Malignant Lymphomas

Georg Lenz, Laura Pasqualucci, Georg Lenz, Steven P. Treon

• Publisher: De Gruyter
• Year: 2016
• ISBN:
  9783110478808
• Edition: 1
• Topic: Medicine
• Subtopic: Hematology

This book is an up to date compendium on the biology and molecular pathogenesis of lymphomas, which represent malignant cancers of the lymphoid system. With its focus on the biology and genetic basis of these diseases, the book is of interest to basic scientists, biologists, clinical hematologists and pathologists as well as medical students. Different chapters will cover all major lymphoma subtypes, as well as chronic lymphocytic leukemia and selected less common lymphoma entities such as T-cell lymphomas and central nervous system lymphomas.

Wolfram Klapper

1Classification of lymphomas – past, present and future

1.1Classification – what is it good for?

“Classification is the language of medicine.” This is the first sentence in the World Health Organization (WHO) book on hematopoietic and lymphoid tumors. Classification is used as a technical term in many fields of science to describe the diversity of objects. Generally, classification describes how elements are recognized and differentiated. To translate this into medicine, classification describes the diagnostic criteria and the differential diagnosis – or simply the disease. Similar to the words in our language, the implicit meaning of a diagnosis as defined by a classification is a prerequisite for medicine, since it is the fixed point for treatment and the common ground for research.

Furthermore, the term classification implies that it helps us to understand the elements, as their arrangement reflects a scientific concept. Therefore, one should assume that the features used for medical classification should not only be based on clinical presentation and histopathology but should also include pathomechanisms. However, so far in the field of medicine, including the lymphoid tumors, molecular processes/pathomechanisms as an organizing principle have only been selectively applied in classifications. One example is the category of “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1” in which primarily the genetic aberrations and the pathomechanisms induced by them define the disease, but not the morphology or clinical presentation.

In biology, classification belongs to the field of taxonomy and its aim is to establish categories of species. This concept is based on the initial work by Carl Linnaeus (Carl von Linné), who established a classification of species based on shared physiological features. It was further developed by a number of scientists, including Charles Darwin, so as to also reflect the principle of common descent. An important feature of most biological classifications is that they are hierarchically organized. The hierarchy is based on morphological, biochemical or evolutionary relatedness. This hierarchy is reflected in the binomial nomenclature that, for example, is applied to bacterial species. Medical classifications of diseases, such as the classification of lymphoma, differ in several ways from biological classifications. The most obvious difference is the lack of a systematic nomenclature, since most disease names are not systematic but historical in nature. A second obvious difference between medical and biological classifications is the lack of a hierarchical regulatory principle. As described below, historical lymphoma classifications were searching for such a hierarchal principle of classification (e.g. by defining high- and low-grade lymphomas). Nevertheless, in the current WHO classification it is stated that there is currently no evidence for a hierarchical classification principle for hematopoietic and lymphoid neoplasms, and it regards it as a list of diseases that is arranged arbitrarily, e.g. by predominant clinical presentation. Later we will discuss the possibility that future developments in molecular-genetic analysis could in fact reveal such hierarchical principles based on molecular pathomechanisms that might profoundly change our current ideas as to how to classify lymphoid tumors.

1.2The history of lymphoma classification

The history of lymphoma classification is not a straightforward story. Nevertheless, it has been described both compellingly and in detail [1–3]. This current chapter provides only a brief overview of the developments in lymphoma classification from the 19th century to the present.

Why look at the history at all? First, understanding the history of lymphoma classification also helps to understand current classifications. The origins of disease definitions and the nomenclature used for the majority of lymphomas are historical in nature and are primarily based on morphological features. Since then, entities have continuously been either confirmed, redefined or subdivided on the basis of phenotypic features, especially molecular-genetic ones. Second, knowing the history of lymphoma classification will help us to appreciate a worldwide consensus. Many scientists and pathologists who developed our current lymphoma classification started their career at a time before the current WHO classification. This experience made them aware of the importance of worldwide consensus in classification. However, it should not be taken for granted that future classifications will also represent a worldwide consensus. An increasing number of molecular-genetic tests in diagnostics and disease definition may not be available in many areas of the world. This is a challenge that future WHO classifications will have to face.

1.2.119th century: Tumors of lymphoid cells and their relation to leukemia

Most of the literature dates the beginning of lymphoma classification to the work of Thomas Hodgkin in 1832 [4]. Hodgkin described a progressive lymphadenopathy in patients that he distinguished from tuberculosis, the most frequent cause of lymph node swelling at that time, and also from other known infectious diseases and metastasis. Although Hodgkin did not draw definite conclusions about the neoplastic nature of the disease, he did certainly describe a lymphoma entity, which we now refer to as Hodgkin lymphoma. In the 19th century and until the first decades of the twentieth century, the origin and the functional properties of lymphocytes and the lymphoid tissues were largely unknown. After the first description of a leukemia in 1845, Rudolf Virchow reported tumors of lymphoid tissue that seemed to be composed of cells similar to the leukemias he had been observing and used the term “lymphosarcoma” to describe these “aleukemic leukemias.” In the second half of the 19th century, Theodor Billroth used the term “malignant lymphoma”, and from then on the term began to be used for most neoplasms of lymphoid cells (reviewed in [1]). However, at that time a large group of lymphomas were not recognized as lymphoid in nature and were referred to as “reticulum cell sarcoma”. This name was derived from the generally accepted hypothesis that lymphocytes are small differentiated cells that develop from large (undifferentiated) cells, the latter being part of the reticulohistiocytic system, a system of cells that are phagocytically active like histiocytes and that form the fundamental structure of lymphoid tissue. The possibility of a reverse differentiation from small lymphocytes to large cells was denied. As a consequence of this incorrect assumption about the origin of lymphocytes, most lymphomas in the group of large cell lymphomas, which are composed of large blasts (e.g. diffuse large B-cell lymphoma), were called “reticulum cell sarcoma” at that time. It took until the 1960s–1970s before it was proved that “reticulum cell sarcomas” are in fact tumors derived from lymphoid cells (reviewed in [1] and [3]).

1.2.220th century: Description of individual diseases and historical lymphoma classifications

The first half of the 20th century was characterized by the description of individual entities. The entities that were characterized at this time included the follicular lymphoma described by Gall in 19405 (previously described by Brill and Symers [6, 7] as “giant lymph follicle hyperplasia“). Similarly, extranodal neoplasms and lymphoid neoplasms involving the bone marrow, multiple myeloma, Waldenström’s macroglobulinemia, mycosis fungoides, and Sézary syndrome were characterized as entities in the mid-1940s [1]. Probably one of the most fascinating discoveries was the identification of Burkitt lymphoma in African children by the surgeon Dennis Burkitt, a prime example of how precise clinical observation provides deep insights into the pathogenesis of a disease [8]. Despite the fact that the definitions of the diseases were mostly the individual achievements of one or two researchers and were only based on clinical or morphological observations, they all turned out to be very valid and all of these entities, with modified diagnostic criteria, are still part of the current WHO classification. Nevertheless, in addition to the descriptions of individual lymphoma entities, researchers in the 20th century attempted to establish a systematic classification of lymphoid tumors for two reasons. First, the individually described entities did not cover the whole spectrum of neoplasms observed in lymphoid tissue, and second, they wanted to apply the principles of scientific classification from biology (see above) to human cancer. These historical classifications were published between 1934 and 1942, with the most relevant one being that by Robb-Smith and Gall and Malloy (reviewed in [1] and [3]). In contrast to the general opinion, these classifications were complex and consisted of a large number of entities [3]. The major deficiencies of these historical classifications were (i) ambiguous terminology (that did not always clearly distinguish between reactive and neoplastic conditions), (ii) incompleteness (not all tumors of the lymphatic system were covered), (iii) poor reproducibility (due to their nature as single-center concepts, poor illustration and complex criteria) and (iv) neglect of the biology of the lymphatic system (even becoming contradictory with growing knowledge of the function of the lymphatic system).

1.2.3The second half of the 20th century: Modern lymphoma classifications, controversy and consensus

A milestone in the development of lymphoma classification was that published by Henry Rappaport in 1956. This classification system overcame most of the deficits of the historical classification in that it used clear terminology (separating reactive from neoplastic conditions), was comprehensive (most of the neoplasms of the lymphoid tissue could be assigned to one of the categories) and was finally reproducible by other pathologists (due to the excellent illustrations in the publication). The initial version of the Rappaport classification distinguished two growth pattern of lymphomas, diffuse and nodular (“follicular”) and five major entities defined by the cytology occurring in any of the two growth patterns: “lymphocytic type, well differentiated,” “lymphocytic type, poorly differentiated”, “mixed type (lymphocytic and reticulum cell),” “reticulum cell type” and “Hodgkin’s type.” The classification was developed in a large cohort of clinically well-characterized lymphoma patient samples at the Armed Forces Institute of Pathology. Understandably, this classification became widely accepted among pathologists in the United States. The success of this classification scheme was enhanced by the prognostic value of the categories, with diffuse lymphomas being more aggressive in their clinical course than nodular lymphomas. However, in the late 1960s and 1970s one feature of the Rappaport classification became more and more controversial among hematopathologists: the lack of accordance with the biology of the lymphatic system. It were two milestone findings about lymphocyte biology in the sixties that challenged the historical and the Rappaport classifications. First, phytohemagglutinin (PHA) was shown to transform small nonproliferating lymphocytes into large proliferating blasts in cell culture, demonstrating that lymphoid cells possess the capability to differentiate from small to large cells and vice versa [9]. This cast doubt on the origin of lymphocytes from large reticulum cells. Instead, it appeared more likely that lymphoid cells also differentiate in vivo from small cells to blasts and vice versa, and that the large cells observed under the microscope in lymphoid tissue might, like the small lymphocytes, be lymphoid in nature. Consequently, tumors of lymphoid tissues composed of large cells might in fact be lymphomas rather than “reticulum cell sarcomas.” The second milestone publication that raised questions about the Rappaport classification was the discovery of two types of lymphoid cells: B cells and T cells. Experiments in chickens revealed that antibody producing plasma cells and cells of the follicles were derived from the bursa fabricii (B cells), whereas the periarteriolar lymphoid cells in the spleen seemed to be derived from the thymus (T cells) [10]. This concept of two types of lymphoid cells was soon transferred to human tissues and human lymphoma specimens, as immunoglobulins were detected in extracts of ...

Table of contents

• Cover
• Title Page
• Copyright
• Preface
• Acknowledgements
• Contents
• List of contributing authors
• 1 Classification of lymphomas – past, present and future
• 2 Mature B-cell development and the germinal center reaction
• 3 T-cell development
• 4 Mantle cell lymphoma
• 5 Follicular lymphoma
• 6 Genetics and molecular pathogenesis of marginal zone lymphoma
• 7 Burkitt lymphoma
• 8 Diffuse large B-cell lymphoma
• 9 The biology of primary mediastinal large B-cell lymphoma
• 10 Molecular pathogenesis of primary central nervous system lymphoma
• 11 Chronic lymphocytic leukemia
• 12 Waldenström’s macroglobulinemia
• 13 Molecular pathogenesis of multiple myeloma
• 14 Biology of Hodgkin’s lymphoma
• 15 Anaplastic large cell lymphoma
• 16 Molecular pathogenesis of malignant lymphomas: PTCL, NOS and AITL
• 17 Extranodal NK/T-cell lymphoma
• 18 Lymphomas associated with viral infection
• 19 Translating science into therapy of lymphoma
• Index