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
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:
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.
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.