Lymphadenopathy and lymphoma

ANATOMY OR SYSTEM AFFECTED: Lymphatic system

DEFINITION: Lymphadenopathy, or enlarged lymph nodes, refers to any disorder related to the lymphatic vessels of lymph nodes; lymphoma is a group of cancers consisting of unchecked multiplication of lymphatic tissue cells

CAUSES: Disease, allergies, infection, viruses, genetic factors

SYMPTOMS: Enlarged lymph nodes, fatigue, mild fever, night sweats, weight loss

DURATION: Varies from acute to long-term

TREATMENTS: Vary; may include antibiotics, radiation therapy, chemotherapy, bone marrow transplantation

Causes and Symptoms

The lymphatic system consists of a large complex of lymph vessels and groups of lymph nodes. The lymph vessels include a vast number of capillaries that collect fluid and dissolved proteins, carbohydrates, and fats from tissue fluids. The lacteals of the intestinal villi are lymph vessels that serve to absorb fats from the intestine and transport them to the bloodstream.

Lymph nodes are found throughout the body but are concentrated most heavily in regions of the head, neck, armpits, abdomen, and groin. Nodes function to filter out foreign materials, such as bacteria or viruses, that make their way into lymphatic vessels.

The sizes of lymph nodes vary; some are as small as a pinhead, some as large as a bean. In general, they are shaped much like kidney beans, with an outer covering. They consist of a compartmentalized mass of tissue that contains large numbers of B and T lymphocytes as well as antigen-presenting cells (APC). The lymphatic circulation into the lymph nodes consists of a series of entering, or afferent, vessels, which empty into internal spaces, or sinuses. A network of connective tissue, the reticulum, regulates the lymph flow and serves as a site of attachment for lymphocytes and macrophages. The lymphatic circulation leaves the node through efferent, or exiting, vessels in the lower portion of the organ, the hilum.

Among the functions of lymph nodes are those of the immune response. B and T lymphocytes tend to congregate in specialized areas of the lymph nodes: B cells in the outer region, or cortex, and T cells in the underlying paracortex. When an antigen is presented by an APC, T- and B-cell interaction triggers B-cell maturation and proliferation within the germinal centers of the cortex. The result may be a significant enlargement of the germinal centers and subsequently of the lymph node itself.

Lymphadenopathy, or enlarged lymph nodes, may signify a lymphoma, or cancer of the lymphatic system. More commonly, however, the enlarged node is secondary to other phenomena, usually local infections. For example, an ear infection may result in the entrance of bacteria into local lymphatic vessels. These vessels drain into regional nodes of the neck. The result is an enlargement of the nodes in this area, as an immune response is carried out.

Enlarged nodes caused by infections can generally be easily differentiated from those caused by malignancies. Infectious nodes are generally smaller than two centimeters in diameter, soft, and tender. They usually occur in areas where common infections occur, such as the ears or the throat. Malignant lymph nodes are often large and occur in groups. They are generally firm and hard, and they often appear in unusual areas of the body (for example, along the diaphragm). To confirm a malignancy, a biopsy of material may be necessary.

Infectious nodes can also be caused by diseases such as infectious mononucleosis, tuberculosis, and acquired immunodeficiency syndrome (AIDS). Lymphadenopathy syndrome (LAS), a generalized enlargement of the lymph nodes, is a common feature of the prodromal AIDS-related complex (ARC).

Since lymphadenopathy can be caused by any immune proliferation in the germinal centers, allergy-related illnesses may also cause enlargement of the lymph nodes. Consequently, immune disorders such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and even hay fever allergies may show enlarged nodes as part of their syndromes.

As is the case for any cell in the body, cells constituting the lymphatic system may undergo a malignant transformation. The broadest definition of these lymphoproliferative diseases, or lymphomas, can include both Hodgkin disease and Hodgkin lymphomas, in addition to acute and chronic lymphocytic leukemias (ALL and CLL). With the understanding of, and ability to detect, specific cell markers, it is possible to classify many of these lymphomas on the basis of their cellular origin. Such is the case for ALL, CLL, Burkitt lymphoma, and many other forms of non-Hodgkin lymphomas. The cell type that ultimately forms the basis for Hodgkin disease remains uncertain.

Hodgkin disease is a malignant lymphoma that first manifests itself as a painless enlargement of lymphoid tissue. Often, this is initially observed in the form of swollen lymph nodes in the neck or cervical region. Occasionally, the victim may exhibit a mild fever, night sweats, and weight loss. Untreated, the disease spreads from one lymphatic region to another, resulting in diffuse adenopathy. An enlarged spleen (splenomegaly) is a common result. As the disease spreads, other organs such as the liver, lungs, and bone marrow may be involved.

The disease is characterized by the presence of a characteristic cell type, the Reed-Sternberg cell. These cells appear to be of macrophage origin, with multilobed nuclei or multiple nuclei. They may also be present in other lymphatic disorders, but their presence is considered to be indicative of all cases of Hodgkin disease. The precise relationship of the cell to the lymphoma is unclear, but some researchers in the field believe that the Reed-Sternberg cell is the actual malignant cell of the disease. The other infiltrative cells present in the node, including many B and T lymphocytes, may simply represent the reaction to the neoplasm. This interpretation, however, has been disputed.

Lymphoma staging is a system of classifying lymphomas according to the stage of development of the disease. Staging is important in that the prognosis and basis for treatment are in part determined by the stage of disease. Characterizing the form of Hodgkin disease, therefore, involves two forms of classification. The first is a four-part classification based on the histology or cell type (Rye Conference classification). This scheme is based on the proportion of Reed-Sternberg cells, ranging from their being “hard to find” to their being the predominant type. The prognosis becomes less favorable as the proportion of these cells increases.

Clinical staging, like that based on histology, is a four-part classification scheme (it is actually six parts, since stage 3 can be divided into subclasses). In this system, classification is based upon the extent of spread or extralymphatic involvement. For example, stage 1 features the involvement of a single lymph node region or a single extralymphatic site. Stage 4 involves multiple disseminated foci. Early-stage disease is more easily treated and has a better prognosis than late-stage disease.

Non-Hodgkin lymphomas (NHLs) represent a multitude of malignant disorders. Unlike Hodgkin disease, they frequently arise in lymphatic tissue that is not easily observed, such as in the gastrointestinal tract, tonsils, bone, or central nervous system. They have a tendency to spread rapidly, with malignant cells being released into the bloodstream early in the disease. Consequently, by the time diagnosis of NHL is made, the disease has often spread and the prognosis may be poor.

Though the etiology of most forms of NHL remains unknown, certain characteristics are evident in some forms of these diseases. For example, a portion of chromosome 14 is elongated in about 60 percent of NHL patients. Nearly one-third of patients with NHLs of B-cell origin demonstrate a chromosomal translocation, often involving a piece of chromosome 14 being translocated to chromosome 18. Though the relationship of these changes to disease is unclear, one can surmise that chromosomal defects play at least some role in the development of some forms of these disorders.

At least two forms of NHL are either caused by viruses or related to their presence: Burkitt lymphoma and adult T-cell lymphoma/leukemia. Burkitt lymphoma, which was first described by Denis Burkitt in central Africa, is a B-cell tumor that occurs primarily in children. It is generally manifested as a large tumor of the jaw. This type of lymphoma is associated with early infection by the Epstein-Barr virus, or EBV (also the etiological agent of infectious mononucleosis). The relationship of the disorder to the virus remains unclear, and EBV may be either a specific cause or a necessary cofactor.

Specific chromosomal abnormalities are also associated with Burkitt lymphoma. In 75 percent of cases, a translocation from chromosome 8 to chromosome 14 is evident, while in most other cases, a portion of chromosome 8 is translocated to either chromosome 2 or chromosome 22. Each of these translocations involves the transfer of the same gene from chromosome 8, the c-myc gene. The site to which the c-myc is translocated is in each instance a region that encodes protein chains for antibody production, proteins that are produced in large quantities. The c-myc gene product normally plays a role in committing a cell to divide. By being translocated into these specific regions, the c-myc gene product is overproduced, and the B cell undergoes continual replication.

Approximately 80 percent of NHL tumors are of B-cell origin; the remainder are primarily of T-cell origin. Those lymphomas that arise within the thymus, the organ of T-cell maturation, are called lymphoblastic lymphomas. Those that originate as more differentiated and mature T cells outside the thymus include a heterogeneous group of diseases (for example, peripheral T-cell lymphomas and Sézary syndrome). Often, by the time of diagnosis, these disorders have spread beyond the early stage of classification and have become difficult to treat.

Treatment and Therapy

Treatment and other means of dealing with lymphadenopathy depend on the specific cause. In the case of lymph node enlargement that is secondary to infections, treatment of the primary cause is sufficient to restore the normal appearance of the node. For example, in a situation in which nodes in the neck region are enlarged as the result of a throat infection, antibiotic treatment of the primary cause—that is, the bacterial infection—is sufficient. The nodes will resume their normal size after a short time.

Dealing with lymph node enlargement caused by lymphoma requires a much more aggressive form of treatment. There are many kinds of lymphomas, which differ in type of cell involvement and stage of differentiation of the involved cells. The manifestations of most lymphomas, however, are similar. In general, these disorders first present themselves as painless, enlarged nodes. Often, this occurs in the neck region, but in many forms of NHL, the lymphadenopathy may manifest itself elsewhere in the lymphatic system. As the disease progresses, splenomegaly (enlarged spleen) and hepatomegaly (enlarged liver) may manifest themselves. Frequently, the bone marrow becomes involved. If the enlarged node compresses a vital organ or vessel in the body, immediate surgery may be necessary. For example, if one of the of the heart is compressed, the patient may be in immediate, life-threatening danger. Treatment generally includes radiation therapy and/or chemotherapy.

As is true for lymphomas in general, Hodgkin disease is found more commonly in males than in females. In the United States, it occurs at a rate of 3.2 per 100,000 population per year for men and 2.4 per 100,000 for women, with the American Cancer Society estimating that 8,570 cases would be diagnosed in 2024, with an estimated 910 deaths. The cause of the disease is unknown, though attempts have been made to assign the Epstein-Barr virus to this role.

Hodgkin disease has an unusual age incidence. The age-specific incidence exhibits a bimodal curve. The disease shows an initial peak among young adults between fifteen and thirty years of age. The incidence drops after age thirty, only to show an additional increase in frequency after age fifty. This is in contrast to NHL, which shows a sharp increase in incidence only after age forty-five. The reasons are unknown.

As noted earlier, the staging of Hodgkin disease is important in determining methods of treatment; the earlier the stage, the better the prognosis. Patients in stage 1 (single node or site of involvement) or stage II (two or more nodes on the same side of the diaphragm involved, or limited extralymphatic involvement) have a much better prognosis than patients in stages 3 and 4 (splenic or disseminated disease). Prior to the mid-1960s, a diagnosis of Hodgkin disease was almost a death sentence. The development of radiation therapy and chemotherapy has dramatically increased the chances for survival; long-term remission can be achieved in nearly 70 percent of patients, and the “cure” rate may be higher than 90 percent with early detection. In part, this has been the result of understanding the progression of the disease (reflected in the process of staging) and utilizing a therapeutic approach to eradicate the disease both at its current site and at likely sites of spreading.

Radiation therapy is the treatment of choice for patients in stages 1 and 2; spreading beyond local nodes is still unlikely in these stages. The body is divided into three regions to which radiation may be delivered: The mantle field covers the upper chest and armpits; the para-aortic field is the region of the diaphragm and spleen; and the third field is the pelvic area. For example, a patient manifesting lymphadenopathy in a single node in the neck region may undergo only “mantle” irradiation. As noted above, with early detection, such treatment is effective 90 percent of the time (based on five-year disease-free survival).

Beyond stage II, a combination of radiation therapy and chemotherapy treatment is warranted. A variety of chemotherapy programs have been developed, the most common of which is known by the acronym MOPP (nitrogen mustard/Oncovin/procarbazine/prednisone). With combined radiation therapy and chemotherapy, even stage III disease may go into remission 60 to 70 percent of the time, while 40 to 50 percent of stage IV patients may enter remission. In general, therapy takes six to twelve months.

Non-Hodgkin lymphomas represent a heterogeneous group of malignancies. Eighty percent are of B-lymphocyte origin. The wide variety of types has made classification difficult. The most useful method of classification for clinical purposes is based on the relative aggressiveness of the disease, low-grade being the slowest growing, followed by intermediate-grade and high-grade, which is the most aggressive.

NHLs often arise in lymphoid areas outside the mainstream. For example, the first sign of disease may be an abdominal mass or pain. Fever and night sweats are uncommon, at least in the early stages. Consequently, once the disease is manifested, it is often deep and widespread. Because the disorder is no longer localized by this stage, radiation therapy by itself is of limited use. For comparison, nearly half of Hodgkin disease patients are in stage I at presentation; not quite 15 percent of NHL patients are in stages 1 and 2. Consequently, treatment almost always involves extensive chemotherapy.

A variety of aggressive forms of chemotherapy may be applied. These may include either single drugs such as alkaloids (vincristine sulfate) and alkylating agents (chlorambucil) or combination programs such as that of MOPP. Low-grade types of NHL are frequently slow growing and respond well to less aggressive forms of therapy. Low-grade NHL patients often enter remission for years. Unfortunately, the disorder often recurs with time and may become resistant to treatment; remission may occur in 50 percent of the patients, but only about 10 percent survive disease-free after ten years. High-grade lymphomas are rapidly growing, and the prognosis for most patients in the short term is not good. Those patients who do achieve remission with aggressive therapy, however, often show no recurrence of disease. As many as 50 percent of these persons may be “cured.” The difference in prognosis between low-grade and high-grade disease may relate to the characteristics of the malignant cell. A rapidly growing cancer cell may be more susceptible to aggressive therapy than a slow-growing cancer and more likely to die as a result. Thus, if a patient enters remission following therapy, there is greater likelihood that the cancer has been eradicated.

Perspective and Prospects

What was likely Hodgkin disease was first described in 1666 as an illness in which lymphoid tissues and the spleen had the appearance of a “cluster of grapes.” The disorder was invariably fatal. In 1832, Thomas Hodgkin published a thorough description of the disease, including its progression from the cervical region of the body to other lymphatic regions and organs. The unusual histological appearance of the cellular mixture characteristic of Hodgkin disease was noted during the nineteenth century. It was early in the twentieth century, however, that Dorothy Reed and Karl Sternberg described the cell that is characteristic of the disorder: the Reed-Sternberg cell. As noted earlier, the number and proportion of such cells are the bases for the classification of the disease.

Two forms of non-Hodgkin lymphoma are known to be associated with specific viruses: Burkitt lymphoma (BL) and adult T-cell leukemia (ATL). BL was described by Denis Burkitt, who studied the pattern of certain forms of lymphomas among Ugandan children during the late 1950s. He noted that nearly all cases were found in children between the ages of two and fourteen, and noted that most cases in Africa were found in the malarial belt. Burkitt suspected that a mosquito might be involved in the transmissions of BL. Though no link has been found with arthropod transmission, the idea that BL might be associated with a viral agent bore fruit. In 1964, Michael Epstein and Yvonne Barr reported the presence of a particle in BL tissue that resembled the herpes virus. The Epstein-Barr virus was eventually linked to BL, though the specific role played by the virus remains elusive.

Adult T-cell leukemia was first noted in Japan during the 1970s. Japanese scientists observed that the majority of NHLs there were of T-cell origin and exhibited a similar clinical spectrum. The disease was later observed in the Caribbean basin, the southeastern United States, South America, and central Africa. In 1980, Robert Gallo isolated the etiological agent, the human T-cell lymphotrophic type I virus (HTLV-I).

The treatment of Hodgkin disease represents one of the few success stories in dealing with cancers. In addition, some forms of NHL—notably, Burkitt lymphoma—respond well to treatment. The prognosis for most patients with NHL, however, is less than optimal. In addition, the specific causes of most NHL syndromes are not known. Those with which a virus is linked may, in theory, be prevented by means of vaccination. The etiological agents or factors associated with the development of other forms of lymphomas remain elusive.

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