What is Hodgkin disease?
Malignant lymphomas are neoplasms of lymphoid tissues and are of two general categories: those related to Hodgkin (also known as Hodgkin’s) disease and others that are collectively called non-Hodgkin lymphomas. The lymphoid tissues represent the structural expressions of the immune system, which defends the body against microbes. This system is widely spread throughout the body, is highly complex, and interacts closely with other physiologic systems of the body—especially the mucosa that lines the airways and digestive tract, where there is direct exposure to environmental microbes and other foreign substances. The components of this system are aggregations of lymphocytes in the mucosal linings (such as tonsils and adenoids), lymph nodes, and the spleen. The components of the lymphatic system connect with one another via small lymphatic vessels. The lymph nodes, which are situated in anatomical regions all over the body, interconnect and drain centrally toward the great veins of the body. The cellular components of the immune system are the lymphocytes, also called immunocytes. These account for about 20 percent of blood cells; lymphocytes make up the bulk of the lymphoid tissue that makes up the lymphatic system. The blood cells have a finite life and are disposed of in the spleen, which is the largest lymphoid organ in the body.
There are two major functional immunologic classes of lymphocytes and several other subclasses. Nevertheless, all share similar morphologic appearance, being small round cells almost completely occupied by a round nucleus. The B lymphocyte (the B refers to its bone marrow derivation) can, under proper antigenic stimulation, transform and mature into a plasma cell, which is the cell in charge of producing antibodies. Antibodies are the protein products of the immune system that act by capturing and removing foreign substances, called antigens. The other major class of lymphocytes is the T lymphocyte (the T refers to its thymus derivation). T lymphocytes are of at least two major functional subclasses, which either help or suppress the B lymphocytes in their transformation into plasma cells; thus they are termed helper and suppressor T cells, respectively. Other cellular components of the immune system, cellular monocytes and macrophages, play an important role in carrying and transferring specific immunologic information between the various cellular components of the immune-lymphatic system. This, then, is a highly organized and complex system, with positive and negative biofeedback that maintains optimal, balanced proportions of all the cellular components that make up the system.
Hodgkin disease is a neoplasm of the lymphoid tissues that usually arises in lymph nodes, often in the neck, and has a varied histologic appearance characterized by the presence of Reed-Sternberg cells. The Reed-Sternberg cell is a giant cell having two nuclei that are situated in a mirror-image fashion. Treatment and prognosis in Hodgkin disease are determined by two parameters: the histopathologic classification, whereby the morphologic appearance is evaluated by the pathologist, and the clinical staging classification, whereby the extent of spread of the disease and its localization are determined by clinical studies. The pathology is studied by reviewing thinly cut sections of diseased lymph nodes removed from the patient. This study is most important for establishing a diagnosis of Hodgkin disease and ruling out other conditions that may closely simulate its clinical and/or pathologic features. At times, peer consultations are used to confirm the diagnosis.
Reed-Sternberg cells have a characteristic appearance and must be identified to make a diagnosis of Hodgkin disease. The pathologic classification of this disease, based on microscopic study, recognizes four different types, each with its own clinical implications regarding survival and prognosis. The classification is based on the relative dominance of lymphocytes when compared to the number of the neoplastic Reed-Sternberg cells. In the most favorable type, the lymphocytes predominate and Reed-Sternberg cells are sparse; this type is called lymphocyte predominance. In the worst type, the lymphocytes are very sparse and there are many more Reed-Sternberg cells and their variants; this type is called lymphocyte depletion. In between these two extremes are the mixed-cellularity type, in which there is an even mixture of lymphocytes and Reed-Sternberg cells, and nodular sclerosis, which forms nodules of fibrous scar tissue that surround the mixture of lymphocytes and Reed-Sternberg cells.
This classification has important prognostic implications. It correctly presumes that the neoplastic cells are the Reed-Sternberg cells and their variants, and that the lymphocytes are induced by the immune system to multiply and to fight the spread of the neoplastic cells. It follows that the more the process is successful, the better is the prognosis. Hence lymphocyte predominance carries a more favorable outlook than lymphocyte depletion, with mixed-cellularity types somewhere in between. Nodular sclerosis also carries a good prognosis. Other inflammatory cells are invariably mixed with the lymphocytes and Reed-Sternberg cells; these cells are also part of the body’s immune response against cancer cells.
The clinical staging classification of Hodgkin disease was formulated by a group of experts who met at a workshop in Ann Arbor, Michigan, in 1971. It is based on the proposition that the disease begins in a single group of lymph nodes (usually in the neck) and then spreads to the next adjacent group of lymph nodes, on the same side, before it crosses over to the other side of the body. The disease then advances farther across the diaphragm muscle, which separates the thorax from the abdominal cavity, and finally disseminates into the blood to involve the bone marrow and other distant sites. In this schema, stage I represents early stage, with involvement of only a single lymph node region, and stage II is the condition in which two or more such regions are involved on the same side of the diaphragm (that is, either above or below the diaphragm).
In the United States, Hodgkin disease is an uncommon neoplasm accounting for an estimated 9,000 cases. As of 2013, the disease accounts for approximately 1,300 deaths annually, according to American Cancer Society statistics. The incidence in the United States is slightly higher in males than females, and in whites than blacks. As of 2010, approximately 94,000 men and 88,000 women were alive who had histories of Hodgkin disease.
Hodgkin disease can occur at any age, although the highest peak incidence occurs in adolescents and young adults, and smaller peaks occur in the fifth and sixth decades of life. Most patients come to clinical attention because of painless, nontender, enlarged lymph nodes in the neck or armpits (above the diaphragm) or, less commonly, in the groin. In the young adult or adolescent, a mass in the chest may press against the airways to produce a dry, hacking cough and shortness of breath, which may be the patient’s first symptoms. Some patients may have anemia or severe itching. At times, especially when the disease is aggressive and extensive, the patient may have a fever, which may run for a few days and then disappear, only to recur after a week or two; there can also be night sweats and weight loss. These symptoms—fever, night sweats, and weight loss—indicate a less favorable prognosis. Younger patients and those with lymphocyte predominance and nodular sclerosis histologic types (favorable histologic types) tend to have limited disease—that is, stages I and II—found primarily above the diaphragm. Older patients and those with mixed-cellularity or lymphocyte depletion types are more likely to have extensive disease involving lymph nodes on both sides of the diaphragm (stage III) or even involving the liver, spleen, and bone marrow (stage IV).
When a patient with persistent lymph node enlargement seeks medical attention, a lymph node biopsy is usually made to make sure of the diagnosis. Other cancers that may simulate Hodgkin disease must be excluded, as well as a long list of benign conditions such as infectious mononucleosis and tuberculosis. A series of blood tests, x-ray and other imaging studies, and a bone marrow biopsy are done in order to evaluate the spread of disease and to assign the proper clinical stage. At times, even surgical exploration of the abdomen, with biopsies of abdominal lymph nodes, the liver, and the spleen, is done to assign an accurate stage of Hodgkin disease; this procedure is called staging laparotomy.
Modern cancer therapy has achieved its greatest triumph in the treatment of Hodgkin disease. The advent of a generally acceptable histopathologic classification, accurate staging, improved radiotherapy, effective chemotherapy, and supportive care, such as antibiotics and the transfusion of platelets, have contributed to the impressive 80 percent overall cure rate. The therapy is enhanced by an effective teamwork of medical experts in oncology, radiation therapy, surgery, pathology, and diagnostic radiology.
Because Hodgkin disease spreads in an orderly fashion through adjacent lymph node groups, effective high-dose radiation can be directed at affected lymph nodes and at their neighboring, uninvolved nodes. Irradiation, with a full dose of 3,500 to 4,000 rads in three to four weeks, can eradicate Hodgkin disease in involved nodes within the treatment field more than 95 percent of the time. In addition, extended-field irradiation of the adjacent uninvolved nodes is a standard practice used to eradicate minimal or early disease in these lymph nodes.
Stages I and II can be treated with radiotherapy alone by an extended field to include all areas above the diaphragm bearing lymph nodes (the axilla, neck, and chest), and in most cases the lymph nodes in the abdomen. Such treatment cures about 90 percent of patients. For patients in which the disease is found extensively in the chest, chemotherapy is added to the radiotherapy and results in prolonged, relapse-free survival in 85 percent of patients.
A variety of cytotoxic drugs (those that kill cells) are available to treat Hodgkin disease. Such drugs are similar to nitrogen mustard (which was once used in war) and are toxic to the body. It has been found that when more than one drug is used, each in a smaller dose, the toxicity can be reduced without diminishing effectiveness. Thus, combination chemotherapy has evolved. There are many effective regimens of combination chemotherapy that are called by the initials of the individual components; the most widely used is MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone). In stage III, chemotherapy with or without radiotherapy is used, depending upon specific variations within the stage, with cure rates achieved in 80 percent of patients. Even in stage IV disease, combination chemotherapy (particularly with MOPP) has produced a complete remission in about 65 percent of patients, with a cure rate of more than 50 percent.
Bone marrow transplantation , which is the intravenous infusion of normal marrow cells into the patient shortly after treatment in order to protect the patient from toxicity, has permitted the use of much higher doses of certain drugs. It allows the therapist to irradiate all the patient’s bone marrow, eradicating both “good” and “bad” cells, with the hope that the normal marrow cells that are infused will populate the bone marrow and grow there. Bone marrow transplantation has been successfully used mainly in young patients who were resistant to conventional chemotherapy.
Thomas Hodgkin of Guy’s Hospital in London was the first to recognize the disease that would bear his name. In 1832, he described the autopsy findings and clinical features of seven patients who had simultaneous enlargement of grossly diseased lymph nodes and spleens, and he considered the condition to be a primary affliction of these organs. This condition, he himself records, was vaguely outlined by Marcello Malpighi in 1665. Four years earlier than Hodgkin, David Craige had described the autopsy findings of a similar case. Subsequent histologic examination of tissues from Hodgkin’s original cases confirmed the disease in three of them. In 1865, Sir Samuel Wilks elaborated on the autopsy studies of similar cases and published the findings on fifteen patients, calling the condition Hodgkin disease.
Important histopathologic observations were contributed by William Greenfield in 1878 and E. Goldman in 1892. George Sternberg described the giant cells but believed the condition to be a peculiar form of tuberculosis. The recognition that these cells were an integral part of the disease awaited the careful pathologic observation of Dorothy Reed of Johns Hopkins Hospital in Baltimore. These cells, appropriately named Reed-Sternberg cells, are the hallmark of Hodgkin disease.
Controversy as to the nature of this disease led early investigators to study infectious agents as possible etiologic causes, especially the tuberculosis bacillus, but to no avail. More recent studies have examined the roles of other viral infectious agents, especially the agent of infectious mononucleosis, but with no consistent results. At present, the condition is accepted as neoplastic, probably triggered by some unknown environmental agent or agents.
Between 1930 and 1950, major advances included the recognition of meaningful histologic subtypes of Hodgkin disease correlating with prognosis, and the development by Vera Peters of a clinical staging system. Impressive responses to X-ray therapy were reported at the beginning of the twentieth century, and treatment with megavoltage therapy was further developed. By World War II, it became realistic to speak of curing some patients with early Hodgkin disease. The potential for a cure meant that accurate histologic diagnosis and estimation of the extent and localization of disease were imperative in planning treatment; a multidisciplinary approach to diagnosis and treatment was developed. Modern concepts of histologic classification became codified at a conference held in Rye, New York, in 1965, and the clinical staging system was refined into its present form at a workshop held at Ann Arbor, Michigan, in 1971.
Modern effective chemotherapy was developed concurrently with these advances in classification, staging, and radiotherapy. The alkylating agents, created as an outgrowth of studies on nitrogen mustard gas during World War II, provided the first drugs to produce impressive shrinkage of the tumor and significant palliation of the disease. The subsequent developments in modern pharmacology and therapeutics enabled Vince DeVita and his coworkers, in 1970, to design the first effective combination chemotherapy regimen, MOPP.
Today, many more such regimens are being tested; the possibility for cure has become a realistic hope for every patient with Hodgkin disease. This is the case because of the refinement of ancillary therapies with antibiotics (for infections that may occur during the necessary phases of suppression of the immune system by these powerful toxic drugs) and platelet transfusion technology. Bone marrow transplantation technology also offers strong hope of curing patients with advanced cases who are resistant. The bone marrow is harvested and then reintroduced into a patient whose marrow has been effectively disabled. Immunotherapy is also being investigated. It can boost the patient’s ability to combat disease by modulating the body’s responses. The drawback to aggressive combinations of chemotherapy and radiotherapy, however, is the emergence of therapy-related leukemia and leukemia-like malignancies several years after the completion of successful therapy for Hodgkin disease.
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