Hodgkin’s lymphoma is a neoplastic disorder affecting the lymphatic system. It was named after Thomas Hodgkin (1798-1866), the English physician and pathologist, who described this disorder in 1832 in his paper, entitled “Some Morbid Appearances of the Absorbent Glands and Spleen. ” This paper contained detailed descriptions of the disease presentations and a detailed description of Reed Sternberg cells, the characteristic cells seen in Hodgkin’s disease.
The National Cancer Institute web page shows that in 2007 alone, 8,190 new cases of Hodgkin’s lymphoma have been diagnosed in the United States and 1,070 deaths have occurred due to Hodgkin’s lymphoma(Unknown). Hodgkin’s lymphoma accounts for nearly 0. 7% of all cancers in the United States. Since 1983, according to the National cancer Institute’s statistics report, there has been a gradual decrease in the incidence of Hodgkin’s lymphoma due to the recent developments in the treatment guidelines for this disease. In most of the cases, the condition is now curable.
Unlike the non-Hodgkin’s lymphoma which spreads unpredictably to extranodal sites, Hodgkin’s lymphoma limits itself to the lymph nodes. It could affect a single lymphnode or a group of lymph nodes. The disease progression follows the anatomical pattern of lymph node distribution in the body. This particular character of Hodgkin’s lymphoma that differentiates it from other types of lymphoma, explains the reason for a better prognosis associated with this disease. Along with this, the neoplastic cells form only a minor fraction of the tumor cell mass. Over all, the disease is limited to the affected lymph nodes with little metastatic potential.
This helps in the treatment also and thereby facilitates in the complete cure of the condition. Etiology Etiologically Hodgkin’s lymphoma differs from other lymphomas in many aspects. There is a bimodal age-specific incidence in this disease while a linear increase in incidence with age is seen in other lymphomas. The disease incidence is high during younger age group (15 to 35 years) and in adults above 50 years (Freedman A. S. ). Hodgkin’s lymphoma is more prevalent in males compared to females and this distribution shifts more to a male predominance in young adults and in childhood Hodgkin’s disease.
The chance of developing Hodgkin’s lymphoma is more if an identical twin is affected. This points to a possible genetic contribution which is still inconclusive. There is an increased risk for the disease with certain HLA antigens, single family dwellings, early birth order, tonsillectomy, a sibling with Hodgkin’s disease and decreased number of siblings. There appears to be a viral role in the pathogenesis of Hodgkin’s lymphoma. Ebstein-Barr virus (EBV) is found to be an important etiologic agent. The role of EBV is demonstrated by the presence of EBV genomes and RNA transcripts in Reed-Sternberg cells.
Moreover EBV positive tumor cells may express a protein encoded by the EBV genome called latent membrane protein–1. So patients with EBV infection or with increase titers of antibodies against EBV antigens are at a high risk of developing Hodgkin’s lymphoma. Pathogenesis Hodgkin’s lymphoma is characterized by the diagnostic Reed-Sternberg cell (RS), which is a giant tumor cell. RS cells are essential for the histologic diagnosis as it is a neoplastic cell. RS cells are large (15 to 45 microns in diameter), binucleate or bilobed with both the halves appearing as mirror images of each other(Aster J.
). The nucleus is enclosed with in an abundant cytoplasm and contains large Owl-Eyed nucleoli of the size of a small lymphocyte. There are different variants of RS cells like lacunar cells, mononuclear variants, and lymphocytic and histiocytic variants. The multitude of RS cell variants and the presence of cells similar in appearance to RS cells in other diseases make the histological diagnosis of Hodgkin’s lymphoma difficult. There are four major subtypes of Hodgkin’s disease called Nodular sclerosis, mixed cellularity, lymphocyte predominant and lymphocyte depleted types.
Nodular sclerosis type is the most common form of Hodgkin’s lymphoma affecting three-fourths of patients. It is characterized by the lacunar type of RS cell and the presence of collagen bands. This is the only form of Hodgkin’s lymphoma more common in women. It is characteristically seen in the lower cervical, supraclavicular and mediastinal lymph nodes, with the histology showing evidence of fibrosis. It has an excellent prognosis. Mixed cellularity type is seen in nearly twenty percent of cases.
The characteristic features are classic RS cells and mono nuclear variants which are diffusely dispersed in lymph nodes among a heterogenous cellular infiltrate. Mixed cellularity form is more commonly seen in men. It is associated with older age groups and has a good prognosis. Lymphocyte predominance type is seen in 5 percent of cases and is characterized by a vague nodular infiltrare of small lymphocytes containing lymphocytic and histiocytic variants of RS cells. It is mostly seen in males less than 35 years of age and affects the cervical, axillary and mediastinal lymph nodes.
The overall prognosis is excellent. Clinical features Hodgkin’s lymphoma usually presents with a localized painless enlargement of lymph nodes. It spreads to contiguous lymph nodes. Initially the lymph nodes are firm and freely movable. In majority of the cases it presents with superficial lymph node enlargement mainly affecting the neck or supraclavicular region. The growth of lymph nodes is quite variable with lesions that may remain stable for long periods or causing spontaneous growths and temporary regression. There are few or no symptoms associated with this disease.
The most common symptom is a low grade fever associated with recurrent night sweats. The fever may persist for several weeks followed by afebrile intervals. This type of fever is characteristically called Pel-Epstein fever (Freedman A. S. ). This may be associated with unexplained weight loss and other constitutional symptoms like fatigue, malaise and weakness. Pruritus occurs in less than ten percent of patients. It may be associated with a generalized skin rash. Mediastinal, pulmonary, pleural or pericardial involvement may be associated with cough, chest pain, shortness of breath or hypertrophic osteoarthropathy.
It may involve the bones where there can be symptoms of spinal cord compression and bone pain. In intracranial Hodgkin’s lymphoma headache and visual disturbances may be seen. Diagnosis The diagnosis of Hodgkin’s lymphoma is based on the histological examination of biopsy material. Biopsy specimens are usually taken from enlarged superficial lymph nodes. The diagnosis and classification of Hodgkin’s lymphoma is based on Rye classification adopted in 1966. Central to the diagnosis of Hodgkin’s disease is the presence of either classic RS cells or its variants.
Apart from the RS cells, the cellular and stromal background of the lymph node helps in diagnosing the histological subtypes. The extent of disease is defined according to Ann Arbor staging classification. The disease is divided into four stages (stage I, II, III and IV) based on the extent of lymphoid involvement. The staging is done by physical examination and other non invasive studies. Sometimes a staging laparotomy may have to be performed to understand the extent of abdominal lymphnode involvement. The staging of Hodgkin’s lymphoma helps in determining the effective treatment for these patients.
Stages I and II are treated effectively with radiotherapy alone while stages III and IV are effectively treated with combination chemotherapy. Once Hodgkin’s lymphoma is diagnosed by histology, staging evaluation is done using different invasive and noninvasive techniques. Radiographs and CT (computerized tomography) scans help in detecting the mediastinal and abdominal involvement of Hodgkin’s disease. Bone scan, bone radiograph and bone marrow biopsy helps in identifying bone involvement. Liver function test, liver biopsy and Gallium scan confirms hepatic involvement of the disease.
Lymphangiogram, ultrasonography and magnetic resonance imaging provides a useful method for diagnosing splenic involvement and understanding the staging of the disease. Gallium scintigraphy is also useful in following response to treatment and to detect early recurrences. Screening Screening of Hodgkin’s lymphoma has to be done in patients with high risk factors for the disease. The currently available practice is to test the patients who present with signs and symptoms suggestive of Hodgkin’s disease and diagnose the condition in them. This is not sufficient.
There should be adequate methods for screening patients of Hodgkin’s lymphoma. But this is rather very difficult in the current scenario due to many reasons. First of all, the disease may present without any symptoms (especially in initial mediastinal involvement) and this makes the screening difficult. Secondly, patients with the high risk factors are very difficult to be found out. There are genetic tests to screen the neoplastic diseases. But these are largely inefficient in screening for Hodgkin’s lymphoma. Identifying the patients with EBV infection may help to a certain extent.
This can be made possible by detecting the antibody titers to EBV antigens. High levels of antibody titers may contribute to a high risk of developing Hodgkin’s lymphoma in later life. Detection of EBV genomes may also help in identifying patients with EBV infection. Similarly, there is an increased incidence of Hodgkin’s disease in patients with immunodeficiency and HIV virus infections. Screening should be done in patients with immunodeficiency. If one of the identical twins develops Hodgkin’s disease, the other identical twin must also be screened for the disease as the disease may occur in the other twin also.
Detection of tumor markers like soluble CD30, soluble CD25 and soluble CD4 are helpful in screening the disease. Treatment The choice of treatment is dependent on the stage of disease. Early stages (Stage I and II) can be treated with radiation therapy. As the disease spreads by lymphatics, three radiation fields are considered to cover the likely sites of the disease. 3000-3600 cGy of radiation is given along with an additional dose so that the total dose comes around 4000 cGy. In short, radiotherapy may cure about 80% of localized Hodgkin’s disease.
The treatment of advanced disease (Stages III and IV) is usually done using combination chemotherapy. Chemotherapy is also the mainstay of treatment for disseminated cases. Drugs used in combination are Mechlorethamine, Vincristine, Procarbazine and Prednisone. This is called MOPP therapy. For MOPP resistant patients, Adriamycin, Bleomycin, Vinblastine and Dacarbazine are preferred. Prognosis Large mediastinal involvements in early stage patients show a high risk of relapse after radiation therapy alone. Patients above forty years of age show a decreased survival rate.
Patients with fever and weight loss (but not night sweats) who are treated with radiation alone show less survival. Certain factors like male sex, mixed cellularity and lymphocyte depleted histologies, high erythrocyte sedimentation rates, multiple diseased sites, bulky mediastinal disease and treatment with involved-field radiations will adversely affect the outcome of the disease. In patients with advanced stage disease, inguinal node involvement, stage IV, anemia, leukocytosis, lymphocytosis and bulky disease offers unfavourable survival. Even with all these factors, the survival chances of patients with Hodgkin’s disease are more.
So in general, this disease is well known to have an excellent prognosis. Conclusion Hodgkin’s lymphoma is a neoplastic disease affecting the lymphatic system. The disease usually presents without any symptoms or signs, which makes the screening very difficult. Histological and other invasive and noninvasive methods are used to diagnose the disease. Treatment of the disease is based on the staging and the extent of disease progression. Being a disease limited to lymphnodes and the lymphatic system, the treatment of the disease is mostly effective and the prognosis of the disease is excellent.
REFERENCES
Aster J. , and Kumar V.”White Cells, Lymph Nodes, Spleen and Thymus. ” Robbins Pathologic Basis of Disease. Ed. Kumar V. Cotran R. S. , Collins T. 6th ed. Vol. 1. Singapore: Harcourt Asia Pte Ltd, 1999. 670-5. Freedman A. S. , Nadler L. M. “Malignancies of Lymphoid Cells. ” Harrison’s Principles of Internal Medicine. Ed. Braunwald E. Fauci A. S. , Isselbacher K. J. , Wilson J. D. , Martin J. B. , Kasper D. L. , Hauser S. L. , Longo D. L. 14th ed. Vol. 1. New York: McGraw-Hill, 1998. 707-11. Unknown. Hodgkin’s Lymphoma Home Page-National Cancer Institute. 2007. Web page. Available: http://www. cancer. gov/cancertopics/types/hodgkinslymphoma. March 17 2007.