May 2002 for rapidly progressive blurred vision of the right eye, bilateral deafness and marked gait disturbance. Physical examination demonstrated hepatosplenomegaly, ataxia, bilateral deafness and loss of visual acuity mainly in the right eye. MR imaging of the brain demonstrated white matter abnormalities. Cerebrospinal fluid (CSF) study showed mild protein level (0.43g/l), low glucose level and 16/mm3 histiocytic cells. Bone marrow biopsy, liver biopsies, bone scan, thoracic CT scan were all normal. A diagnostic splenectomy was performed. Pathological study was consistent with HS. Despite high dose systemic chemotherapy containing cytosine-arabinoside, methotrexate, methylprednisolone and intrathecal therapy, he developed kidneys' tumoral infiltration. After two courses of cladribine the patient died with intra cranial hypertension symptoms. Bone marrow smears demonstrated tumoral infiltration. Case 2: A 63-year-old white female patient presented in november 2002 a one month history of paresthesias in the left trigeminal nerve. CSF study demonstrated high protein level (0.5 g/l), normal glucose, increased cells (21/mm3). Brain MR imaging showed nodular lesions of both trigeminal nerves and protuberance. After 5 days course of intravenous high dose methylprednisolone her state worsened. A left trigeminal nerve chirurgical biopsy was performed. Histologic study diagnosed HS. Abdominal and thoracic CT scan and bone marrow biopsy were normal. Despite high dose chemotherapy including ifosfamide, cytosine-arabinoside and methotrexate, she died with progressive neurological symptoms. Pathological study performed on spleen (case1) and on trigeminal nerve (case2) demonstrated diffuse infiltration by non-cohesive large cells with abundant eosinophilic cytoplasm. Hemophagocytosis in tumoral cells were noted in the 2 cases. Immunophenotyping asserted HS (Table1). Cytogenetic study performed in bone marrow of patient 1 demonstrated clonal complexe karyotype. We report the first 2 cases of HS with initial cranial nerve involvement and complete immunophenotypic study. Only 5 other cases with neurological involvement, either cerebral or spinal cord mass are described to date. The two cases fulfil the WHO and ILSG criteria for HS and immunostaining for CD163 (hemoglobin scavenger receptor), the most histiocyte specific marker, is strongly positive in the two cases. Clonality is demonstrated in case1.Table 1HMB45,CD20CD3,CD30, ALKCD35CD68CD1alysosymeCD 163case 1−−−+−−+case 2−−−+−weak+

Prevalence and characterization of anaplastic large cell lymphoma and its association with Epstein-Barr virus in Pakistani patients

Anaplastic large cell lymphoma (ALCL), CD30+, is a subtype of T-non-Hodgkin's lymphoma (NHL). Its most common form is a classical systemic type that involves multiple nodal and extranodal sites. In this study, morphologic, immunohistologic, and genetic studies were performed on ALCL cases in Pakistani patients. The median age of the patients in this study was 45 years (age range: 5–70 years), with a male to female ratio of 3.4:1. Thirty-seven (37) patients were diagnosed to have Ki-1 (CD30+) ALCL, which constituted 2% of all NHLs and 12.6% of all T-NHLs, over a period of 11 years (January 01, 1992–December 31, 2002). The tumors were of either T- or null-cell type with constant (100%) expression of CD30 (Ki-1). The majority of the cases (89.2%) expressed EMA, whereas 40.5% of the cases expressed either CD45 (LCA), CD45RO (UCHL1), or ALK. The mean age of ALCL patients with null-cell phenotype was 33.8 years as compared to those with T-cell phenotype having a mean age of 36.3 years. Out of the 37 cases diagnosed as ALCL, amplifiable DNA was isolated from 28 cases, which were further assessed for T-cell clonality for T-cell receptor (TCR)-β, γ, and immunoglobulin heavy chain (IgH) for the FR2 and FR3 regions. The polymerase chain reaction (PCR) technique demonstrated clonal rearrangement of the TCR β, γ, and IgH regions in 15 (53.6%), 11 (39.3%), and 2 (7.1%) ALCL cases, respectively, out of 28 cases. Association of Epstein-Barr virus (EBV) was noted in seven out of 28 cases (25%) of ALCL by PCR, whereas ISH for EBV-encoded nuclear RNA-1 (EBER-1) detected the presence of EBV in two (16.7%) out of 12 cases, where one was T-cell ALCL and the other null-cell ALCL. Immunostaining for LMP-1 could not be performed, because tissue material was not available. In conclusion, our study demonstrated that the prevalence of ALCL in Pakistan is comparable to that reported for some of the Asian communities and by the International Lymphoma Study Group and that EBV could be partly responsible for the pathogenesis of ALCL.

Clinical Characteristics and Pathological Classification of Non-Hodgkin's Lymphoma in Kuwait. Results of a Collaborative Study with the International Lymphoma Study Group (ILSG)

Kuwait was chosen by the International Lymphoma Study Group (ILSG) as one of the sites attending in the project on "Clinical characteristics and pathological classification of non Hodgkin's lymphoma (NHL) in the developing countries". The Kuwait study involved 206 cases of NHL, diagnosed, staged and treated in the Kuwait Cancer Control Center (KCCC). All cases were reviewed and reclassified independently by the pathologists of KCCC and the International Lymphoma Study Group (ISLG) using the latest World Health Organization (WHO) classification of neoplastic disease of the hematopoietic and lymphoid tissues. Immunophenotyping as to B- or T-cell was documented in all cases. Three main pathological entities (diffuse large B-cell lymphoma, follicular lymphoma, peripheral T-cell lymphoma) were identified and studied thoroughly. The intense cooperation between experts of the ISLG and pathologists of the KCCC proved that the WHO classification was fully reproducible in Kuwait. The high incidence of extranodal lymphomas (53%) observed in the KCCC may not be due to special ethnic or environmental conditions in Kuwait but rather be due to a selection of patients coming to our center.

Eleven-year experience of low grade lymphoma in Korea (based on REAL classification).

Low grade lymphomas are malignancies of predominantly small lymphocytes that typically have long median survival periods due to low proliferative rates. It is considered an indolent disease, but patients with low grade lymphoma can almost never be cured with conventional treatment. New low- grade lymphoma entities have been classified by the International Lymphoma Study Group (ILSG) and are also categorized into the Revised European American Lymphoma (REAL) classification. The REAL classification utilizes a multiparameter definition of clinico-pathologic and biologic entities. According to this classification, we investigated the incidence, various clinical characteristics, treatment outcome and prognostic factors of low grade lymphoma. Many clinical characteristics of low grade lymphoma in Korea differed from those of Western countries, especially in the incidence, therapeutic outcome and prognostic factors. In Korea, although the general incidence of low grade lymphoma is relatively low, the relative number of mucosa-associated lymphoid tissue lymphoma (MALToma) is very high, and the overall survival rate is better than that reported of Western countries. Thus, further investigation on treatment outcome and prognosis of low grade lymphoma entities, other than mucosa- associated lymphoid tissue lymphoma, are warranted.

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.

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.

Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases.

Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.

The World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting--Airlie House, Virginia, November, 1997.

Since 1995, the European Association of Pathologists and the Society for Hematopathology have been developing a new World Health Organization (WHO) classification of hematologic malignancies. The classification includes lymphoid, myeloid, histiocytic, and mast cell neoplasms. The WHO project involves ten committees of pathologists, who have developed lists and definitions of disease entities. A Clinical Advisory Committee (CAC) of international hematologists and oncologists was formed to ensure that the classification will be useful to clinicians. A meeting was held in November 1997 to discuss clinical issues related to the classification. WHO has adopted the 'Revised European-American Classification of Lymphoid Neoplasms' (REAL), published in 1994 by the International Lymphoma Study Group (ILSG), as the classification of lymphoid neoplasms. This approach to classification is based on the principle that a classification is a list of 'real' disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one 'gold standard'. The WHO classification has applied the principles of the REAL classification to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. The CAC meeting, which was organized around a series of clinical questions, was able to reach a consensus on most of the questions posed. The questions and the consensus are discussed in detail below. Among other things, the CAC concluded that clinical groupings of lymphoid neoplasms were neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors such as the international prognostic index (IPI). The experience of developing the WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies.

The World Health Organization Classification of Hematological Malignancies Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997

Since 1995, the European Association of Pathologists and the Society for Hematopathology have been developing a new World Health Organization (WHO) classification of hematologic malignancies. The classification includes lymphoid, myeloid, histiocytic, and mast cell neoplasms.The WHO project involves 10 committees of pathologists, who have developed lists and definitions of disease entities. A Clinical Advisory Committee of international hematologists and oncologists was formed to ensure that the classification will be useful to clinicians. A meeting was held in November 1997 to discuss clinical issues related to the classification. The WHO has adopted the Revised European-American Classification of Lymphoid Neoplasms, published in 1994 by the International Lymphoma Study Group, as the classification of lymphoid neoplasms. This approach to classification is based on the principle that a classification is a list of “real” disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one “gold standard.” The WHO classification has applied the principles of the Revised European-American Classification of Lymphoid Neoplasms to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities.The Clinical Advisory Committee meeting, which was organized around a series of clinical questions, was able to reach a consensus on most of the questions posed. The questions and the consensus are discussed in detail in this article. Among other things, the Clinical Advisory Committee concluded that clinical grouping of lymphoid neoplasms was neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors such as the international prognostic index.The experience of developing the WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world. This should facilitate progress in the understanding and treatment of hematologic malignancies.

The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997.

Since 1995, the European Association of Pathologists (EAHP) and the Society for Hematopathology (SH) have been developing a new World Health Organization (WHO) classification of haematological malignancies. The classification includes lymphoid, myeloid, histiocytic and mast cell neoplasms. The WHO project involves 10 committees of pathologists, who have developed lists and definitions of disease entities. A Clinical Advisory Committee (CAC) of international haematologists and oncologists was formed to ensure that the classification will be useful to clinicians. A meeting was held in November 1997 to discuss clinical issues related to the classification. The WHO has adopted the 'Revised European-American Classification of Lymphoid Neoplasms' (REAL), published in 1994 by the International Lymphoma Study Group (ILSG), as the classification of lymphoid neoplasms. This approach to classification is based on the principle that a classification is a list of 'real' disease entities, which are defined by a combination of morphology, immunophenotype, genetic features and clinical features. The relative importance of each of these features varies among diseases, and there is no one 'gold standard'. The WHO classification has applied the principles of the REAL classification to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. The CAC meeting, which was organized around a series of clinical questions, was able to reach a consensus on most of the questions posed. The questions and the consensus are discussed in detail below. Among other things, the CAC concluded that clinical groupings of lymphoid neoplasms was neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumour type, if applicable, and clinical prognostic factors such as the international prognostic index (IPI). The experience of developing the WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of haematological malignancies.

Lymphoma classification – from controversy to consensus: The R.E.A.L. and WHO Classification of lymphoid neoplasms

Controversy in lymphoma classification dates back to the first attempts to formulate such classifications. Over the years, much of this controversy arose from the assumption that there had to be a single guiding principle--a 'gold standard'--for classification, and from the existence of multiple different classifications. The International Lymphoma Study Group (I.L.S.G.) developed a consensus list of lymphoid neoplasms, which was published in 1994 as the 'Revised European-American Classification of Lymphoid Neoplasms' (R.E.A.L.). The classification is based on the principle that a classification is a list of 'real' disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one 'gold standard'. In some tumors morphology is paramount, in others it is immunophenotype, a specific genetic abnormality, or clinical features. An international study of 1300 patients, supported by the San Salvatore Foundation, was conducted to determine whether the R.E.A.L. Classification could be used by expert pathologists and had clinical relevance. Since 1995, the European Association of Pathologists (EAHP) and the Society for Hematopathology (SH) have been developing a new World Health Organization (WHO) Classification of hematologic malignancies, using an updated R.E.A.L. Classification for lymphomas and applying the principles of the R.E.A.L. Classification to myeloid and histiocytic neoplasms. A Clinical Advisory Committee (CAC) was formed to ensure that the WHO Classification will be useful to clinicians. The International Lymphoma Study showed that the R.E.A.L. Classification could be used by pathologists, with inter-observer reproducibility better than for other classifications (> 85%). Immunophenotyping was helpful in some diagnoses, but not required for many others. New entities not specifically recognized in the Working Formulation accounted for 27% of the cases. Diseases that would have been lumped together as 'low grade' or 'intermediate/high grade' in the Working Formulation showed marked differences in survival, confirming that they need to be treated as distinct entities. Clinical features such as the International Prognostic Index were also important in determining patient outcome. The WHO Clinical Advisory Committee concluded that clinical groupings of lymphoid neoplasms was neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors such as the International Prognostic Index (IPI). The experience of developing the WHO Classification has produced a new and existing degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies.

World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.

The European Association of Hematopathologists and the Society for Hematopathology have developed a new World Health Organization (WHO) classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell neoplasms. Ten committees of pathologists developed lists and definitions of disease entities. A clinical advisory committee (CAC) of international hematologists and oncologists was formed to ensure that the classification would be useful to clinicians. The CAC met in November 1997 to discuss clinical issues related to the classification. The WHO uses the Revised European-American Lymphoma (REAL) classification, published in 1994 by the International Lymphoma Study Group, to categorize lymphoid neoplasms. The REAL classification is based on the principle that a classification is a list of "real" disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one gold standard. The WHO Neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. At the CAC meeting, which was organized around a series of clinical questions, participants reached a consensus on most of the questions posed. They concluded that clinical groupings of lymphoid neoplasms were neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors, such as the International Prognostic Index. The WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies.