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Hodgkins Disease & Non Hodgkins Lymphoma



The malignant lymphomas, Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL), comprise a group of clinically and pathologically diverse malignant lymphomas of largely unknown cause. Their successful management involves a multidisciplinary approach, proceeding from an accurate diagnosis to a comprehensive staging evaluation and appropriate therapeutic recommendation and regimen.

Etiology / Pathogenesis

In 1832, Thomas Hodgkin presented a paper entitled “On Some Morbid Appearances of the Absorbent Glands and Spleen”. His report was an autopsy description of seven patients with an entity he described as a primary process involving the lymph nodes and spleen rather than a reactive inflammatory condition. Independent reports by Sternberg and Reed described the giant cells characteristic of Hodgkin’s disease, which are known today as Reed-Sternberg (RS) cells.

The RS cell is characterized by its large size and classic binucleated structure and large eosinophilic nucleoli. It is the tumor cell characterizing HD and must be identified within the appropriate cellular milieu of lymphocytes, eosinophiles and histiocytes in order for the diagnosis to be established. Hodgkin’s disease is unique pathologically because the tumor cells comprise a minority of the cell population in which normal inflammatory cells are the major cellular components. The RS cell is characterized as both a macrophage and lymphocyte and has the ability to phagocytose. RS cells are not absolutely specific for HD and have been noted in infectious mononucleosis4 and in other malignancies including lymphomas, carcinomas and sarcomas.

In the years that have followed the initial identification of Hodgkin’s disease as a neoplastic entity, a heterogeneous group of over 20 additional and discrete non-Hodgkin lymphomatous neoplasms have been described with characteristic morphologic, immunophentypic, genetic and clinical features. This group has been classified as non-Hodgkin lymphomas (NHL) and, with an ever-increasing incidence, now is the sixth most common cause of cancer in the United States.

The precise etiology and pathogenesis of both HD and NHL are unknown. There is, however, convincing evidence that most types of HD and non-Hodgkin’s lymphoma are derived from germinal center or post-germinal center B-cells (bone marrow) and that the B-cell germinal center plays a key role in both normal B-cell differentiation and in the genesis of B-cell neoplasms. Lymphoid neoplasms of T-cell (thymus) origin constitute less than 15% of NHL group, the vast majority being of B-cell origin.

The exact mechanism that triggers the transformation to malignancy is unknown, but over the years a variety of infectious agents, congenital and acquired immunodeficiency states, autoimmune disorders and physical and chemical agents have been associated with an increased risk of these disorders.

The arguments for an infectious etiology of HD date back to its early descriptions. Mycobacterium tuberculosis was the first organism to be suspected of causing HD. However, once it was realized that HD is associated with immune defects, M. tuberculosis was recognized as a consequence of HD rather than a cause of the disease. Reports of clustering of cases tended to support the infectious etiology, but these reports were subsequently recognized as chance occurrence.

The Epstein-Barr virus (EBV) has been another proposed cause of Hodgkin’s disease, and the circumstantial evidence is impressive. The incidence of HD is elevated in patients with a history of EBV infection. he E-B virus, which infects and immortalizes B-lymphocytes in vitro, has been implicated in the pathogenesis of African Burkitt’s lymphoma and B-cell malignancies in immuno-compromised patients such as those that occur after organ transplantation. Using molecular biological techniques, EBV genome fractions have been found in Reed-Sternberg cells.

The possibility that an abnormal immune response is related to the development of HD has been given support by reports that there is as much as a twenty-fold increase in HD among HIV-infected individuals. The data are even more impressive for the incidence of non-Hodgkin’s lymphoma; patients with long-standing human immunodeficiency virus (HIV) infection are also estimated to have a 100-fold increased risk for the development of NHLs. In the early 1980’s, an increase in intermediate and high-grade NHL was noticed among young homosexual men. Analysis of a series of 90 such cases revealed that their age distribution was identical to that of AIDS, with the highest percentage seen between ages 30 and 39, in contrast to NHL in the general population where the median age was between 55 and 60 years. In this and subsequent series, 30% to 40% of patients had a lymphoma similar in histology to Burkitt’s lymphoma, a tumor that is epidemic in equatorial Africa and rare in the United States.

Helicobacter pylori infection of the stomach results in chronic gastritis and the development of mucosa-associated lymphoid tissue (MALT) and associated gastric lymphomas. This link between H. pylori infection and primary gastric MALT lymphomas had prompted the development of treatment strategies based on the eradication of the H. pylori infection. The human T-cell leukemia virus (HTLV) and the Kaposi’s sarcoma-associated herpes virus (KSHV) are two rare viruses that have also been associated with NHL. Additionally, certain chemical and physical agents have been associated with an increased risk of NHL, as is the case with the survivors of nuclear explosions or reactor accidents and in patients with other tumors that have been treated with certain chemotherapies and/or radiation.

The idea that HD may represent an uncommon host response to a common agent has received support from a study of monozygotic and dizygotic twins. Monozygotic twins, who would be expected to have similar immune responses, had a 99-fold increased risk of being concordant for having HD, supporting a role for genetic susceptibility and/or an abnormal immune response in the etiology of HD.

Accurate classification of the malignant lymphoid neoplasms is essential for the correct diagnosis and for the evaluation of prognosis and treatment of patients. Hodgkin’s disease has been classified into four histological subtypes. Each subtype classification is based on the number and appearance of Reed-Sternberg cells as well as the background histological milieu.

Several classifications have been proposed for the complex array of non-Hodgkin’s lymphomas. These have been based on the degree of differentiation of the tumor and on whether the growth pattern is nodular or diffuse. Other classifications have been based on the cell of origin of the malignancy. The International Panel Working Formulation of the National Cancer Institute has separated NHL into categories, each incorporating the above-mentioned items and having therapeutic implications18. Their generally accepted NHL classification identifies four subtypes and their respective incidences:

Low grade or favorable prognosis lymphomas (38%)

Diffuse, well differentiated

Nodular, poorly differentiated

Nodular, mixed types

Intermediate grade or intermediate prognosis lymphomas (40%)

Nodular, histiocytic

Diffuse, poorly differentiated


Diffuse – mixed types

High grade or unfavorable prognosis lymphoma (20%)

Diffuse histiocytic lymphoma (diffuse large cell cleaved, noncleaved, and immunoblastic types)

Diffuse, undifferentiated (Burkitt’s and non-Burkitt’s type)

Miscellaneous lymphomas (2%)

Composite lymphoma

Mycosis fungoides

True histiocytic, other, and unclassifiable types

The obvious complexity of the current classification of NHLs has taxed the ability of hematopathologists. The diagnosis of a non-Hodgkin’s lymphoma is unquestionably one of the most difficult tasks confronting a general surgical pathologist. The difficulties involved have resulted in many institutions routinely referring new cases of NHL to expert hematopathologists for review and consultation.

Demographics / Epidemiology

Approximately 7,500 new cases of Hodgkin’s disease are diagnosed annually in the United States. In contrast to the increasing incidence of non-Hodgkin’s lymphoma, the annual incidence of HD has remained stable over the last several decades. The male to female ratio of HD incidence is 1.3 – 1.4 to 1. In most economically developed countries, there is a bimodal age distribution with one peak occurring in the third decade of life (age range 15-39 years) and a second smaller peak occurring after age 50. The second peak may be an artifact of histologic misclassification because recent studies have demonstrated that many of the older-age cases originally diagnosed as HD turned out to be NHLs. The age-specific incidence is low, no early incidence peak occurs. In some developing countries, the peak shifts into childhood, mostly boys.

In contrast to the stable and relatively static incidence of Hodgkin’s disease, non-Hodgkin’s lymphoma is emerging as a worldwide epidemic. More than 50,000 new cases were diagnosed annually in the United States during the 1990’s and there is evidence that the incidence is increasing. Some of this increase is undoubtedly related to the predilection for the development of NHL in patients with AIDS. However, a large number of other factors may be contributing to the increase in incidence since NHL was manifesting a steady increase of 3% to 4% per year in the 1970’s prior to the emergence of the AIDS crisis. The rise in NHL incidence is faster and higher than that of all other malignancies except lung cancer in women and prostate cancer.

The incidence of NHL increased 86.6% in males from 1973 to 1991 with an estimated annual change of 3.8%. As a result, NHL now constitutes about 6% of all malignancies in the United States.

The incidence of the various non-Hodgkin’s lymphomas is age-dependent, has a variable distribution, and is more common in males than females. Lymphomas represent approximately 10% of all childhood cancers in developed countries and are third in relative frequency behind acute leukemias and brain tumors. They are more common in adults than in children and manifest a steady increase in incidence from childhood through age 80. The mean age at diagnosis of NHL is 45 to 55 years and the median age is 60 to 65 years. The greatest rise in new cases of NHL has been in elderly white males and the least increase has been seen in young white females. The increase in incidence of NHL has been accompanied by an increase in extra and diffuses involvement such as involvement of the gastrointestinal tract and oropharynx. Other common extranodal sites include the brain, skin, bone, thyroid, lung, breast and testis.



  • It is important that the history include any occurrence of lymphoma in the family and a history of previous infectious mononucleosis or exposure to radiation or toxic chemicals by the patient. Stigmata suggesting the presence of an immunodeficiency disorder should be sought because of the predilection for patients with AIDS to develop non-Hodgkin’s lymphoma.

Key aspects of the medical history of HD or NHL patient include the determination of whether he/she has symptoms that have a prognostic significance as well as a possible influence on the therapeutic regimen. The physician should focus on symptoms that suggest a specific extranodal site (e.g., bone pain), as well as symptoms such as fever, night sweats and a weight loss equal or greater than 10% of the patient’s body weight, since these complaints usually signal the presence of diffuse disease and have a significant influence on prognosis and future therapy. In lymphomatous malignancies fever may be manifest in any pattern including a low-grade continuous fever or occasional high spikes of fever. The pattern of recurrent episodes of daily high fever separated by days without fever is known as Pel-Epstein fever. Pain at the site of Hodgkin’s disease involvement in association with the ingestion of alcohol has been well recognized. Its mechanism is unknown and its presence does not have prognostic significance.

Physical Examination

  • A meticulous examination of all lymph node-bearing sites is mandatory. In addition to the frequently encountered cervical and supraclavicular sites, the axillae and groins merit careful palpation. Splenomegaly is another frequent physical finding in lymphomatous malignancies.

Hodgkin’s disease almost always presents with lympadenopathy and the involved nodes are usually freely movable and have a rubbery consistency. Cases in which the histology demonstrates fibrosis or sclerosis can be associated with hard and firm adenopathy. Although any lymph node group can be involved, cervical and supraclavicular adenopathy are the most common physical findings, although axillary adenopathy is not rare. Mediastinal disease is often present, but rarely is the only site of involvement because it usually occurs in association with cervical and supraclavicular adenopathy. HD can also present with iliac, inguinal and femoral adenopathy, and in approximately 3% of cases, there may be only subdiaphragmatic disease. Splenomegaly is noted at presentation in approximately 10% of cases of HD. However, splenomegaly may occur as a nonspecific manifestation of HD and in only half of the cases is there actual splenic involvement with HD found at laparatomy. Additionally, splenic involvement has been reported in 30% of HD cases in the absence of splenomegaly.

Extranodal HD can occur at any site. Lung, liver, bone and bone marrow are the most common sites of extranodal involvement and each of these sites is seen in approximately 5% to 10% of cases.

Hodgkin’s disease tends to spread in a contiguous fashion. For example, because of contiguity with the thoracic duct, left supraclavicular nodal involvement is often seen in association with mediastinal involvement.

As is the case with Hodgkin’s disease, most patients with non-Hodgkin’s lymphoma present with painless lymphadenopathy, most commonly in the cervical and supraclavicular regions. Systemic symptoms occur in less than 25% of patients in most large series. When present, they are usually associated with advanced disease.

Gastrointestinal lymphoma occurs in less than 3% of NHL, with stomach and colon the most common sites of involvement, and with vague abdominal pain the most common presentation. Obstruction, specifically intussusception in children, or perforation, may be complications of intestinal lymphoma. Genitourinary presentations include renal mass, ureteral obstruction, testicular and ovarian masses and vaginal bleeding. Neurological signs and symptoms include headache, cranial nerve palsies and signs of leukoencephalopathy. Unusual metabolic presentations include hyperuricemia, renal failure, hypercalcemia and severe hypoglycemia.

Disease Staging

The symptoms and physical findings play key roles in the important process of the staging of Hodgkin’s disease and non-Hodgkin’s lymphoma, a process which is of utmost value in the prognosis of the disease and in the planning of a therapeutic program. Several staging classifications have been proposed for both HD and NHL. Table 4 presents the widely used Cotswald classification for HD.

Table 4-Cotswald Staging Classification for Hodgkin’s Disease

The staging classification of HD into A (asymptomatic) and B (symptomatic) has a relationship to prognosis. The presence of symptoms is a suggestive indication of advanced disease. Symptoms are found in fewer than 10% of patients with Stage I disease and in approximately 65% of patients with Stage IV disease.

The purpose of clinical evaluation is not only to determine the stage of the disease and the therapeutic regimen, but also to establish an appropriate clinical baseline so that success or failure of therapy can be assessed.

Table 5 shows the classification of HD cases with respect to Stage and Symptomatic Status.

Table 5-Distribution of Hodgkin’s Disease Cases with Respect to Stage and Symptomatic Status

A number of staging classifications have been proposed for the non-Hodgkin’s lymphomas. In essence, they parallel those of Hodgkin’s disease in respect to Stages I and II with only minor modifications of Stages III and, if present, Stage IV.

Testing Procedures for HD and NHL

Office and Laboratory Studies

  • Hodgkin’s disease and non-Hodgkin’s lymphoma patients are prone to develop a variety of hematologic and blood chemistry abnormalities and blood specimens should be withdrawn for appropriate baseline values.

A slight to moderate polymorphonuclear leukocytosis may be present. Lymphocytopenia may occur early and become pronounced with advancing disease. Eosinophilia is present in about 20% of patients and thromocytosis may be observed. Anemia, often hypochromic and microcytic, usually develops with advancing disease. Defective iron utilization is characterized by low serum iron levels and low iron-binding capacity. Hypersplenism may occur producing cytopenias alone or in any combination in the presence of marked splenomegaly.

Lymphomatous infiltration of bones and liver is characterized by elevations of serum levels of the respective isoenzymes of alkaline phosphatase. Other blood chemistry studies should include levels of blood glucose, urea nitrogen and creatinine. Serum bilirubin levels and measurements of hepatic enzymes are helpful in assessing liver involvement. Serum uric acid should be monitored especially during therapy to detect increases that may predict hyperuricemic renal shutdown. Serum electrolytes should also be checked to monitor fluid and electrolyte balance in patients who are often depleted by the underlying disease as well as therapy.

Serum levels of lactic dehydrogenase (LDH) and beta-2 microglobulin (beta 2-M) represent surrogate quantitative measures of metastatic potential and tumor burden respectively. They have been used as indicators and serological staging agents to predict freedom from relapse and survival. Patients at low risk for disease recurrence have normal levels of both markers whereas elevations predict shortened remission and survival.

Radiologic Studies

  • Radiologic studies are particularly valuable in assessing disease extent. The specific studies to be performed will vary with the individual patient and depend on the physician’s assessment of the likelihood of diffuse disease involvement.

A chest radiograph is indicated in all patients with HD and NHL primarily to assess lung status and in particular, mediastinal disease involvement. Most authorities also recommend computerized tomographic (CT) studies of the chest, abdomen, pelvis and neck to assess the presence of disease not readily assessable by physical examination. Other radiologic procedures are performed as deemed clinically appropriate and include gallium scanning, magnetic resonance imaging (MRI), ultrasound and bone and liver scans. Lymphangiography is occasionally performed when there is a strong suspicion of periaortic and retroperitoneal nodal involvement.

Invasive Procedures

  • The diagnosis of both HD and NHL requires a biopsy that contains sufficient tissue to permit an accurate microscopic diagnosis by an experienced hematopathologist. Biopsy specimens are usually obtained from palpable lymph nodes but may occasionally be obtained from other tissues. Needle aspirations or biopsies are inadequate for the primary histologic diagnosis.

A bone marrow aspiration and biopsy should be performed as part of the initial staging procedure although these tests are rarely positive unless other evidence of advanced disease (at least Stage III) is present. The majority of patients with bone marrow involvement will be symptomatic; nevertheless, a bone marrow biopsy should be obtained at baseline in all patients because the results may not only influence the use of initial therapy but might affect future decisions at the time of relapse (e.g., a decision on the feasibility of an autologous bone marrow transplantation).

A major controversy surround the performance of a staging laparatomy. A staging laparoscopy can only be justified when the results will influence therapy. Some physicians recommend the procedure whenever therapeutic planning includes radiation. Others reserve it for those cases where clinical staging is equivocal. When performed, it should include inspection of the liver and spleen and liver and nodal biopsies.

Currently, laparoscopy is being performed far less frequently because chemotherapy is incorporated in many clinical settings and because retrospective studies provide a basis for determining the likelihood of intraabdominal disease with different clinical perspectives. Several studies have demonstrated that laparotomy had no significant impact on survival or relapse rate in patients with a favorable prognosis who were randomized to staging with laparotomy or clinical staging. The risk of occult subdiaphragmatic disease can be estimated on the basis of sex, age, erythrocyte sedimentation rate (ESR), number of involved lymph node sites, and histologic subtype. A bone marrow biopsy is included in the routine staging of patients who have advanced-stage disease, constitutional symptoms, or both.

Differential Diagnosis

  • The differential diagnosis of both Hodgkin’s disease and non-Hodgkin’s lymphoma involves the ruling out of obvious and common conditions as well as other malignancies. The exact diagnosis hinges on the histological findings and the opinion of an experienced hematopathologist.

In patients with cervical adenopathy, infections, including bacterial or viral pharyngitis, infectious mononucleosis and histoplasmosis must be excluded. Other malignancies, such as nasopharyngeal and thyroid cancers, can present with localized cervical adenopathy and axillary adenopathy is a common metastatic manifestation of breast cancer. Mediastinal lymphomatous involvement must be distinguished from infections, sarcoidosis and other thoracic neoplasms.

In other patients, the differential diagnosis includes tumors of the lung and mediastinum, specifically of small cell and non-small cell type. Reactive mediastinitis and hilar lymphadenopathy from histoplasmosis can be confused with lymphoma since it occurs in otherwise asymptomatic patients.

The pathologic diagnosis of HD has traditionally been considered to be easier and safer than that of the more complex non-Hodgkin’s lymphomas. However, a 1968 review of the histopathologic material of 600 patients in whom an initial diagnosis of HD had been made revealed a mistaken diagnosis in an astonishing 47% of cases. The most common error in pathological diagnosis was the confusion of inflammatory or other non-neoplastic conditions with HD (32%). The high rate of error was attributed to the relative inexperience of the contributing general pathologists in the diagnosis of hematopathologic malignancies. In a study reported by the Southwest Oncology Group (SWOG) in 1982, the rate of misdiagnosis in 575 cases of HD was again high, but the most common class of error was confusion of HD with NHL. In subsequent similar studies of HD, the confusion with NHL was always found to be the most common diagnostic error. Although the incidence of misdiagnosis has decreased, major errors still exist in up to 10% of cases.

The correct diagnosis of both Hodgkin’s disease and non-Hodgkin’s lymphoma is completely dependent on a correct interpretation of the histopathology of the biopsy material and it is mandatory that assistance in this area be obtained from experienced hematopathologists.


The currently successful treatment of Hodgkin’s disease is one of the triumphs of modern cancer therapeutics. The death rate due to Hodgkin’s disease has decreased by two-thirds in the last 40 years because of the introduction of effective diagnostic and therapeutic modalities. All patients regardless of the stage of the disease can and should be treated with curative intent.

The therapy of Hodgkin’s disease and non-Hodgkin’s lymphoma involves three main modalities:

  • Radiation
  • Chemotherapy
  • Combination radiotherapy and chemotherapy

In the case of Hodgkin’s disease, staging is critical in choosing the therapeutic modality. In non-Hodgkin’s lymphoma, the histologic tissue type, as well as staging, is a major determinant of therapy.

Radiation Therapy

Radiation is the standard approved therapy in Hodgkin’s disease stages I and II.

In disease limited to lymph nodes above the diaphragm, therapy is usually directed only to the involved area (limited field radiation). Before the advent of effective salvage chemotherapy, radiotherapy was often directed at both involved and uninvolved lymphoid areas (extended field radiation involving total or subtotal lymphoid radiation). The tendency today is to limit the field of radiation to the “mantle” of involvement if the disease is confined to the upper chest (above the carina) with a resultant cure rate in excess of 80% (reaching as high as 92% when causes of death other than Hodgkin’s disease are excluded.

Radiotherapy alone remains an option in some patients with minimal splenic, splenic hilar or celiac node involvement (stage IIIA). In these patients, it is possible to effect a cure in 60% to 70% of patients using total nodal irradiation, but those with extensive splenic involvement will require systemic therapy because of the high rate of recurrence with radiation therapy alone. Most relapses (75%) occur within the first 3 years after completing therapy; late relapses thereafter are uncommon. There is a tendency to offer such patients combined modality therapy because it is associated with the lowest recurrence rate.

An alternative treatment applicable to early-stage disease is to use both radiation and chemotherapy in selected patients such as those with bulky mediastinal disease and significant B symptoms. Other candidates are those at a high risk for subdiaphragmatic involvement, mixed cellularity or lymphocytic depleted Hodgkin’s Disease histology, or over 40 years-old.

The radiation dose required to eradicate Hodgkin’s disease in demonstrably involved nodes is 40 to 45 Gy (1 Gy=100 rads). A standard regimen is a total dose of 36 Gy delivered in 20 daily functions of 1.8 Gy over a period of 4 weeks.


It is important to note that more than half of the patients with Hodgkin’s disease who experience relapse after radiation therapy alone have disease that is still curable with chemotherapy.

Until recently, MOPP (mechlorethamine, Oncovin, procarbazine and prednisone) was the chemotherapeutic combination of choice but is now used much less frequently because of its side effects including myelosuppression, susceptibility to infection, infertility and autonomic and peripheral neuropathy.

The combination chemotherapy of choice today is ABVD (doxorubicin) [Adriomycin], bleomycin, vincristine, and dacarbazine). It has been shown to be both more effective as well as less toxic than MOPP. A cycle of ABVD therapy includes:

Advanced Hodgkin’s disease is classically defined as stages IIIB and IV. In these stages, Hodgkin’s disease is curable only with a systemic approach. ABVD is the standard combination chemotherapy generally administered for 6 cycles. It remains controversial whether post chemotherapy adjuvant radiotherapy improves the outcome in advance Hodgkin’s disease. If it is to be utilized, the radiotherapy field should be kept minimized, doses kept low and sites to be eradicated limited to “bulky” disease.

ABVD is generally well tolerated. Its primary side effects are nausea, fatigue, moderate hair loss, some increased susceptibility to infections, neuropathy secondary to vincristine and pulmonary fibrosis secondary to bleomycin. Pulmonary function should be monitored and bleomycin withheld if there is a fall of 25% or more in pulmonary diffusion capacity. Doxorubicin cardiotoxicity is rare; however, it is recommended that all patients have left ventricular ejection fraction measured before therapy. Infertility is not a major problem with ABVD but all men should be advised to bank sperm. ABVD had rarely been administered during the second and third trimesters of pregnancy; no adverse effects have been noted in the few such cases where it was administered. All women of childbearing age should have a pregnancy test before therapy and be advised to delay pregnancy for 2 years after treatment to avoid the coincidence of pregnancy and relapse.

In the case of non-Hodgkin’s lymphoma, the choice of therapy depends not only on the staging of the disease, but also on the histological classification of the tumor.

Low-grade lymphomas (indolent or favorable) are usually small lymphocytic or follicular center lymphomas. Grade I and II low grade lymphomas are uncommonly diagnosed, but may be curable with involved field radiation. One study reported a relapse-free survival rate of 62% at 5 years in all patients and 80% in 15 years or later in patients 40 years of age or younger. Generally, no benefit from additional adjuvant chemotherapy has been documented.

Usually low-grade lymphomas are diagnosed in stages III or IV (75% to 90%) and there is bone marrow involvement in approximately 70%. The median survival of this group is 5 to 7 years with an initial response to radiotherapy or chemotherapy and then relapse eventually leading to death. Some have adopted a “watch and wait” approach to this advanced stage, but in one study, 5 year survival was only 12% with this approach compared to 51% for aggressive therapy.

Intermediate grade lymphomas are more aggressive than low-grade lymphomas with untreated survival times measured in months rather than in years. The most common intermediate grade lymphomas are the large cell lymphomas, which are curable in about 50% of cases. Most are treated similarly, even those with apparent stage I and II disease because of the now-recognized systemic nature of these stages. Recommended therapy consists of standard anthracycline combination chemotherapy, usually in the form of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) administered in three cycles (CHOP-3) and followed by radiotherapy. This regimen has produced a 4-year survival as high as 97% on stage I patients less than 60 years of age and with a normal performance status. In advanced (stage III or IV) intermediate grade non-Hodgkin’s lymphoma, CHOP has been shown to produce long-term complete remission rates of up to 75%.

High-grade lymphoma, including precursor lymphoblastic lymphoma, Burkitt’s lymphoma and Burkitt’s-like lymphoma, tend to occur in younger age patients and have an untreated survival time usually measured in weeks. They usually present with advanced stage disease and are always treated with systemic chemotherapy. Many have CNS involvement and require intrathecal therapy. Low risk patients, i.e., those with a serum LDL level less than 300 IU/L and without bone marrow or CNS involvement, may have a 5 year remission rate as high as 94%.

Monoclonal antibody (MAb) therapy for non-Hodgkin’s lymphoma

Studies have revealed that more than 90% of lymphomas of B-cell origin express the CD20 antigen, thus identifying CD20 as a potential target for monoclonal antibody (MAb) therapy. In 1987, the first such MAb, rituximab, was approved by the FDA for the treatment of patients with relapsed or refractory low-grade or follicular, CD-20 positive, B-cell non-Hodgkin’s lymphoma. This was followed by the approval of tositumomab in 1998.

Rituximab is a mouse-human chimeric IgG1-kappa immunoglobulin that selectively binds the CD20 antigen on lymphoma cells inducing complement-and antibody-dependent cytotoxicity. It has also been shown to induce apoptosis in the tumor cell. Several phase I and phase II trials suggest an approximate 50% response rate in the therapy of indolent and relapsed or refractory low-grade or follicular-B lymphoma, but imply no change in survival. Significantly lower response rates were seen in patients with lymphocytic histology or in patients with bone marrow involvement and with two or more extranodal sites of disease.

Rituximab was well tolerated in multiple infusions of 375 mg/m2. The most common adverse effects were low-grade fever, chills, nausea and headache. These were not commonly seen after the initial infusion and were much less frequent or absent with subsequent infusions. The objective of multiple clinical trials in progress is to incorporate MAb therapy in primary management strategies in combination with other cytotoxic therapies. Anti-CD20 therapy has produced favorable results when used in combination with chemotherapy. In one trial, patients with newly diagnosed or relapsed/refractory CD20-positive low-grade or follicular lymphomas received 6 cycles of ADVP (cyclophosphamide, doxorubicin, vincristine and prednisone) administered every three weeks with 6 infusions of rituximab. There was a complete remission response rate of 55% and partial response rate of 40%. Several studies have evaluated rituximab in the treatment of aggressive non-Hodgkin’s lymphoma.

The results were significantly less favorable than those with indolent lymphoma with overall response rates of 30% to 40%. The greater the tumor burden, the less was the response Rte with no response seen in patients with tumors larger than 10 cm.

Another aspect of MAb therapy is it’s in conjugation with radioactive materials such as the radioisotopes iodine-131 and yttrium-90. The follicular lymphomas are extremely sensitive to irradiation and these agents have the advantage that the radiotherapy is targeted to tumor cells, thereby limiting toxic effects on normal cells. Results have been encouraging.

Developing Therapies

Stem cells

A recent development has been the use of stem cell transplantation. Significantly higher response rates to cytotoxic agents have been reported in patients who had received prior stem cell transplantation than in those who had not (78% vs. 34%, respectively, p<0.01.


The idiotype, the molecular determinant of the variable region of the surface immunoglobulin, of a B-cell lymphoma can function as a tumor-specific marker. Immune responses against the idiotype have been induced in patients by tailor-made vaccines. Lymphoma vaccines are prepared by isolating the idiotype protein from the lymphoma tissue, conjugating it to a protein carrier and mixing it with an immunologic adjuvant in vitro.


Early complications of Hodgkin’s disease and non-Hodgkin’s lymphoma are usually related to therapy

Complications of radiotherapy depend on the radiated volume of tissue, dose administered and the technique employed. The acute effects are usually mild and transient and may include dryness of the mouth, changes in taste, pharyngitis, nausea, dry cough, dermatitis, and fatigue. Six weeks to 3 months after radiation therapy, patients may note an electric shock sensation in the lower extremities on flexion of the neck. This so-called Lhermitte’s syndrome is related to transient demyelinization of the cervical spinal cord. Radiation pneumonitis and pericarditis are other rare delayed complications of radiotherapy.

Acute and subacute adverse effects to chemotherapy are fairly common. In fact, MOPP therapy, which was widely used up until recently, has been discontinued in many cancer clinics due to its association with myelosuppression (particularly thrombocytopenia), susceptibility to infections, infertility and autonomic and peripheral neuropathy. The current “gold standard” chemotherapy, ABVD is better tolerated although associated with hair loss, nausea and vomiting, fatigue and myelosuppression (particularly neutropenia).

Delayed and long-term complications include hypothyroidism secondary to thyroid gland radiation, pericardial fibrosis, focal carcinoma or sarcoma secondary to radiation therapy, sterility, anemia and hematological complications of chemotherapy such as thrombocytopenia. Late-appearing infections may occur due to the chronic state of immune depression following therapy and patients who have had splenectomy may have a predilection for bacterial infections.

Special Considerations

Lymphomatous malignancies occurring in children, the elderly, patients with HIV infection and during pregnancy have special therapeutic needs. These patients should be referred to health providers with training and experience in these specialized areas.

In patients with low-grade lymphomas, age does not usually make a difference in type of therapy or prognosis and nonaggressive therapy is usually broken. However, in the treatment of diffuse aggressive lymphomas, age is an important prognostic factor. The Southwest Oncology Group (SWOG) has reported a complete response rate of 65% and a median survival of 101 months in patients under 40 years-old in comparison with a response rate of 37% and a median survival of only 16 months in patients over the age of 65. Similarly, the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group reported superior results in elderly patients with the use of aggressive chemotherapy (CHOP) compared to the results obtained with a less aggressive anthracycline regimen.

Patients with HIV infection also constitute a special group of lymphoma patients because of their predilection for the development of non-Hodgkin’s lymphoma, usually of high-grade B-cell type (immunoblastic or small uncleaved cell types); about 30% unusual extranodal involvement. Studies have demonstrated that aggressive chemotherapy induces remissions and prolongs life. However, chemotherapy toxicity has been reported to shorten survival in these seriously ill patients.

When to Refer

For the primary physician, determination of the presenting signs and symptoms should be followed by biopsy of the most accessible tissue, usually a peripheral node. Following examination and the determination of a definitive diagnosis by an experienced hematopathologist, referral to an oncologist is advisable for recommendations for appropriate therapy. Lymphomatous neoplasms occurring in children, the elderly, during pregnancy or in patients with HIV infection will require specialists experienced in those fields and who are prepared to anticipate the increased demands that these special populations will impose.

Radiotherapy requires the availability of modern appropriate facilities and administration by trained radiotherapists. Chemotherapeutic protocols are best administered by experienced medical oncologists.


All patients with both localized and disseminated Hodgkin’s disease should be treated with curative intent.

The prognosis of patients with stage IA and IIA disease treated by radiotherapy is excellent with 10-year survivals in excess of 80%. Patients with disseminated disease (IIIB, IV) have a 5-year survival rates of 50% to 60%. Poorer results are seen in patients who are older, those who have bulky disease and those with lymphocytic depletion or mixed cellularity on histologic examination. Patients whose disease recurs after radiation may still be curable with chemotherapy. The treatment of choice for patients who relapse after initial chemotherapy is high-dose chemotherapy with autologous stem cell transplantation. This offers a 35% to 50% chance of cure in patients whose disease is still chemotherapy sensitive. Although early stage non-Hodgkin’s lymphoma share the same prognosis as Hodgkin’s disease patients, those with more complex patterns fare less well. The median survival of indolent lymphomas is 6 to 8 years. These diseases ultimately become refractory to chemotherapy, often associated with histologic progression of the disease to a more aggressive form.

The International Prognostic Index is now widely used to categorize patients with intermediate grade lymphomas into risk groups. Factors that confer an adverse prognosis include:

  • Over 60 years-old
  • Elevated serum LDH
  • Advanced stage (III or IV) disease
  • Poor performance status

Patients with no or one risk factor may have a complete (80%) response to standard chemotherapy and most responses (80%) are durable. Patients with two risk factors have a complete 7% complete response and 70% are long-lasting. Patients with higher risk disease have lower response rates and poor survival with standard regimens of treatment and alternative therapies are needed. Early treatment with high-dose therapy and autologous stem cell transplantation improves the outcome. For patients who relapse after initial chemotherapy, the prognosis depends on whether the lymphoma is still partially sensitive to chemotherapy. If so, autologous transplantation offers a 50% chance of long-term salvage.

Patient Education

Patients should be informed of the nature of their disease, its course and prognosis. Most patients with Hodgkin’s disease and non-Hodgkin’s lymphoma have some degree of familiarity with the nature, course and prognosis of their disease. As with other conditions, this knowledge has been reinforced by the ready availability of medical information supplied by the Internet and other sources.

The physician should independently provide the patient with accurate and factual information, correcting any misconceptions the patient may have acquired from other sources. The excellent prognosis of Hodgkin’s disease and non-Hodgkin’s lymphoma and their actual curability with today’s therapeutic armamentarium should be emphasized. This will not alone maintain morale on the part of the patient, but also will support his/her compliance with the program.

As with any disease, the physician should alert the patient to potential therapeutic side effects and significant signs and symptoms that may herald a relapse.

Follow up

Long term survivors of successful therapy should be followed for long-term. Complications such as hypothyroidism, pericardial fibrosis, focal carcinoma or sarcoma secondary to radiation therapy, sterility, anemia and hematological complications of chemotherapy such as thrombocytopenia. The chronic state of immune depression following therapy can result in late-appearing infections such as herpes zoster. Patients who have had splenectomy may have a predilection for bacterial infections.

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