Die neue WHO Klassifikation der malignen Lymphome Nach „REAL” ein weiterer Schritt auf dem Weg zu einem weltweiten Konsens

For decades, rival classification systems for malignant lymphoma that were hardly even comparable have existed side by side: the Kiel Classification has so far been used in the German-speaking parts of Europe and the "Working Formulation" mainly in the USA. At the beginning of the 1990's it became possible to overcome this unsatisfactory situation, when pathologists in the Old and New Worlds joined forces to elaborate a new classification for lymphoma, the Revised European-American Lymphoma (REAL) Classification, based on current scientific data. One new feature is the absence of a malignancy grading that is applicable to more than one entity. The system centres on the definition of distinct lymphomatous diseases that can be diagnosed with a high degree of reproducibility. Morphological and clinical characteristics are used for diagnosis, but so, consistently, are immuno-phenotypical and molecular genetic ones. An international cooperative study has confirmed the high reproducibility and clinical practicability of this tentative classification system. An international panel of pathologists appointed by the World Health Organization has updated the REAL classification, which is expected to be published in the updated version in 2001 under the title New WHO Classification. The articles that follow are based on the new WHO classification.     

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

INTRODUCTION: 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. DESIGN: 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. RESULTS: 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). CONCLUSION: 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.     

Primary diagnosis and REAL/WHO classification of non-Hodgkin's lymphoma by fine-needle aspiration: cytomorphologic and immunophenotypic approach

The Revised European American lymphoma (REAL) and World Health Organization (WHO) classification of non-Hodgkin's lymphoma (NHL) relies on the constellation of cytologic, phenotypic, genotypic, and clinical characteristics of NHL. For the most part, the classification does not rely on architectural pattern for classification of neoplasms. This classification makes it possible to diagnose and classify lymphomas by fine-needle aspiration (FNA). In this study, we attempted to evaluate the accuracy of FNA in diagnosing and classifying NHL within the context of the REAL/WHO classifications. Cases included only those in which FNA was the primary diagnosis, followed by a surgical biopsy for confirmation. Flow cytometry (FCM) for phenotyping was carried out whenever material was available. Two groups of pathologists were identified. Group A consisted of pathologists with background training in cytopathology and/or hematopathology (three pathologists). Group B consisted of experienced surgical pathologists with no training in cytopathology and/or hematopathology (four pathologists). Seventy-four cases were included in the study. FCM phenotyping was performed in 53 cases (71%). Large cell lymphoma constituted 63% of the cases. The remaining lymphomas included Burkitt's, small lymphocytic, lymphoblastic, follicle center cell, Ki-1, mantle cell, marginal zone, and natural killer cell lymphoma. The diagnosis of lymphoma was rendered for all cases. The correct classification was seen in 63% of the cases. Classification was more accurate in immunophenotyped than in nonimmunophenotyped cases (84% vs 33%; P = 0.00004). Group A pathologists showed higher incidence of proper classification than group B (80% vs 56%; P = 0.046). The diagnosis and classification of NHL can be achieved in a large number of cases on FNA material. This accuracy can be increased if cytomorphologic criteria are established for different entities of NHL aided by FCM for phenotyping.     

Comments on the proposal of a new WHO classification of non-Hodgkin's malignant lymphoma

Newly proposed WHO classification of non-Hodgkin's malignant lymphomas (17) is based on the principles of the REAL classification. According to these principles, the classification represents a list of tumor disease entities, which have been accepted by clinical practice. The entities are defined by a multiparameter approach, which involves morphology, immunophenotype and genotype of the tumor cells, as well as clinical presentation and course of the disease requiring an appropriate therapy. All the categories of the WHO classification are briefly described, together with their relationship to the categories of the Kiel classification.     

Non-hodgkin lymphomas of the thyroid

Summary Twenty-nine cases of non-Hodgkin lymphomas presenting in the thyroid were classified according to Rappaport and Lukes and Collins. In the Rappaport classification there were 19 histiocytic, three mixed, five nodular PDL and two undifferentiated lymphomas. According to Lukes and Collins, 21 cases were follicular center cell lymphomas, eight were immunoblastic sarcomas. Cases classified as histiocytic according to Rappaport fell into the immunoblastic sarcoma and large cleaved or non-cleaved follicular center cell lymphoma groups. Immunoperoxidase studies confirmed the B cell nature of some of these cases.Survival was dependent on clinical stage, but this appeared to reflect the predominant cell type. Thus, follicular center cell lymphomas of the large non-cleaved type presented predominantly in stage I, while immunoblastic sarcoma was mostly stage IV and tumors of the small cleaved follicular center cell (FCC) type had excellent survival despite a usual presentation in stage IV. It is concluded that probably only lymphomas of the large non-cleaved FCC type and immunoblastic sarcoma (IBS) occur as true primary thyroid tumors, while small cleaved FCC lymphomas most likely represent systemic disease when first presenting in the gland. The median survival for large non-cleaved lymphomas in stages I and II was 31.5 months compared to 5.5 months for stage IV IBS. Although strongly suggestive these correlations were not statistically significant.An association with severe chronic lymphocytic thyroiditis was observed in 22 cases, including all cases of immunoblastic sarcoma as well as nine of ten large non-cleaved follicular center cell tumors.The prognostic significance of the Lukes-Collins classification is discussed in relation to these examples of thyroid lymphoma.Supported in part by grant CA 19449 National Institutes of Health.Dr. Maurer was supported by a scholarship of the Swiss and Zurich Cancer League.     

Overview of 2008 WHO Classification of Malignant Lymphoma

Lymphoma classification is now evolving. The 4th edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues was published in 2008, regarded as a revised and updated version of the 2001 3rd edition; an effort that involved 138 authors from 22 countries and two clinical advisory committees comprising 62 clinical specialists with expertise in lymphoid and myeloid disorders. New aspects of the 2008 WHO classification can be briefly summarized as follows: 1) a greater recognition of "early" lesions, i.e., an incipient neoplasm, e.g., in situ follicular lymphoma, has been incorporated; 2) age was highlighted as a defining feature of some neoplasms, e.g., EBV+ diffuse large B-cell lymphoma of the elderly, pediatric follicular lymphoma, and EBV+ T-cell lymphoproliferative diseases of childhood; 3) anatomical sites were noted as having an important impact on disease definitions; and 4) newly recognized borderline categories were listed on the basis of their biological overlap between diffuse large B-cell lymphoma and Burkitt lymphoma or classical Hodgkin lymphoma.     

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.     

The World Health Organization classification of lymphomas

The Revised European-American Classification of Lymphoid Neoplasms (REAL) classification has been validated by a multi-institutional study, and project data showed that it is both reproducible and clinically relevant. The new World Health Organization (WHO) Classification of Neoplastic Diseases of Hematopoietic and Lymphoid Tissues, as a joint project of the Society of Hematopathology and European Association of Hematopathologists, is an update of the REAL classification, with minor changes based on newly available information. We analyzed the incidence of different histological types of non-Hodgkin s lymphomas diagnosed in Zagreb University Hospital Center, which were reclassified according to the WHO classification. Furthermore, we present a conceptual grouping of lymphomas into four categories (indolent, aggressive, highly aggressive, and localized indolent).     

Overview of Gastrointestinal Lymphoproliferative disorders✰

Lymphoproliferative processes which occur in the gastrointestinal tract range from benign reactive processes such as follicular hyperplasia (rectal tonsil) to high grade malignant lymphomas and histiocytic sarcoma. The WHO Classification of Tumors: Digestive System Tumors, 5th Edition was published in 2019 and shows several impactful changes as compared to the 4th Edition published in 2010. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues 2017 also included detailed changes in hematopoietic neoplasms within the gastrointestinal tract. New entities or renamed hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma, duodenal-type follicular lymphoma, intestinal T-cell lymphoma, NOS and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. A brief overview of WHO classification of digestive tumors and WHO classification of tumors of hematopoietic and lymphoid tissue is discussed focusing on the changes in the most recent WHO texts. In depth discussions will be presented in other papers in this series.     

Clinicopathological analysis of 501 non-Hodgkin's lymphomas in Korea according to the revised European-American classification of lymphoid neoplasms

AIMS: The clinical relevance of the Revised European-American Classification of Lymphoid Neoplasms (REAL) is still debated. To test the clinical validity of the REAL classification in Korea, where the incidence of T-cell lymphoma is higher, we investigated the clinicopathological features of non-Hodgkin's lymphoma (NHL) from Korea Cancer Center Hospital. METHODS AND RESULTS: Five hundred and one patients with NHL were reclassified according to the REAL classification and clinicopathologically analysed. Immunophenotypically, B-cell lymphoma accounted for 67.9% and T- and NK-cell type for 30.5%. Approximately 48.5% of cases were forms of diffuse large B-cell lymphoma (DLBCL), while only 5.4% were follicular lymphoma. Peripheral T-cell lymphoma unspecified (PTCL-U; 10.8%) and angiocentric lymphomas (11.8%) comprised the majority of T-cell lymphomas. Most of the angiocentric lymphomas presented with localized nasal/nasopharyngeal or tonsillar primaries. All peripheral T-cell lymphomas (PTCL) showed a significantly low overall survival compared to DLBCL (P = 0.02, log rank). Overall survival rates for DLBCL and PTCL-U were also significantly different (P = 0.0043, log rank), though for DLBCL and angiocentric lymphoma there was no significant difference (P = 0.2142, log rank). Angiocentric lymphoma, however, was characterized by a shorter median survival time than DLBCL (54 months vs. 96 months). Among DLBCL patients according to the REAL classification, overall survival was significantly better in nonimmunoblastic type (intermediate-grade, WF-F,G) as compared to large cell immunoblastic type (high-grade, WF-H) (log rank, P < 0.001). The morphological distinction of the immunoblastic and nonimmunoblastic among DLBCL of the REAL classification bears significant prognostic relevance worthy of further consideration. CONCLUSION: We conclude that lineage assignment (T vs. B) in the REAL classification is a clinically important distinction, but that it is necessary to subdivide the broad category of DLBCL.     

Diagnostic pathology of lymphoproliferative disorders

The last 20 years have seen a dramatic change in the way we classify, and therefore diagnose, lymphoma. Two decades ago, the International Working Formulation enabled diagnosis and management on the basis of H&E sections alone, with no mandatory requirement for immunophenotyping, molecular studies or any other ancillary investigations. The concept of categorisation by 'clinicopathological entities' defined by clinical features, morphology, immunophenotype and more recently, genotype, began with the Kiel, and Lukes and Collins classifications in the late 1970s, becoming fully expressed in the REAL and subsequently WHO classifications. The current, multidisciplinary approach to categorisation adds significantly to the task facing the anatomical pathologist, since it requires distribution of biopsy material to all the appropriate specialised laboratories, the gathering of a range of cross-disciplinary information, the correlation of all diagnostic findings, deduction of a definitive diagnosis and, finally, integration of all the above into a single multiparameter report. In this review, we summarise the contemporary approach to the biopsy, diagnosis and reporting of lymphoproliferative disorders.     

Cutaneous lymphomas: which pathological classification?

Cutaneous lymphomas are rare and although some are a manifestation of systemic lymphoma, the majority arise primarily from the skin. These primary cutaneous lymphomas comprise predominantly T cell subtypes and represent a wide spectrum of disorders. Pathologists can currently choose to label these conditions according to three classifications (REAL, EORTC or WHO) but each has shortcomings. Nonetheless, in an attempt to unify the field, we would recommend that pathologists make every attempt to categorise these conditions according to the WHO classification. This classification can encompass all the conditions and aligns the cutaneous lymphomas with the broader systemic lymphoproliferative conditions.     

Absence of Epstein-Barr virus in anaplastic large cell lymphoma: a study of 64 cases classified according to World Health Organization criteria

The frequency of Epstein-Barr virus (EBV) in anaplastic large cell lymphoma (ALCL) has been controversial. The interpretation of previous studies is complicated by the use of nonuniform EBV detection methods and the inclusion of cases of CD30-positive diffuse large B-cell lymphoma and so-called "ALCL, Hodgkin-like," as defined in the Revised European-American Lymphoma classification scheme. In the current World Health Organization (WHO) classification system, both of these tumors are excluded from the ALCL category. Also, recently developed antibodies (eg, the antibody specific for PAX-5/B-cell-specific activator protein [BSAP]) provide new, sensitive tools for identifying neoplasms of B-cell lineage that can morphologically resemble ALCL. In this study we evaluated 64 cases of ALCL of T- or null-cell lineage, defined according to the WHO classification system, for the presence of EBV. All tumors were negative for B-cell antigens, including PAX-5/BSAP and CD20 or CD79a. The study group included 27 (42%) anaplastic lymphoma kinase (ALK)-positive (18 T-cell and 9 null-cell) and 37 (58%) ALK-negative (30 T-cell and 7 null-cell) tumors analyzed by in situ hybridization for EBV-encoded RNA (EBER) or immunohistochemistry for EBV-latent membrane protein type 1. All 64 cases were negative for EBV. We conclude, based on the current definition of ALCL in the WHO classification, there is no role for EBV in ALCL arising in Western patients. We suggest that published reports of EBV in a small proportion of ALCL cases in Western patients can be explained by the inclusion of tumors no longer considered to be in the current classification of ALCL, such as CD30-positive anaplastic tumors of B-cell origin.     

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.     

Peripheral T-cell lymphomas: an evaluation of reproducibility of the updated Kiel classification

Haematoxylin and eosin, and Giemsa stained sections from 100 peripheral T-cell lymphomas were examined blind on two occasions by four experienced haematopathologists in order to evaluate the inter- and intra-observer reproducibility of the updated Kiel classification for these malignancies. In all cases, the T-cell phenotype had been established previously in frozen section using a panel of monoclonal antibodies. Analysis by kappa statistics showed poor reproducibility, both overall and for most subtypes, with the exception of large cell anaplastic lymphoma. The distinction between low- and high-grade lymphomas was also unsatisfactory. These results indicate the need for improved precision in the definition of histological categories of peripheral T-cell lymphoma. The reproducibility of the update Kiel classification for peripheral T-cell lymphomas in its present form is inadequate.     

Some problems on the histopathological diagnosis of non-Hodgkin's malignant lymphoma -- a proposal of a new type.

A new classification for non-Hodgkin's malignant lymphoma is proposed as the one suited for the Lymphomas in Japan, which is to provide a new subtype "pleomorphic" for those more or less rapid-growing lymphomas of peripheral T-cell nature, along with another subtype lymphoblastic, after Nathwani et al. for those of central T-cell nature. The proposal is based on the result of the investigation by the Study Group for Histopathological Diagnosis on Malignant Lymphoma that (1) the presence of a significant number of T-cell lymphomas with peculiar "pleomorphism" is responsible for the very low reproducibility rate of histopathological diagnosis on the diffuse, mixed L&H type of Rappaport classification, and (2) the relative incidence of lymphoms as peripheral T-cell nature including the so-called adult T-cell leukemia is much higher in Japan than in the Western countries.     

Distribution of lymphomas in Poland according to World Health Organization classification: analysis of 11718 cases from National Histopathological Lymphoma Register project - the Polish Lymphoma Research Group study

Most national lymphoma registers rely on broad classifications which include Hodgkin and non-Hodgkin lymphomas (NHL), multiple myeloma and leukaemia. In Poland the National Histopathological Lymphoma Register project (NHLR) was implemented by hematopathologists in accordance with the 2008 WHO classification into haematopoietic and lymphoid tissues. We present the NHLR data and compare lymphoma distribution in Poland, Europe, as well as in North Central and South America. Records of 11718 patients diagnosed in 24 pathology departments from all over the country were retrieved and reclassified into indolent and aggressive lymphomas according to the 2008 revised WHO classification system. DLBCL (32.9%; 2587), CLL/SLL (31.84%; 2504) and MCL (9.04%; 711) were the three most frequent NHL. The ratio of indolent to aggressive NHL was 1.72; 63.25% (4809) to 36.25% (2794) of cases respectively. Multiple myeloma was less frequent as compared to the data from population-based national cancer register (13.32% vs. 28.94%). Major differences between NHLR and European and American data on NHL subtypes concered: higher incidence of aggressive B-cell lymphomas including DLBCL, lower FL and MALT incidence rate. The percentage of unclassified lymphomas in the study was minimal due to participation of hematopathologists.     

A proposal for classification of lymphoid neoplasms (by the International Lymphoma Study Group)

A new classification of lymphoid neoplasms, mostly based on existing terminology, is proposed by the International Lymphoma Study Group. The proposed classification was reached through a consensus of the members, despite their diverse backgrounds, and consists of a listing of currently recognized clinicopathological entities. These tumours are divided into three major categories: B-cell neoplasms, T-cell and postulated natural killer cell neoplasms, and Hodgkin's disease. The characterization of each entity is based on a synthesis of all available information. This concept departs from a purely morphological approach to lymphoma classification, which is considered to be inadequate, because many biologically distinctive lymphoma types can exhibit a broad and overlapping morphological spectrum. Some entities are provisional, pending further data to confirm that their recognition is reproducible. The salient clinicopathological features of each entity are summarized in this review.     

Morphological variability of lymphohistiocytic variant of anaplastic large cell lymphoma (former lymphohistiocytic lymphoma according to the Kiel classification)

According to the WHO classification, anaplastic large cell lymphoma (ALCL) is a distinct T-cell lymphoma entity with a number of morphological variants. The characteristic feature of lymphohistiocytic variant of ALCL according to the WHO classification is the abundance of histiocytes that exceed and mask the tumour cell population. In the current, study we reanalysed a historical series of 17 lymphomas, diagnosed as lymphohistiocytic lymphoma according to the criteria of the Kiel classification, with the presence of large purple macrophages (LPM) as the decisive finding for diagnosing this lymphoma subtype. We assessed the cellular composition of the tumour and correlated the results with the definition of lymphohistiocytic variant of ALCL given in the WHO classification. Although all cases in our cohort matched the criteria of ALCL according to the WHO, in 30% of the cases, the total amount of macrophages did not exceed the number of CD30-positive tumour cells. Our results indicate that the presence of LPM might be helpful to identify this subgroup of ALCL. Because the distinction of morphological subtypes of ALCL is of clinical relevance, improved criteria for subtyping ALCL are urgently needed that might include the presence LPM as one criteria.