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Introduction to Non-Hodgkin Lymphomas (NHLs)

LYMPHOMAS are clonal, uncontrollably expanding, destructive proliferations of lymphoid cells. Although 25-40% of NHLs arise extra-nodally, lymphoma cells are most at home in lymph nodes or other primary lymphoid organs, such as the spleen, thymus, Waldeyer's ring, or mucosa-associated lymphoid tissue. Lymphoid neoplasms that predominantly involve the bone marrow and peripheral blood are usually considered leukemias.
         Plasma cell malignancies such as multiple myeloma are certainly lymphoid; but somewhat arbitrarily they often discussed separately. Another distinct entity is Hodgkin lymphoma (HL), formerly known as Hodgkin disease. Because this B-cell neoplasm has some unique features, it, too, is discussed in its own section.

Diffuse large cell
Non-Hodgkin lymphoma, large cell
Hodgkin's disease
Hodgkin lymphoma
Multiple myeloma
Multiple myeloma
        Like carcinomas and sarcomas, NHLs more or less resemble the normal tissue from which they derive. What makes life for the diagnostician more difficult is that normal lymphocytes go through many stages as they develop from small, resting, inexperienced cells to larger, atypical-appearing, proliferating cells. The stimulus for this change, of course, is exposure to antigen. Malignancies may arise from lymphoid cells arrested at any of these stages. Morphologically, immunophenotypically, and genetically, the NHLs fall into categories with important therapeutic and prognostic associations.
         Both cytologically and architecturally, lymphoid proliferations may lack some of the morphological complexity seen in non-lymphoid organs with more obvious structure. In some cases, ancillary laboratory studies are necessary to determine if a lymphoid proliferation is benign or malignant or to identify its lymphoma subtype. These studies include:
  • Immunophenotyping to determine what kind of surface molecules are present on the cells.
  • Cytogenetics to identify any abnormal chromosomes.
  • Molecular diagnostics including Southern blotting, the polymerase chain reaction, and DNA/oligonucleotide microarrays to uncover clonal rearrangements of immune system genes or other subchromosomal evidence of malignancy.
        Many attempts have been made to classify NHLs. The most up-to-date and "scientific" classification is the World Health Organization (WHO) classification, which began to see light in the late 90's. It is an outgrowth and slight modification of the so-called REAL classification devised several years earlier. The WHO classification attempts to name and describe all lymphomas that are identifiable as biological entities using every tool in the hematopathologist's kit. It does not group lymphomas into prognostic categories; clinicians are expected to be familiar with their prognostic and therapeutic features. The WHO classification is described and used in this tutorial.
         In its goal of teasing out actual biologic diseases with immunologic and genetic qualities from the confusing mass of lymphoid malignancies, the WHO classification has replaced the Working Formulation, which is now some 20 years old. This classifcation was devised by examining 2 types of morphologic features of lymphomas: 1) the cytologic appearance of individual cells and 2) the follicular or diffuse nature of the proliferation. NHLs were named and then categorized as low grade, intermediate grade, or high grade. These categories have clinical significance that was demonstrated in an initial study of over a thousand cases.
        Some senior clinicians are accustomed to this classification and like the fact that each type of lymphoma is placed in a category with prognostic and therapeutic significance. Nonetheless the classification is limited because it is based only on morphologic findings. It is like diagnosing someone with "red-face disease", when the patient may have erythroderma, SVC compression, carcinoid syndrome, or sunburn.
         For the patient and clinician the most important distinction is between low grade NHLs on the one hand and higher grade ones on the other. These 2 forms of NHL have morphological, biological, and clinical differences that are discussed later.

Epidemiology:
In the United States the incidence of NHL in the last few years has been 17.9/100,00 in males and 11.5/100,000 in females. The table below shows estimated new case and death data in 2000 for NHL and HD in comparison to 2 other common cancers. At these rates, NHL is the fifth or sixth most common cause of both new cases of cancer and cancer deaths. The rate of NHL is twice as high in whites than in blacks.
Non Hodgkin's Lymphomas Hodgkin's Disease Prostate Cancer Breast Cancer
New Cases 54,900 7,400 180,400 184,200
Deaths 26,100 1,400 31,900 41,200

         Since the early 1970's the incidence of NHL has been increasing at the rate of 3-4% per year, which is impressive even after adjustment for the aging U.S. population and AIDS-related cases. The current aged-adjusted death rate for NHL is about 37% higher than it was 20 years ago, despite improved therapies that allow a 52% five-year survival rate compared to an earlier 41%. Only lung cancer in women and melanomas are increasing more rapidly. Unlike Hodgkin lymphoma, which has a bimodal age distribution, the incidence rate of NHL steadily and steeply increases after age 30 years, although childhood NHLs are not rare.
         The 1980s saw a startling incidence of NHL among patients with AIDS, who have a particularly high rate of high grade, extra-nodal, or central nervous system NHL. In this setting these types of lymphomas occur 60 times more frequently than in the general population. In one study the rate of NHL, measured from the initiation of zidovudine therapy, was 12% at 2 years and 29% at 3 years.
         NHLs are also very prevalent among patients with primary immunodeficiencies or with therapeutic immunosuppression such as transplantation regimes. In post-transplant patients, evidence of clonal Epstein-Barr virus infection can be found in most NHLs.
         Besides immunodefects, risk factors for NHLs are hard to identify. The second strongest risk factor is a family history of the disease, which entails a 3-4 times greater risk to relatives. A weaker and not completely persuasive factor is occupational exposure, especially to pesticides and herbicides. Finally a weak, inconsistent association has been unearthed between NHLs and hair dye use.

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