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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 more highly structured organs. 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 and the polymerase chain reaction to uncover
clonal rearrangements of immune system genes or other genetic, 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 actual biologic diseases with immunologic and genetic qualities out of the confusing mass of lymphoid malignancies, the REAL/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.
Many 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 intermediate and high grade ones on the other. These 2 groups of NHLs 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's 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 NHLs. 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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