The Lymphoid Neoplasm PDF

Preface to the third edition

The third edition of this book differs considerably from the second edition - most obviously with respect to its title, which reflects the fact that the subject matter is no longer confined to the non-Hodgkin lymphomas. There are two main reasons for this. The first is the recognition that the distinction between lymphoid leukemia and lymphoma is artificial, although this was the first distinction made among lymphoid neoplasms at the beginning of the modern era when clinical features and gross pathology were the only diagnostic tools available (histopathology slowly emerged throughout the nineteenth century). It is now clear that the terms leukemia and lymphoma (in the context of lymphoid neoplasia, at least) do not indicate separate disease categories or ‘taxons,' (to steal a term more often used in the classification of living organisms). Essentially identical diseases by morphology, immunophenotype and genetic criteria, as described in the pages of this book, may sometimes be manifested as leukemias (involvement of the bone marrow and often peripheral blood by neoplastic cells) and sometimes as lymphoma (i.e., no evidence of such involvement, although this may depend upon the sensitivity of the technique used). Moreover, bone marrow or peripheral blood involvement may be absent at presentation, but emerge prior to therapy or at relapse.

The second reason for the change in the title of the book relates to the term ‘non-Hodgkin lymphoma.' It was not until the very late 19th /early 20th century, that the distinction at a microscopic level between Hodgkin's disease and other lymphomas was made. Indeed, the recognition of the ‘granulomatous' appearance of some tumors of lymph nodes, if not the first evidence of microscopic heterogeneity, was, initially at least, the most reproducible. The observations of Sternberg and Reed must have given considerable impetus to the emerging era of histological classification but while the microscopic appearance rapidly became the preeminent taxonomic tool, its power to discriminate between specific disease entities improved rather slowly until its dramatic augmentation by the introduction of immunophenotyping and molecular genetic methods such as in situ hybridization (preceded of course by the development of the field of cytogenetics) in the last few decades. Modern techniques, however, also led to the demonstration that Hodgkin lymphoma, like many other lymphoid neoplasms, is derived from the B-lymphocyte lineage. This meant that the obvious histological watershed between Hodgkin lymphoma and all other lymphomas could no longer be considered as of primary importance to classification. Hodgkin lymphoma, like a number of other lymphoid neoplasms of B-cell lineage is of germinal center origin, and although, unlike the vast majority of other B-lineage neoplasms, its tumor cells fail to express surface immunoglobulin and, for the most part, other B cell markers, it represents no more and no less a category than many other neoplasms, such as mantle cell lymphoma or anaplastic large cell lymphoma, both of which, like Hodgkin lymphoma, have several histological and molecular variants. In short, just as leukemia and lymphoma do not define discrete groups of neoplasms, there appears to be no scientific reason for separating lymphomas into Hodgkin and non- Hodgkin subtypes.

It is clear, then, that neither the leukemia/lymphoma, not the Hodgkin/non-Hodgkin lymphoma dichotomies are indicative of basic subdivisions within the broad spectrum of lymphoid neoplasia in the sense that precursor versus mature, or B-cell lineage versus NK/T-cell lineage are. Moreover, in this modern era, when treatment approaches and the prognosis for different categories of lymphoid neoplasms differ so much, there is little value in designating a tumor a non-Hodgkin lymphoma - although in the early days of the development of specific approaches to the radiation therapy of Hodgkin lymphoma a ‘two category' classification approach probably was justifiable. Nonetheless, the term ‘non-Hodgkin lymphoma' has a lengthy heritage compared to other negatively defined categories such as non-Burkitt's lymphoma, or nonlymphoblastic lymphoma, which may explain why it has taken on the mantle of a legitimate subdivision and remains a widely used term in contrast to the other ‘nonlymphomas,' that have largely faded from use. In general, saying what something is not does not constitute a diagnosis (how useful, for example, would the term ‘non-reptile' be in biology?) excepting when one is faced with a true dichotomy (e.g., ALK+ and ALK- anaplastic large cell lymphoma). Moreover, the implication that a dichotomy exists in the absence of supportive evidence could lead to a negative impact on the construction of a true framework for classification - as, for example, may have been the case with respect to the division of lymphomas into nodular and diffuse subtypes. We should not, of course, be too critical of pioneer taxonomists who, by today's standards, had extremely limited equipment and reagents with which to work. In spite of everything, including the several false conclusions that largely resulted from the speculation that filled the evidentiary vacuum, their persistence in continuously attempting to improve upon existing tools, coupled to insights from other disciplines (especially immunology - see below), eventually laid the foundation upon which modern diagnosis is based. But equally, as improvements in classification are made, we should continue to eliminate terms that have the capacity to mislead, as has been done in the case, for example, of reticulum cell sarcoma and histiocytic lymphoma (although some will always strenuously argue against such a view, presumably for nostalgic reasons). For better or for worse, The Non-Hodgkin's Lymphomas has become The Lymphoid Neoplasms, and Hodgkin lymphoma has been given no more and no less a position in lymphoma taxonomy than any other entity or group of closely related entities. The new title has had the additional repercussion that the book now includes diseases that were not covered (or only partially covered) in previous editions - particularly those that most frequently present as leukemia (e.g., the acute and chronic lymphoid leukemias), as well as Hodgkin lymphoma itself and plasma cell tumors. The intent has been to ensure as comprehensive a coverage of the neoplastic diseases of lymphoid cells as possible.

A second major change in the book is the inclusion of a section on immunobiology. Lymphoid neoplasms are now known to arise, or at least, to have the phenotype (whether identified by monoclonal antibodies or by molecular profiling of one kind or another), of discrete or closely related lymphocyte populations. Such populations may represent steps in the process of development into mature lymphoid cells (ontogeny), or alternatively, elements of the immune response, although, with occasional exceptions, it remains unknown whether such pathological immune responses (or partial immune responses) have been precipitated by antigen or not. Knowledge of immunological differentiation or activation pathways therefore provides a basis for the understanding of the pathogenesis of lymphoid neoplasia, at least at a cellular level. Coupled to an understanding of both the normal molecular pathways involved in lymphocyte differentiation and activation and the molecular genetic lesions that are present in such pathways in lymphoid neoplasms, we have reached a point in history in which the broad elements of the pathogenetic process (and in some individual neoplasms, rather precise details) are known. While many oncologists may not wish to attempt to understand lymphomas at the level of their immunobiology, being more concerned with the specific diagnosis and predictors of treatment response, an understanding of pathogenesis, which implies knowledge of immunobiology, is not only inherent to the pathology of any given neoplasm, but may provide clues to causation – something which is presently based exclusively on epidemiology but which may someday be legible in the runes of the molecular lesions. And who knows what new insights into therapy may derive from a sufficient knowledge of molecular pathogenetic pathways? While the inhibition of the expression of a single pathogenetically relevant gene could provide major therapeutic benefit (although a pathogenetic role is not essential for effective targeting), as with combination chemotherapy the best results are likely to be achieved by targeting more than one gene or more than one molecular pathway. In any event, it seems highly likely that the more that is known about pathogenesis, the more opportunities will be identified for developing targeted approaches to therapy.

In the light of these considerations, it is inevitable that the book covers the molecular lesions of lymphoid neoplasms in considerable detail. Histology is now only one of the many characteristics used to define individual neoplasms and their variants. Indeed, based on the new entities included in the latest (2008) WHO classification, we are rapidly moving into an era when molecular characteristics may even take precedence over other taxonomic tools - whether at the level of single genes/proteins (such as ALK in the context of anaplastic large cell lymphoma) or, when molecular profiling data is available, as is increasingly the case, at the level of molecular signatures. An increasingly molecular approach to classification also has advantages in identifying previously unrecognized relationships between neoplasms - e.g., the similarities discerned in the molecular profiles of Hodgkin disease and mediastinal B cell lymphoma - one that makes sense in light of the fact that both neoplasms tend to arise in thymic B cells. Whether or not such insights will have therapeutic value remains to be seen. Unfortunately, molecular approaches to classification do not always result in sharp definitions of entities, in part because lymphoid differentiation pathways must, by their very nature, include what we perceive as intermediate stages, and in part because the pathogenetic molecular abnormalities, while to a considerable extent neoplasm-specific, are not necessarily identical in a given disease, while the same, or a similar, abnormality may be found in different diseases. This is because some of the most basic molecular pathways - those involved with cell proliferation, differentiation and programmed cell death - may be influenced in a broad range of neoplasms, while different lesions in the same molecular pathway, or involvement of partially redundant molecular pathways could lead to similar functional end-points relevant to the neoplastic state. Intermediate or atypical categories will continue to make life difficult for taxonomists, although perhaps less so for therapists who may, increasingly, as targeted therapy takes hold, require the mere presence or absence of a therapeutic target to decide on treatment.

One pragmatic problem faced by this increasingly molecular approach is the problem of gene nomenclature. Genes have often been discovered in more than one laboratory, such that they may have several quite different designations. In addition, the symbols for genes and proteins have undergone significant evolution. Now that international nomenclatures for symbols and gene names, as well as standard procedures for naming new genes have been developed (e.g., by the Human Genome Organization Gene Nomenclature Committee, HGNC) we have attempted to use these internationally recognized symbols and names for genes throughout the book, although acceptance of international nomenclature has not been as high in the scientific community as might be hoped. Inevitably, therefore, some authors have used former names, or aliases for some genes, while new symbols for other genes have yet to be widely accepted and are uncommonly used by anyone. To the extent possible, the editors have converted obsolete names and aliases to approved names, although one major exception to this is the genes involved in regulation of the cell cycle - particularly inhibitors of cell cycle progression. These genes have multiple aliases (alternative symbols) which are still much more widely used than the HUGO approved or official names. CDKN1A, for example, is the approved symbol for a gene officially named cyclin-dependent kinase inhibitor 1A (p21, Cip1) whose multiple aliases include CIP1, P21, p21CIP1, WAF1 and one or two more. The gene whose official symbol is CDKN2A and approved gene name cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4), has many aliases (ARF, p14, p16, p19, INK4a, to name but a few) as well as at least three splice variants coding for separate proteins, two of which are structurally similar (p16 and p19) and inhibit CDK4 kinase, while the third (ARF) contains an alternate first exon, is transcribed from an alternate reading frame, and functions as a stabilizer of p53. Splice variants are designated by the appendices-v1, v2 etc., by HGNC. Sometimes, different genes have been given the same symbols - e.g., both CDKN2A and CDKN2D have been referred to as p19. Given these complexities, it seemed counterproductive to use approved or official symbols for this subset of genes, but rather to stick to the designations used by the authors. Wherever possible, however, we have used the recommended convention that human gene symbols are written in capitalized italic letters, while only the first letter is capitalized in mouse genes (which are also italicized) and capital letters are used for both human and mouse proteins. Punctuation (e.g., hyphenation) is not used. Gene names are neither capitalized nor italicized. Appropriate nomenclature is also followed to the extent possible for Drosophila and nematode genes. Readers may wish to refer to the many gene catalogues such as that of the HGNC or the National Center for Biotechnology Entrez gene data base for lists of gene symbols, aliases, names and obsolete terms. In gene catalogues, incidentally, it is standard practice not to write gene symbols in italics.

As in the past, this book is intended for a wide audience, but in spite of its size, it cannot possibly address all relevant topics in great detail. It is designed to provide overviews of each general area, followed by more detailed information on the pathology and clinical characteristics of specific diseases. Although this approach has inevitably resulted in some duplication, it is hoped that it has also led to increased readability of individual chapters and avoided the need for frequent cross referencing. Books, of course, now find themselves in strong competition with electronic media, and suffer from the disadvantage of the rapid pace of advance, particularly in the area of pathogenesis with which standard publishing procedures cannot keep pace. Journals, particularly of the electronic kind, can make new material available in a matter of days or weeks. While standard books cannot compete with this, for the foreseeable future at least, books will continue to have an important role in collecting a large amount of information in a logical sequence and in one place, providing a valuable starting point or conceptual framework - an idea of where we have come from and where we seem to be going - that may be much more difficult to achieve by surfing the internet. For this reason The Lymphoid Neoplasms should, even in this electronic era, be of value to a broad range of health professionals as well as to scientists more interested in pathogenesis, but for whom some understanding of the classification, clinical features and even treatment of lymphoid neoplasms is useful.

Finally, a book of this kind cannot possibly be written, or even edited by a single person. Indeed, some 198 authors have contributed to the text, and 9 section editors have taken on responsibility for different areas of the book. Without this large and eminent team, this book could not have come to fruition, and I sincerely thank them all - authors and editors alike - for their dedication and for their exceptional efforts.