Burkitt's lymphoma

Definition

Burkitt's lymphoma (BL) is a type of non-Hodgkin's lymphoma (NHL) that is sometimes called a B-cell lymphoma or small noncleaved cell lymphoma. It is an endemic (characteristic of a specific place) disease in central Africa but sporadic (occurring in scattered instances) in other countries. Burkitt's lymphoma is one of the most rapidly growing forms of human cancer. In addition, the number of new cases of this tumor is rising in most countries.

Description

Burkitt's lymphoma was first described in 1957 by Denis Parsons Burkitt, an Irish surgeon. While this type of lymphoma is still relatively rare in the United States, it is responsible for 50% of cancer deaths in children in Uganda and central Africa. The endemic form of Burkitt's lymphoma is characterized by rapid enlargement of the patient's jaw, loosening of the teeth, protruding eyeballs, or an abdominal tumor in the region of the kidneys or ovaries.

In the sporadic form of Burkitt's, the patient may have a facial tumor but is much more likely to have an abdominal swelling, often in the area of the ileocecal valve (the valve between the lower portion of the small intestine and the beginning of the large intestine). About 90% of American children with Burkitt's have abdominal tumors. Others may develop tumors in the testes, ovaries, skin, nasal sinuses, or lymph nodes. In adults, Burkitt's lymphoma frequently produces a bulky abdomen and may involve the liver, spleen, and bone marrow.

Demographics

In Western countries, Burkitt's lymphoma is more common in male than in female children. While the average age of patients with endemic Burkitt's is seven years, outside Africa the average age is closer to 11 years. In the United States, the non-Hodgkin's lymphomas as a group account for about 7% of cancers in persons under 20 years of age. Between 40% and 50% of these cases are Burkitt's lymphoma.

In adults, Burkitt's lymphoma is again more common in males than in females. It is 1,000 times more common in persons with AIDS than in the general population. Currently, about 2% of AIDS patients develop Burkitt's lymphoma. The majority of these patients have stage IV disease by the time the tumor is diagnosed.

Causes and symptoms

Causes

Oncogenes

Burkitt's lymphoma affects a part of the immune system known as the lymphatic or lymphoid system. The lymphatic system is a network of tissues, glands, and channels that produces lymphocytes, a type of white blood cell. Some lymphocytes remain in clusters within the lymph nodes, while others circulate throughout the body in the bloodstream or in the lymph, which is a clear yellowish fluid carried by the lymphatic channels. Lymphocytes fall into two groups: T cells, which regulate the immune system; and B cells, which produce antibodies. Burkitt's lymphoma involves the B-cell lymphocytes. In 1982, researchers discovered an oncogene (a gene that can release cells from growth constraints, possibly converting them into tumors) in 90% of patients with Burkitt's lymphoma. Called the C-myc oncogene, it is responsible for the uncontrolled production of B-lymphocytes. It results from a translocation, or exchange, of genetic material between the long arm of human chromosome 8 and the long arm of human chromosome 14. In a smaller number of patients with Burkitt's, the translocation involves chromosomes 2 and 22 or chromosomes 2 and 8.

In the summer of 2000, researchers reported that a gene called the HMG-I/Y gene is also involved in the development of Burkitt's lymphoma. The C-myc oncogene appears to stimulate the HMG-I/Y gene, which then triggers the changes in normal B cells that cause them to multiply rapidly and form tumors.

Viruses

In addition to translocations of genetic material, Burkitt's lymphoma is also associated with oncogenic viruses-the Epstein-Barr virus (EBV) in endemic Burkitt's and human immunodeficiency virus (HIV) in the sporadic form. EBV, or human herpesvirus 4, is the virus that causes infectious mononucleosis. The presence of EBV in patients with endemic Burkitt's has been interpreted as a side effect of the high rates of malaria in central Africa. African children may have immune systems that cannot fight off infection with EBV because they have been weakened by malaria. The children's B-lymphocytes then reproduce at an unusually high rate. Currently, however, the precise role of EBV in Burkitt's lymphoma is still being investigated, because the virus is less common in patients outside Africa. In the United States, about 25% of children and 40% of adult AIDS patients with Burkitt's have the Epstein-Barr virus.

Symptoms

In children, symptoms may appear as soon as four to six weeks after the lymphoma begins to grow. The more common symptom pattern is a large tumor in the child's abdomen accompanied by fluid buildup, pain, and vomiting. If the lymphoma begins in the blood marrow, the child may bleed easily and become anemic.

In adults, the first symptoms of Burkitt's lymphoma may include swelling in a lymph node in the upper body or a swollen and painful abdomen. If the tumor is located in the chest, it may put pressure on the airway and cause difficulty in breathing. There may be unexplained itching or weight loss. Other patients may have more general symptoms, such as fever or a loss of energy. Adults with AIDS often have tumors developing in several different locations in the body by the time they are diagnosed.

Diagnosis

Burkitt's lymphoma is usually diagnosed by examining a piece of tissue from a surgical biopsy of a swollen area in the patient's body-often the jaw area in endemic Burkitt's or the abdomen in the sporadic form. The tissue is examined under a microscope by a pathologist, who is a physician with special training in the study of tissue or body fluid samples. In Burkitt's lymphoma, the tumor cells will show a very high rate of cell division and a characteristic "starry sky" pattern. The pathologist may also test the tissue sample for the presence of EBV, which is found in about 30% of patients diagnosed with Burkitt's lymphoma in the United States.

In addition to a tissue biopsy, the patient is also given a complete blood count (CBC) test, a platelet count, and a lumbar puncture (spinal tap). A small sample of bone marrow is usually taken as well. Most cases of Burkitt's lymphoma do not require extensive x rays, although CT (computed tomography) scans of the chest and abdomen are usually taken, as well as a gallium scan. This scan involves being injected with the radioactive isotope gallium, which is attracted to cancerous cells. Thus, when technicians scan images the body, they are able to pinpoint those cells.

Treatment team

Because cancer in children and adolescents is rare, young people with cancer should be referred to pediatric cancer centers with multidisciplinary teams that specialize in treating cancers in this age group. The specialty teams usually include primary care doctors, pediatric oncologists (pediatricians who specialize in the treatment of childhood cancers), radiation oncologists, social workers, pediatric nurses, and rehabilitation specialists.

Adult AIDS patients who develop Burkitt's lymphoma require specialists in treating HIV infection on their treatment team as well as oncologists, radiologists, and nursing specialists.

Clinical staging, treatments, and prognosis

Staging

The most common system of staging for non-Hodgkin's lymphomas in adults, including Burkitt's lymphoma, is the Ann Arbor system. It specifies four stages as follows:

• Stage I: The lymphoma is either limited to one group of lymph nodes either above or below the diaphragm, or is in an organ or part of the body other than the lymph nodes, but has not spread to other organs or lymph nodes.

• Stage II: The lymphoma is either in two or more lymph node groups on the same side of the diaphragm, or is in only one organ or site other than the lymph nodes but has spread to the lymph nodes near that organ or site.

• Stage III: The lymphoma is present in groups of lymph nodes on both sides of the diaphragm. It may involve an organ or site outside the lymph nodes, the spleen, or both.

• Stage IV: The lymphoma is disseminated (spread) throughout one or more organs outside the lymph nodes. There may or may not be involvement of lymph nodes that are remote from the affected organs.

At each stage, the patient's condition may be described in more detail by using letters to denote the presence of specific general symptoms and/or the body organs that have been affected by the disease. A is used to designate patients who do not have general symptoms; B is used for patients with any of the following:

• unexplained loss of more than 10% of body weight in the last six months

• unexplained fever higher than 38 degrees C (101 degrees F)

• drenching night sweats

The letter E is added if the patient has developed malignancies outside the lymph nodes in areas of the body other than the lymphatic system. Other sites in the body are identified with additional letters, such as D for the skin or H for the liver.

The most commonly used staging system for NHL in children is that of the St. Jude's Children's Research Hospital. It separates patients with a single tumor or diseased lymph node (Stage I) or two or more tumors or diseased lymph nodes on the same side of the diaphragm (Stage II) from those with a large chest or abdominal tumor (Stage III) or involvement of the bone marrow and central nervous system (Stage IV).

Treatment

Because of the rapid rate of tumor growth in this lymphoma, it is important to begin treatment as soon as possible after diagnosis. Bulky abdominal tumors or chest tumors are sometimes removed surgically before the patient begins chemotherapy.

Children with Burkitt's lymphoma are treated with chemotherapy and radiation therapy. The drug used most often to treat endemic Burkitt's is cyclophosphamide (Cytoxan), a drug that suppresses the immune system but has severe side effects. It may be given orally or intravenously. Radiation therapy is used to treat lymphomas that affect the jaw and the area around the eyes. Children with sporadic Burkitt's are treated with a short course of high-dose chemotherapy, usually cyclophosphamide in combination with methotrexate (MTX), vincristine (Oncovin), prednisone (Meticorten), and doxorubicin (Adriamycin). To prevent the spread of the lymphoma to the central nervous system, the patient's head and spine may be treated with radiation therapy and intrathecal methotrexate. In intrathecal chemotherapy, the drug is injected directly into the patient's spinal fluid.

Adults with sporadic Burkitt's lymphoma are treated with a combination of radiation therapy and chemotherapy. A newer high-dose chemotherapy regimen called CODOX-M/IVAC, which is a combination of cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide (Ifex), etoposide (VePesid), and cytarabine (ARA-C), appears to produce good results. Adults with AIDS are usually given low-dose chemotherapy because their immune systems are already damaged. They do not respond as well to treatment as patients without HIV infection.

Newer methods of treatment include bone marrow or stem cell transplantation and monoclonal antibodies (antibodies produced by cloned mouse cells grown in a laboratory). One monoclonal antibody, rituximab (Rituxan), has been approved by the FDA for treatment of non-Hodgkin's lymphomas, including Burkitt's lymphoma. Clinical trials in France indicate that rituximab combined with standard chemotherapy improves the rates of remission and survival in high-risk patients.

Prognosis

The prognosis for children with Burkitt's lymphoma is generally good, as this type of lymphoma responds well to chemotherapy. Children with African Burkitt's often show a significant improvement after only one dose of cyclophosphamide. In the United States, 80% of children treated for early-stage Burkitt's lymphoma remain free from relapse three years after treatment. The newer CODOX-M/IVAC combination chemotherapy has been credited with a cure rate above 90% in both children and adults.

The prognosis for adults depends on a number of factors. In recent years, the International Prognostic Index, or IPI, has been used to predict a specific patient's chance of recurrence and length of survival on the basis of five factors. Each of the following factors is given one point:

• age over 60 years

• the lymphoma is classified as Stage III or Stage IV

• the lymphoma has spread to more than one site outside the lymph nodes

• high levels of lactate dehydrogenase (an enzyme used to measure tumor burden)

• poor general health

An IPI score of 0 or 1 is associated with a 70% rate of disease-free survival at the end of five years and an overall survival rate of 73% at the end of five years. An IPI score of 5, on the other hand, is associated with five-year rates of 40% disease-free survival and 26% overall survival respectively.

In patients with AIDS, the factors that affect the prognosis include: the CD4 lymphocyte count; the presence of opportunistic infections (AIDS-defining illnesses); involvement of the bone marrow; spread of the lymphoma beyond the lymph nodes; age; and the patient's overall strength. A history of opportunistic infections, a CD4 count below 200, age above 35, and being too weak to walk indicate a poor prognosis. The average length of survival of HIV-positive patients with Burkitt's lymphoma is six months.

Alternative and complementary therapies

Alternative and complementary treatments that have been reported as helpful to lymphoma patients include yoga, therapeutic massage, meditation, creative visualization, acupuncture, Reiki, journaling, and art therapy.

Coping with cancer treatment

Adults being treated for Burkitt's lymphoma are most likely to be affected by the side effects of chemotherapy (nausea, hair loss, etc.). Patients with AIDS have the additional concern of increased vulnerability to other AIDS-related infections (thrush, pneumonia, etc.).

Children

Children being treated for Burkitt's lymphoma share many of the concerns of children with other types of cancer, such as changes in appearance (hair loss caused by chemotherapy), continuing a normal schedule (school, sports participation), and coping with such other side effects of treatment as nausea or fatigue. One useful resource is the Candlelighters programs, which offer support and practical information to the parents of children with cancer.

Clinical trials

As of 2001, 39 clinical trials of treatments for AIDS-related lymphomas in adults were being conducted at research centers in the United States. Because Burkitt's lymphoma is relatively rare in children, the National Cancer Institute (NCI) requests that all children with Burkitt's (or other non-Hodgkin's lymphomas) be considered as possible subjects for clinical trials. Information about current clinical trials is available at (800) 4-CANCER or <http://www.cancernet.nci.nih.gov/trialsrch>.

Prevention

Prevention of the endemic form of Burkitt's lymphoma is complicated by the high incidence of malaria in central Africa combined with inadequate medical care. In other countries, some risk factors associated with the sporadic form can be lowered, most particularly lifestyle behaviors that increase the risk of HIV infection. In addition, patients with Burkitt's lymphoma may want to consider genetic counseling because of the role of the C-myc oncogene in their disorder.

Special concerns

Patients diagnosed with Burkitt's lymphoma should be followed up at regular intervals after chemotherapy because of the possibility of long-term relapse. Follow-up examinations should include a general physical examination, a complete blood count, and radiologic examinations.

KEY TERMS

Ann Arbor system

A system of tumor staging used to classify non-Hodgkin's lymphomas in adults. It specifies four stages, which can be further defined by the use of letters to identify general physical symptoms and the parts of the body affected by the lymphoma. The corresponding staging system in children is the St. Jude Children's Research Hospital system.

B cell

A type of lymphocyte that produces antibodies. Burkitt's lymphoma is a cancer of the immune system in which the B cells multiply at an extremely fast rate.

Endemic

Natural to or characteristic of a specific place. In central Africa, Burkitt's lymphoma is an endemic disease.

Epstein-Barr virus (EBV)

A type of herpesvirus (human herpesvirus 4), first identified in 1964, that causes infectious mononucleosis. It is found in most patients with the endemic form of Burkitt's lymphoma, though its role in the disease is still unclear.

International Prognostic Index (IPI)

A system for predicting the prognosis of lymphoma patients on the basis of five factors.

Intrathecal chemotherapy

A form of treatment in which the drug is injected directly into the patient's spinal fluid. It is given to prevent a lymphoma from spreading to the brain and spinal cord, or to treat one that has already spread.

Lymphatic system

The system of glands, tissues, and vessels in the body that produces lymphocytes and circulates them through the body in a clear, yellowish fluid called lymph.

Lymphocyte

A type of white blood cell involved in the production of antibodies.

Monoclonal antibody

An antibody produced in the laboratory from a cloned cell rather than in the body.

Non-Hodgkin's lymphoma (NHL)

One of two major subdivisions of lymphomas. Burkitt's lymphoma is a subcategory of NHL.

Oncogene

A gene that causes the uncontrolled cell growth characteristic of cancer.

Sporadic

Occurring in isolated or scattered instances. Burkitt's lymphoma is a sporadic disease in most countries.

Translocation

The movement of a gene or group of genes from one chromosome to another. Burkitt's lymphoma is associated with a genetic translocation.

QUESTIONS TO ASK THE DOCTOR
• Should I consider bone marrow transplant or monoclonal antibodies as treatment options?

• What are the best treatment options in case of a relapse?

• (for AIDS patients) How can I best protect myself against AIDS-related infections during chemotherapy for Burkitt's lymphoma?