Historical landmarks in an understanding of the lymphomas

Abstract

The knowledge that a group of closely related neoplasms, the lymphomas, originated in the mutation of protoncogenes in a single lymphocyte resulted from several principal antecedent discoveries: (1) the description of the anatomy of the lymph nodes and the description of the white matter of the spleen by Malpighi, (2) the definition of the lymphatic system by Thomas Hewson to include the lymph nodes, spleen, thymus, and the lymphatic vessels, (3) the development of techniques to biopsy and prepare tissue for microscopic examination and the application of the compound microscope to the examination of normal and pathological lymphatic tissue, (4) the description by Thomas Hodgkin of the clinical histories and gross postmortem findings of seven patients in whom prominent lymphadenopathy with splenomegaly was identified as a specific morbid condition. (5) Subsequently, (non-Hodgkin) lymphoma (originally called lymphosarcoma) was described, probably first by the great surgeon and pathologist, Billroth, and subsequently by Kundrat, a student of Billroth, and others. The application of microscopic anatomy began to define the histopathology of subsets of lymphoma, notably Hodgkin’s disease and follicular lymphoma, initially. (6) Radiation therapy was applied to treatment of Hodgkin’s disease very soon after Röntgen’s description of X-rays. About 45 years later, chemotherapy was introduced for both Hodgkin’s disease and lymphoma, as a result of the synthesis of nitrogen mustard compounds, developed to permit laboratory studies of solutions rather than gases, such as sulfur mustards, originally developed for gas warfare in World War I, and further explored in anticipation of their use in World War II. (7) Advances in histopathological descriptions lead to the appreciation of the numerous histological types of lymphoma and subsets of Hodgkin’s disease. (8) The development of imaging procedures led to their use in determining the extent of the disease in the lymphoid system, which influenced the approach to therapy. Curative therapy for Hodgkin’s disease first resulted from extended field radiation, including apparently uninvolved neighboring regions, and, later, from multidrug chemotherapy regimens. (9) Although most types of lymphoma are the result of de novo (endogenous) mutations and gene rearrangements, infectious agents, e.g., Helicobacter pylori and human lymphocytotropic virus 1, have been established as causative agents, uncommonly. Other viruses (e.g., Epstein-Barr, hepatitis C) have been associated with lymphoma, but it is unclear how they play a role in the neoplastic-transforming events. (10) Advances in histopathology, immunology, cytoimmunochemistry, cytogenetics, and genetics contribute to the modern classification of the lymphomas. This chapter describes this sequence of events and details the progression of discoveries that have led to the modern concept of lymphoma, its classification, and therapeutic advances. Where space permits, the advances in scientific concepts permitting these discoveries are discussed.