Hodgkin disease

An in-depth report on the causes, diagnosis, treatment, and prevention of Hodgkin's disease.

Highlights

Hodgkin disease is a lymphoma, a cancer of the lymphatic system. Hodgkin disease and non-Hodgkin lymphoma are the two types of lymphomas. Hodgkin disease is distinguished by the presence of large abnormal cells, called Reed-Sternberg cells. The disease is less common than non-Hodgkin lymphoma.

Hodgkin disease is classified into two main types:

• Classical Hodgkin lymphoma , which includes nodular sclerosis and mixed cellularity. These are the two most common subtypes.
• Nodular lymphocyte-predominant Hodgkin disease , which affects about 5% of people with Hodgkin disease.

Hodgkin disease is considered one of the most curable forms of cancer, especially if it is diagnosed and treated early. Five-year survival rates for people diagnosed with stage I or stage II Hodgkin disease are 90 to 95%. Many people with late-stage Hodgkin disease also have good odds for survival.

Hodgkin disease occurs most often in people ages 15 to 40 (especially in their 20s), and in people over age 55. About 10 to 15% of Hodgkin disease cases are diagnosed in children and teenagers. It is slightly more common in males than in females.

Certain types of viral infections may increase the risk of Hodgkin disease. Infectious mononucleosis, which is caused by the Epstein-Barr virus, is associated with increased risk as is infection with the human immunodeficiency virus (HIV).

Chemotherapy and radiation are the main treatments for Hodgkin disease. People who have relapsed may be treated with autologous stem cell transplantation, a procedure which uses the person's own blood cells.

Both chemotherapy and stem cell transplants increase the risk for serious infections. People who undergo these procedures must take precautions to avoid exposure to germs. Ways to prevent infection include:

• Practice good hygiene, including regular hand washing and dental care (brushing, flossing).
• Avoid crowds, especially during cold and flu season.
• Eat only well-cooked foods (no raw fruits or vegetables).
• Boil tap water before drinking it.
• Do not keep fresh flowers or plants in your house as they may carry mold.

Introduction

Hodgkin disease is a type of lymphoma. Lymphomas are cancers of the lymphatic system. They are generally subdivided into two groups: Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Hodgkin disease is also called Hodgkin lymphoma.

The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people talk about swollen glands in the neck, they are usually referring to enlarged lymph nodes. Common areas where lymph nodes can be easily felt, especially if enlarged, are: the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).

Hodgkin disease usually starts in B cell lymphocytes located in lymph nodes in the neck area, although any lymph node may be the site of initial disease.

Types of Hodgkin Disease

There are two main types of Hodgkin disease:

• Classical Hodgkin lymphoma
• Nodular lymphocyte-predominant Hodgkin disease.

• Nodular Sclerosis : Nodular sclerosis is the most common subtype, representing most HD cases. Younger people are more likely to have this type. The nodes first affected are often those located in the center of the chest (the mediastinum) or the neck.
• Mixed Cellularity : Mixed cellularity is the next most common HD form. It occurs mostly in older adults. Mixed cellularity refers to the presence of Reed-Sternberg cells and other cell types.
• Lymphocyte Rich : The lymphocyte-rich subtype accounts for about 5% of all HD cases. It tends to affect men more than women.
• Lymphocyte Depleted: The lymphocyte-depleted subtype is the least common type of HD, occurring in only about 1% of cases. It is usually seen in older people and people infected with HIV. It is also more common in less developed countries. The cancer tends to be diagnosed when it is widespread, affecting the spleen, bone marrow, and liver as well as abdominal lymph nodes.

The Lymphatic System

Lymphomas are tumors of the lymphatic system. This system is a network of organs, ducts, and nodes. The lymphatic system transports a watery clear fluid called lymph throughout the body. The lymphatic system contains lymphocytes, which are important cells involved in defending the body against infections.

• Lymphocytes develop either in the bone marrow (called B cells or bone marrow-derived cells) or in the thymus gland (called T cells or thymus gland-derived cells).
• Both leukemia and lymphomas (Hodgkin disease and non-Hodgkin lymphomas) are cancers of lymphocytes. The difference is that leukemia starts in the bone marrow while lymphomas originate in lymph nodes and then spread to the bone marrow or other organs.

• The normal size of a lymph node varies from that of a pinhead to a bean. Most nodes are clustered throughout the body. Node clusters are found in the neck, lower arm, armpit, and groin, as well throughout the inside of the body.
• In a lymph node, lymphocytes are first exposed to foreign substances, such as bacteria. This exposure prompts the lymphocytes to produce antibodies, which target and attack these foreign proteins (antigens). More lymphocytes may also be made in the lymph node and added to the contents of the lymph fluid.
• Lymphocytes from elsewhere in the body may also be filtered out of the lymph fluid into the lymph node.

• If it spreads below the diaphragm, it usually reaches the spleen first; the disease may then spread to the liver and bone marrow.
• If the disease starts in the nodes in the middle of the chest, it may spread outward toward the chest wall and areas around the heart and lungs.

Risk Factors

Hodgkin disease is less common than non-Hodgkin lymphoma. It accounts for about 10% of all lymphomas. According to the American Cancer Society, about 9,000 new cases of Hodgkin disease (HD) are diagnosed in the United States each year.

The exact causes of Hodgkin disease are unknown. Research indicates that the malignant process leading to Hodgkin disease may be triggered by a combination of environmental and genetic factors along with a susceptible immune system.

Age and Gender

Hodgkin disease occurs most often in people ages 15 to 40 (especially in their 20s), and in people over age 55. About 10 to 15% of Hodgkin disease cases are diagnosed in children and teenagers.

Hodgkin disease is slightly more common among males than females. Women who get Hodgkin disease may have a slightly lower risk for relapse after treatment than men.

Viral Infection

Infectious mononucleosis ("mono"), which is caused by the Epstein-Barr virus (EBV), is linked with increased risk for Hodgkin disease. However, only 1 in 1,000 people with mononucleosis develops Hodgkin disease. The Epstein-Barr virus is present in 90% of all people and, in the great majority of these cases, the virus causes a mild case of mononucleosis or no illness at all. Only a very small percentage of people who have had mononucleosis go on to develop HD. Other factors must be present to trigger the malignancy.

People infected with the human immunodeficiency virus (HIV), which weakens the immune system, are also at increased risk of developing Hodgkin disease.

Family

Hodgkin disease runs in families in about 5% of cases. Siblings of people with Hodgkin disease have a 3 times higher risk than the general population.

Symptoms

Symptoms of Hodgkin disease may include:

• Swollen (but painless) lymph nodes in the neck, armpits, or groin
• Pain in lymph nodes after drinking alcohol
• Itching throughout body (pruritus)
• Persistent fatigue
• Coughing, difficulty breathing, or chest pain may indicate that swollen lymph nodes in the chest are pressing on the windpipe
• Unexplained weight loss
• Persistent fever
• Drenching night sweats

The last three symptoms (weight loss, fever, and night sweats) are classified as "B symptoms." B symptoms are used in staging Hodgkin disease and can indicate that more aggressive treatment will be required.

Sometimes people with Hodgkin disease do not experience any symptoms, or symptoms may not appear until the cancer is very advanced. Enlarged lymph nodes can also be caused by many noncancerous conditions, such as infections.

Diagnosis

The doctor will take a medical history and perform a physical examination. If these procedures indicate Hodgkin disease, a number of additional tests may be needed to either rule out other diseases or confirm HD and determine the extent of the cancer.

Physical Examination

The doctor will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node is evaluated. For example, a stony, hard node is often a sign of cancer, usually one that has metastasized (spread to another part of the body). A firm, rubbery node may indicate lymphoma (including Hodgkin). Soft tender nodes suggest infection or inflammatory conditions.

Blood Tests

Blood tests are performed to measure white and red blood cells, blood protein levels, the uric acid level, blood proteins, and the liver's function.

Imaging Techniques

Biopsy

A biopsy of the suspicious lymph node is the definitive way to diagnose Hodgkin disease. The lymph node sample will be examined by a pathologist for the presence of Reed-Sternberg cells or other abnormal features.

The type of biopsy performed depends in part on the location and accessibility of the lymph node. The doctor may surgically remove the entire lymph node (excisional biopsy) or a small part of it (incisional biopsy). In some cases, fine needle aspiration is used to withdraw a small amount of tissue from the lymph node. Biopsies of bone marrow may also be performed in people with existing Hodgkin disease to see if the cancer has spread to the marrow.

Prognosis

Hodgkin disease is considered one of the most curable forms of cancer, especially if it is diagnosed and treated early. Unlike other cancers, Hodgkin disease is even potentially curable in late stages.

A 5-year survival rate is the percentage of people who live at least 5 years after their cancer is first diagnosed. Five-year survival rates for people diagnosed with stage I or stage II Hodgkin disease are about 90%. With advances in treatment, even most people diagnosed with advanced Hodgkin disease live longer than 5 years.

Outlook tends to be poorer for people who do not respond to first-line therapy or who relapse within a year of treatment. People who survive 15 years after treatment are more likely to later die from other causes than from Hodgkin disease.

Factors that Influence Prognosis

Survival rates are a general term based on data collected from large numbers of people. A person's prognosis depends on factors specific to that individual. Factors that influence prognosis and survival include age, overall health, stage of cancer at time of diagnosis, symptoms associated with the cancer, and how well the cancer responds to treatment.The International Prognostic

Factors Project on Advanced Hodgkin Disease uses 7 factors to help determine which people with advanced Hodgkin disease have a more serious prognosis and could benefit from more aggressive chemotherapy. These factors are also used to predict success in people with relapsed or persistent HD who are undergoing stem cell transplantation.

The more of these factors that are present, the worse the outlook and the more likely the person needs to be treated aggressively:

• Being male
• Age of 45 years or older
• Stage IV disease
• Low blood albumin level (less than 4g/dL; albumin is a type of protein.)
• Low hemoglobin level (less than 10.5g/dL; hemoglobin is the oxygen-carrying component of red blood cells)
• High white blood cell count (more than 15,000)
• Low lymphocyte count (less than 600)

Long-Term Effects of Treatments

The good news about Hodgkin disease is that treatment can cure the disease. The bad news is that survivors face a higher than average risk for long-term complications of these treatments, some very serious.

Many people experience chronic fatigue that can sometimes last for years. The most serious complications are secondary cancers and heart disease, which may develop over the 20 to 30 years following treatments.

Secondary cancers include non-Hodgkin lymphoma, leukemia, melanoma, stomach and lung cancers, and breast and uterine cancers. Heart disease complications include coronary artery disease, stroke, heart valve problems, and cardiomyopathy (weakening of the heart muscle). Thyroid and other endocrine disorders are also a potential complication. Combinations of radiation and chemotherapies pose the highest risk of these problems.

Studies of adult survivors of various childhood cancers have found that 30 years after treatment, people with cured Hodgkin disease are especially likely to have other serious health problems. Female survivors face a significantly greater risk than male survivors. In particular, women who received chest radiation are at very high risk for developing breast cancer.

People with Hodgkin disease should get a written record of the treatments they received as children, and the potential risks of these treatments. These records can help the doctors who later oversee their care monitor for potential health problems.

Survivors of Hodgkin disease should receive regular screening tests for cancer and heart disease. They may need to get these tests at a younger age than most people. In particular, people who were treated with chest radiation should consider getting blood tests every 5 years to measure their cholesterol levels. Women who received chest radiation should be sure to get regular mammograms and breast magnetic resonance imaging (MRI).

Treatment

Treatment options for Hodgkin disease depend on:

• Type of Hodgkin disease
• Tumor stage, size, and location
• Person's age and overall health status
• Presence or absence of "B symptoms" (weight loss, persistent fever, and night sweats)

Certain factors may determine whether more intensive treatment is required. For example, the presence of B symptoms and "bulky" (large mass) tumors usually indicates a more aggressive treatment approach.

Chemotherapy and radiation are the main treatments for Hodgkin disease. Stem cell transplantation or a biologic drug may be recommended for people whose cancer has recurred.

Staging

Hodgkin disease is staged (I through IV) depending on how far the cancer has spread. Staging is the primary method for determining both treatment options and prognosis.

Treatment Options by Stage

Treatments for refractory or relapsed Hodgkin include high dose chemotherapy with stem cell transplantation. People who are not good candidates for transplantation or who have not been helped by it may benefit from treatment with the biologic drug brentuximab (Adcetris).

Preparing for Side Effects before Treatment

For women, egg (oocyte) cryopreservation is recommended. This procedure involves harvesting and freezing a woman's eggs (oocytes), and can be followed by in vitro fertilization and freezing of embryos for later use. It requires several weeks of pre-treatment with ovarian stimulation drugs, so timing is very important. For women who will receive radiation therapy to the pelvic region, a surgical procedure that moves the ovaries out of the path of radiation (ovarian transposition) can also help preserve fertility.

Monitoring after Treatment

Relapse of Hodgkin disease is not uncommon, even after treatment for early stages. It can occur a decade or more after treatment. Relapse can occur in early-stage disease, probably because the limited radiation normally used in such cases does not destroy the disease outside of the area irradiated. People who had large tumors in the chest are also at higher risk for recurrence.

Periodic examinations and imaging tests are necessary for years after treatment, both to check for signs of relapse as well as to monitor the long-term effects of treatments.

Treatment of Pregnant Women

Because Hodgkin disease often occurs in younger adults, treatment during pregnancy is of particular concern. Therapy must be effective enough to protect the mother without hurting the fetus. Chemotherapy is rarely used early in the term, because it poses a risk for birth defects.

Treatment choice must be individualized, taking into consideration the mother's wishes, the severity and pace of the disease, and the remaining length of the pregnancy. The treatment plan may need to be changed as the pregnancy progresses. If the disease develops in the second half of the pregnancy, it may be possible to postpone chemotherapy or radiation therapy until after an early induced delivery.

Chemotherapy

Chemotherapy is usually the first treatment for all stages of Hodgkin disease. Chemotherapy uses drugs to kill cancer cells. The drugs are called cytotoxic (toxic to cells) medications. Chemotherapy is considered a systemic, therapy because the drugs affect cells throughout the body.

Chemotherapy drugs may be taken by mouth as pills or given by injection or infusion. Treatment may be administered at a medical center, outpatient infusion center, medical office, or even at home. Some people receiving chemotherapy may need to remain in the hospital for several days so the effects of the drugs can be monitored.

People typically receive 2 to 6 cycles of chemotherapy, depending on the stage. A cycle is usually 28 days and consists of several doses of drug administration followed by a period of rest.

Specific Drugs and Drug Combinations

Several chemotherapy regimens are used for treating Hodgkin disease. Standard regimens include ABVD, Stanford V, and BEACOPP.

ABVD is used to treat adults and children in both early and late stages of Hodgkin disease. For early stages (I and II), people typically receive 2 cycles of the drugs, followed by radiation. In late stages (III and IV), people receive 6 to 8 cycles of chemotherapy. ABVD consists of a 4-drug combination:

• Doxorubicin (Adriamycin)
• Bleomycin
• Vinblastine
• Dacarbazine

Stanford V consists of a 7-drug combination often given with radiation:

• Doxorubicin (Adriamycin)
• Mechlorethamine (nitrogen mustard)
• Vincristine
• Vinblastine
• Bleomycin
• Etoposide
• Prednisone

BEACOPP is a chemotherapy regimen reserved for late-stage Hodgkin disease. It is effective but can increase risk for developing secondary cancers such as leukemia. People who are treated with BEACOPP should receive long-term follow-up care to monitor for side effects from this therapy. BEACOPP consists of 7 drugs:

• Bleomycin
• Etoposide
• Adriamycin
• Cyclophosphamide
• Vincristine (Oncovin)
• Procarbazine
• Prednisone

Brentuximab (Adcetris) is a newer biologic drug that is used by itself. It is approved for people with Hodgkin disease who have either:

• Failed to respond to at least two prior multidrug chemotherapy regimens and who are not candidates for autologous stem cell transplantation
• Undergone a transplant but have not been helped by it

Brentuximab works by targeting CD-30, a protein found on Hodgkin cancer cells. The drug is given by intravenous infusion. The most common side effects are neutropenia, peripheral sensory neuropathy, fatigue, nausea, and anemia. A more serious but rare side effect is the brain disorder progressive multifocal leukoencephalopathy (PML).

Side Effects and Complications

Side effects and complications of any chemotherapeutic regimen are common, are more severe with higher doses, and increase over the course of treatment.

• Nausea and vomiting
• Diarrhea
• Hair loss
• Mouth sores
• Weight loss

• Neutropenia is a severe drop in the number of white blood cells produced in the bone marrow. Neutropenia increases the chance for infection and is a potentially life-threatening condition. Drugs called granulocyte colony stimulating factor (G-CSF) are used to help boost white blood cell count. These drugs, which include filgrastim (Neupogen) and pegfilgrastim (Neulasta) can help lessen the risk for neutropenia occurrence and, if neutropenia does occur, to reduce its length and severity.
• Anemia is a reduced number of red blood cells. Erythropoietin stimulates red blood cell (hemoglobin) production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). In people with cancer, these drugs should be used to only treat anemia associated with chemotherapy and to increase hemoglobin levels to no more than 12 g/dL. Treatment should stop as soon as chemotherapy is complete. These drugs may not be safe or appropriate for all people.
• Peripheral sensory neuropathy is damage to the peripheral nerves that carry signals to and from the spinal cord to the rest of the body. Symptoms can include tingling, burning, and loss of sensation in the legs and arms. Peripheral neuropathy can also cause problems to muscles, the digestive system, and body organs including the heart.
• Increased susceptibility to infections
• Liver and kidney damage
• Abnormal blood clotting (thrombocytopenia)
• Allergic reactions

• Fatigue and general aches and pains are called somatic symptoms. Fatigue is especially common after chemotherapy and can sometimes last for several years.
• Many women stop menstruating after chemotherapy. The risk for premature menopause and infertility is higher for women with advanced-stage Hodgkin disease who are treated after age 30.
• Bone thinning (osteoporosis) may occur with steroid treatments such as prednisone.
• Heart failure may occur with the use of anthracycline drugs (such as doxorubicin).
• Bleomycin (Blenoxane) is particularly toxic to the lungs. Vinblastine may also pose a risk when used in combination with radiation therapy.
• Certain types of chemotherapy drugs may increase the long-term risk for developing acute leukemia and myelodysplastic syndrome (MDS). Radiation used in combination with chemotherapy may increase the risk for leukemia.

Radiation Therapy

Radiation therapy, which shrinks tumors, used to be the main treatment for Hodgkin disease. Today, radiation therapy is mainly used to treat early stage (I or II) Hodgkin disease and is usually given following chemotherapy.

Radiation Treatment Approaches

Extended field radiation, an older approach that targeted both the diseased lymph nodes as well as surrounding healthy lymph nodes, is no longer used.

Doctors are working on refining radiation therapies for Hodgkin disease so that they more precisely target the affected lymph nodes and deliver the lowest possible effective dose of radiation. The aim is to destroy the cancerous cells while minimizing the damage to healthy cells and causing fewer side effects.

Newer radiation techniques for Hodgkin disease include involved node radiation therapy, involved site radiation therapy, intensity modulated radiation therapy, and proton therapy.

Side Effects of Radiation

Fatigue, nausea, diarrhea, dry mouth, skin irritation, and increased risk for infections are common short-term side effects of radiation therapy. These side effects generally go away after treatment is completed.

Radiation therapy can cause more serious long-term complications, which is why researchers are working on techniques to reduce the radiation doses and increase the accuracy of the beams. These side effects generally depend on the radiation target site in the body. They include:

• Chest radiation can lead to lung damage and difficulty breathing. Lung cancer risk may be increased, especially for people who are current or former smokers. Chest radiation may also increase the long-term risk for heart disease and heart attack.
• Breast cancer is a serious concern for women with Hodgkin who received chest radiation therapy before the age of 35. It is important for these women to begin having mammograms (and breast MRI) at a younger age than usual and to continue regular mammogram screenings.
• Neck radiation can increase the later risk for underactive thyroid (hypothyroidism) and for thyroid cancer.
• Radiation to the head and neck may also increase the risk for stroke. Some research suggests that adults who survived childhood Hodgkin disease have a 4 times higher risk of having a stroke than healthy people.
• Radiation to the pelvic area may increase the risk for infertility, particularly for women. For girls and young women, doctors may recommend surgically moving the ovaries away from the path of the radiation, a procedure called ovarian transposition.

Transplantation

Relapsed or resistant Hodgkin disease is sometimes treated with high-dose chemotherapy followed by stem cell transplantation. This approach allows a person to receive higher doses of chemotherapy than could normally be used.

Transplantation involves removal and replacement of stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Intensive cancer treatments harm stem cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them.

Transplantation Procedure

Stem cells must first be collected in one of the following ways:

• Directly from blood (peripheral blood stem cell transplantation)
• From bone marrow (bone marrow transplantation)

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Stem cells are collected several weeks before the procedure. They are frozen and stored while the person undergoes high-dose chemotherapy. Some people receive high-dose whole body radiation therapy along with chemotherapy.

After pre-transplant therapy is completed, the frozen cells are thawed and then infused into the person through a central line catheter implanted in the chest. The infusion process takes several hours. Within a few weeks, these cells start to generate new white blood cells and then new red blood cells.

Infection

The risk for infection is greatest during the first 6 weeks following the transplant. During this period, the person usually remains in isolation and receives antibiotics and intravenous nutrition. It takes 6 to 12 months post-transplant for a person's immune system to fully recover.

Many people develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, Aspergillus (a type of fungus), and Pneumocystis jiroveci (a fungus) are among the most serious life-threatening infections.

It is very important that people who have stem cell transplants take precautions to avoid infections. Guidelines for infection prevention include:

• Discuss with your health care provider what vaccinations you need and when you should get them.
• Avoid crowds, especially during cold and flu season.
• Be diligent about hand washing, and make sure that visitors wash their hands. Alcohol-based hand rubs are best.
• Avoid eating raw fruits and vegetables. Your food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
• Boil tap water before drinking it.
• Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
• Do not sleep with pets. Avoid contact with pets' excrement.
• Avoid fresh flowers and plants as they may carry mold. Do not garden.
• Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
• Report to your health care provider any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection.
• Report to your ophthalmologist any signs of eye discharge or changes in vision. People who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Other Side Effects and Complications

Early side effects of transplantation are similar to chemotherapy and include nausea, vomiting, fatigue, mouth sores, and loss of appetite. Bleeding because of reduced platelets is a high risk during the first 4 weeks and may require transfusions. Later side effects may include fertility problems (if the ovaries are affected), thyroid gland problems (which can affect metabolism), lung damage (which can cause breathing problems), other organ damage, and bone damage.

In younger people, there is a small long-term risk for leukemia after transplantation. Chemotherapy itself increases the risk of secondary cancers. Studies suggest that transplantation after chemotherapy does not add any additional risks.

Resources

• www.cancer.gov -- National Cancer Institute
• www.cancer.org -- American Cancer Society
• www.lls.org -- Leukemia and Lymphoma Society
• www.lymphoma.org -- Lymphoma Research Foundation
• www.asco.org -- American Society of Clinical Oncology
• www.cancer.net -- Cancer.Net
• www.lymphomainfo.net -- Lymphoma Information Network
• www.cancer.gov/clinicaltrials -- Find clinical trials