Eric Shinohara, MD, MSCI and Elizabeth N. Kuhn
Updated by: Karen Arnold-Korzeniowski, BSN RN
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 19, 2016
Lymph nodes are small, bean-sized glands that exist throughout the body and make up part of the lymphatic fluid circulation system. Lymphatic fluid is a clear fluid that leaks out of blood vessels, and in order for the body to keep the blood volume constant, lymphatic fluid is collected and returned to the blood via the lymphatic circulation. Lymph nodes are connected to each other by small lymph vessels that transfer the lymphatic fluid.
Before returning the lymph to the blood, lymph nodes clean the fluid, looking for possible infection-causing germs (bacteria, viruses, etc.). Most people can remember having swollen "glands" under their neck when they had an infection. Those "glands" were swollen lymph nodes that were reacting to the infection. In most cancers, this network of lymph nodes is one of the first areas to which cancer can spread. However, in Hodgkin's disease (also known as Hodgkin Lymphoma) the cancer arises from the lymph nodes themselves.
Clusters of lymph nodes exist in particular parts of the body, like the neck, the underarm, and the groin. There are also specific organs in the body that are considered part of the lymphatic system, like the spleen and the tonsils; however, small amounts of lymph tissue can also be found in almost every other organ in the body. While there are certain areas in the body where lymph nodes are routinely found, the specific arrangement and number of these lymph nodes is different from person to person.
Hodgkin's disease, or Hodgkin lymphoma, is a cancer of lymph nodes and lymphatic tissues, and is named after the pathologist who originally described the disease in 1832, Dr. Thomas Hodgkin. Hodgkin's disease is a fairly uncommon cancer, with about 9,050 cases diagnosed in 2015. Hodgkin's disease caused approximately 1,150 deaths in 2015. Hodgkin's disease occurs slightly more commonly in men (5,100 men diagnosed in 2015 as compared to 3,950 women), and much more frequently in Caucasians. Hodgkin's lymphoma most commonly affects people ages 15 to 40 (especially those in their 20s) and those over the age of 55. (Pediatric Hodgkin's Disease is discussed separately).
There are other types of lymphomas besides Hodgkin's disease, known as Non-Hodgkin's lymphomas. Although non-Hodgkin's lymphomas are also a cancer of the lymph nodes, they behave differently and are treated differently. Hodgkin's disease occurs when infection-fighting cells in the lymph nodes begin to grow out of control and compress nearby tissues or spread throughout the body via the lymphatic circulation. Hodgkin's disease is distinguished from the other types of lymphomas by the way it looks under a microscope and by the way it grows and spreads.
There are two main types of Hodgkin's disease: Classical Hodgkin disease and Nodular lymphocyte predominant Hodgkin disease. There are four subtypes of the classical type:
Overall, classical Hodgkin's lymphoma accounts for about 95% of all cases, while nodular lymphocyte-predominant (NLP) Hodgkin's lymphoma is quite rare. The type of Hodgkin's disease a person has is determined by a pathologist, who examines a portion of tissue of the involved node(s). Pathologists look for a particular abnormal cell known as a Reed-Sternberg cell (also known as an "owl's eye" cell) in order to diagnose classic Hodgkin's disease, or a "popcorn" cell to diagnose NLP Hodgkin's disease. The distinction between classical Hodgkin's and NLP is important because they are treated differently.
No one knows what causes Hodgkin's disease, however several factors have been identified to be associated with Hodgkin's disease. It is important to note that these factors may increase the risk of developing Hodgkin's disease, but that the majority of people with these conditions still do not develop Hodgkin's disease.
Because no one knows exactly what causes Hodgkin's disease, there are no specific steps you can take to prevent it.
Hodgkin's disease is rare enough that it is not screened for in the general population with any specific blood tests or radiology studies. The best way to pick up a diagnosis of Hodgkin's disease early is to see your healthcare provider regularly for a thorough physical examination. Often, the patient is the first to notice a lump, and if this happens, one should see their healthcare provider for examination and further evaluation.
The early stages of Hodgkin's disease often do not cause any symptoms. As the tumor grows in size, however, it can produce a variety of symptoms. The most common lymph node site affected by Hodgkin's disease is in the neck, and neck swelling is what often brings people to the healthcare provider. However, Hodgkin's disease can also cause swelling of the lymphnodes in the underarm, upper chest, abdomen, or groin; these swellings are often not painful but can feel rubbery. Hodgkin's disease can also cause fevers, drenching night sweats, fatigue, weight loss, and even generalized itching.
If the Hodgkin's lymphoma is affecting the lymph nodes in the chest, which are not typically seen or felt, the swelling can cause symptoms such as cough, shortness of breath, or chest pain. A chest x-ray can often detect these swollen nodes in the chest. Interestingly, some people with Hodgkin's disease will note pain in the lymph nodes after minimal alcohol consumption.
Many of these symptoms are non-specific, and could represent a variety of different conditions; however, your healthcare provider needs to see you if you have any of these problems.
When a patient presents with symptoms suggestive of Hodgkin's disease, his/her healthcare provider will perform a thorough history and physical examination. If there is a node that is enlarged, it will likely be surgically removed in what is called an "excisional biopsy". Either part of or the entire node is removed so that a doctor, called a pathologist, can look at it under a microscope. A biopsy specimen is required to make the diagnosis of Hodgkin's disease. It is important that the provider use an excisional biopsy—the alternative is a core-needle biopsy, where a small needle is inserted into the swollen lymph node and a sample of the lymph node is taken. However, core-needle biopsies may not provide enough tissue to make a diagnosis.
Once the diagnosis is made, a healthcare provider will order a number of tests to get a sense of the extent and severity of the disease. A few different blood tests will probably be ordered, including blood counts, liver function tests, kidney function tests, erythrocyte sedimentation rate (ESR, a marker of inflammation), and a pregnancy test in women of childbearing age.
The physician will also plan for you to get a PET-CT scan to see the extent of the disease. A PET-CT scan combines a CT scan of the body (a 3D xray) with PET. The CT portion helps your provider define the location of lymph nodes that are affected by cancer. The PET scan is a special type of scan where a sugar solution is injected through an IV; tissues that are very active (like cancer cells) use the sugar for energy. These areas "light up" when they are scanned. The PET scan is important for two reasons: 1) It helps confirm where lymphoma is located in the body; and 2) It gives your provider the "before-treatment" picture. PET scan is used after treatment to determine if the cancer has been killed and it is important to be able to compare the "after-treatment" PET with a "before-treatment" PET.
You may have a bone marrow aspiration and biopsy done to determine if the disease is in your bone marrow. You may have a number of other tests depending upon the symptoms you are having. These tests include an echocardiogram to check your heart function, pulmonary function tests to check the function of your lungs, X-rays, CT scans, and MRIs. Your provider will determine which of these tests are necessary.
After your full work-up is complete your care team will stage your cancer. Staging is important because it classifies your cancer by how much disease you have and if/where it has spread. Staging helps guide your treatment plan. The staging system for Hodgkin's disease is known as the Cotswold system. It has four different stages:
Early stage Hodgkin's lymphoma (Stage I-II) is divided further into two groups, "favorable" and "unfavorable", to help predict which patients may benefit from more aggressive treatment. The criteria for unfavorable disease are as follows:
Your cancer staging may include the letters “E”, “S”, “B”, “A” or “X”. Explanations are as follows:
Some other terms used when describing Hodgkin's disease are resistant or progressive disease. These terms are used when treatment does not make the disease go away or the disease gets worse. Recurrent or relapsed disease is the term used when the disease went away with treatment, but has returned in either the same place or in another part of the body.
The treatment plan chosen is dependent upon the stage of the disease and the patient's current health status. The treatment plan should be developed by a provider who specializes in the treatment of lymphomas. The two standards of treatment of Hodgkin's lymphoma are chemotherapy and radiation. Hodgkin's lymphoma can also be treated with multimodal therapy (combination of therapies), which includes chemotherapy, radiation and stem cell transplant. Other therapies may include biotherapy or clinical trials.
Chemotherapy is the use of medications that treat cancer. Chemotherapy is known as a “systemic” treatment, which means that it goes throughout the entire body. These medications may be given through a vein (IV, intravenously) or by mouth, as pills. Chemotherapy is frequently used to treat Hodgkin's disease, and combinations of different chemotherapy medications are typically used to kill the tumor cells. Some chemotherapy regimens may be given prior to treatment with radiation. The most common chemotherapy regimens used are called ABVD, BEACOPP, and Stanford Five (V).
As you may imagine, ABVD is a less rigorous chemotherapy regimen than either BEACOPP or Stanford V. You may receive one of these regimens or a combination of other medications. It is not always clear that one chemotherapy regimen is better than the others, and thus, the regimen selected may vary between providers. Your provider can explain why he or she recommends one particular regimen over another.
There are a number of side effects associated with chemotherapy. These vary based on which kind of chemotherapy is used, and more detailed explanations of chemotherapy can be found on OncoLink.
Another class of drugs often used to treat lymphomas are the monoclonal antibodies, which are a type of targeted therapy. Antibodies are produced normally in the body and are used to "mark" abnormal things (eg. bacteria, viruses, cancer cells), so that the immune system will attack and kill those cells. Monoclonal antibodies are man-made antibodies that are designed to attack specific kinds of cells (in this case, lymphoma cells), taking advantage of the bodies own defense systems to kill cancer. The most common antibodies used in the treatment of Hodgkin's lymphoma are rituximab (Rituxan®) and brentuximab vedotin (Adectris®). Rituximab can be given by itself or in combination with chemotherapy and/or radiation. Brentuximab vedotin is often used for patients whose disease has returned after other treatments. It is being studied to see if it is helpful to be given with chemotherapy.
Radiation therapy uses high-energy rays (similar to x-rays), delivered from an external source, to kill cancer cells. Unlike chemotherapy, which goes everywhere in the body, radiation therapy is a local treatment. It is targeted only to small areas. There are two main types of radiation used to treat Hodgkin's lymphoma: photon (traditional radiation) and proton therapy. Proton therapy is only available at a few centers nation-wide. You should discuss with your provider which type of radiation therapy is right for you.
Radiation therapy has evolved in the last few decades, as concern has grown over the long-term affects of having radiation that involves important organs, like the heart and lungs. For this reason, when possible, radiation is avoided. In patients who need radiation, there is considerable effort to make sure the surrounding healthy tissues receive the least amount of radiation exposure as possible. Advanced radiation techniques and methods, such as IMRT, respiratory gating, breath holding and advanced simulation techniques (4D imaging), allow for highly conforming doses. This means the radiation beams are shaped tightly around the tumor and spare surrounding tissue as much as possible. In addition, the area treated has evolved over time. Many radiation oncologists now choose to treat just the lymph nodes that were involved and the surrounding areas where tumor had spread (called involved site radiation therapy, ISRT). This has largely replaced treating an entire field surrounding the involved lymph nodes (involved field radiation therapy). In the past, even larger fields were treated, including large areas of healthy tissue (called extended field radiation therapy). As you can see, the field of radiation has evolved as it has learned the dangers of exposing healthy tissue to radiation.
Radiation therapy typically requires patients to come to a radiation therapy treatment center 5 days a week, for several weeks. The radiation team will take scans and measurements to determine the number of doses needed and exactly where the radiation beams should be aimed. The treatment takes just a few minutes, and it is painless. You shouldn't feel anything, though you may see some lights on the machines and hear them as they move around. Most radiation providers see patients weekly while they are receiving treatment to monitor for side effects and answer questions.
Radiation side effects are generally limited to the area of treatment. Hence, if the chest is being treated, acute side effects (occurring during treatment) may include: the skin on the chest may become red or sore, the hair in the treatment area may fall out, the throat may become sore. More information about the acute side effects of radiation can be found here.
Longer term, there is the potential for heart damage and earlier onset of coronary artery disease. The lungs and thyroid tissue may be damaged. The damage from radiation occurs over time and some damage can take many years to cause symptoms. We will talk more about long-term effects later in this article. If the abdomen and/or pelvis require radiation, fertility can be affected as well as the abdominal and pelvic organs. Your radiation provider can answer questions about the process and specific side effects of radiation therapy for you.
Sometimes patients receive chemotherapy and/or radiation therapy, but the Hodgkin's disease is still present (also known as refractory Hodgkin's disease). When this happens, the provider may recommend stem cell transplantation (SCT). Stem cells are precursor cells that can develop into other cells of the body when placed in the right environment. In the case of SCT, the stem cells used are pre-destined to become blood cells (white and red blood cells or platelets).
Stem cell transplant is used along with high doses of chemotherapy. The high doses of chemotherapy are so intense that they wipe out a person's bone marrow. Without bone marrow, a person can't make the components of blood and the immune system that are necessary to survive. In order to replace the patient's bone marrow, stem cells are given. In the case of an autologous stem cell transplants, a patient's own stem cells are harvested before the high dose chemotherapy is given, stored, and then finally returned to the patient after the chemotherapy is done. Another option is an allogeneic stem cell transplant, where the stem cells are taken from a donor whose cells "match" those of the recipient. These cells are used in the same way, given to the patient after high dose chemotherapy. In both cases, bone marrow cells can re-grow from the stem cells. This enables a patient to tolerate the high doses of chemotherapy that work against Hodgkin's disease but have the unwanted side effect of wiping out healthy bone marrow.
Stem cell transplantation can sometimes cure patients when other treatment strategies have failed. However, stem cell transplantation is a complex and intense treatment, so it is typically reserved for patients who aren't cured with the initial treatment regimens of chemotherapy and/or radiation therapy.
There are clinical research trials for most types of cancer, and every stage of the disease. Clinical trials are designed to determine the value of specific treatments. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered, or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help manage side effects. Clinical trials are extremely important in furthering our knowledge of disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.
Hodgkin's disease was once believed to be incurable, but tremendous advancements in treatment have led to 5-year survival rates of about 85%. The type and duration of treatment depends on the stage of Hodgkin's lymphoma, whether it is favorable or unfavorable, and if it is NLP Hodgkin's. Most often, however, a combination of both chemotherapy and radiation is used. The following discussion of specific treatments will explain more based on stage and other prognostic information.
The typical treatment of early stage Hodgkin's disease consists of chemotherapy with or without radiation. For combined modality treatment (chemotherapy and radiation) a patient is first treated with chemotherapy, consisting of either ABVD or Stanford V. After completion of chemotherapy the disease will be restaged with either PET or CT scan. If the results of the PET/CT scan show that the disease has responded well to the chemotherapy, then radiation will be started. If there was a suboptimal response, no response, or worsening of the disease despite chemotherapy, most clinicians will repeat a biopsy and then proceed with additional chemotherapy.
Treatment of early stage, unfavorable Hodgkin's disease also consists of both chemotherapy and radiation, but as you may suspect, more intense therapy is used. The most commonly used treatment regimens are ABVD or Stanford V chemotherapy plus radiation. Again, after completing chemotherapy, your provider will obtain a repeat PET scan to see how well the lymphoma responded to treatment and if additional chemotherapy treatment is necessary prior to starting radiation. If there was a suboptimal response, no response, or worsening of the disease despite chemotherapy, most clinicians will repeat a biopsy and then proceed with additional chemotherapy.
Treatment of Stage III-IV Hodgkin's disease is more intense than unfavorable early-stage disease. It begins with an intense chemotherapy regimen of ABVD, Stanford V, or BEACOPP. After chemotherapy, a PET scan is obtained, and radiation is added to areas of disease that were bulky (>10 cm) before chemotherapy, or that remain active on PET after chemotherapy (ie. not completely killed by chemo alone). If there was a suboptimal response, no response, or worsening of the disease despite chemotherapy, most clinicians will repeat a biopsy and then proceed with additional chemotherapy or a bone marrow transplant.
NLP Hodgkin's lymphoma tends to be less aggressive than classical Hodgkin's, and many patients present with early-stage (Stage I-II) disease. Because experience has shown that NLP responds in a distinctly different way from classical Hodgkin's lymphoma, the National Comprehensive Cancer Network (NCCN) has a distinct set of treatment recommendations for NLP Hodgkin's lymphoma. Stage I-II NLP can be treated with radiation alone. Advanced disease (Stage III-IV) is treated similarly to advanced-stage classical Hodgkin's lymphoma, with chemotherapy as the primary treatment and sometimes radiation. Rituximab may be used along with traditional chemotherapy to increase the likelihood of achieving a complete remission. Radiation therapy can also be added if areas of lymphoma are causing pain, discomfort, or impairing the normal function of organs. In these cases, radiation therapy is done for comfort, not necessarily to increase the likelihood of cure.
Once a patient has been treated for Hodgkin's disease, he or she needs to be closely followed for recurrence, or return of the cancer. Your care provider will tell you when he or she wants follow-up CT scans or PET scans. Most relapses are detected clinically (taking a thorough history and performing a good physical exam). Screening PET scans are not recommended because they have a high false-positive rate, meaning that most things that look like relapse on PET scan turn out not to be cancer. At first, follow-up visits will be fairly frequent. The longer a patient is free of disease, the less often the checkups. Usually, follow-up with a provider lasts for 5 years as long as no lymphoma returns; however, relapses can occur even after 5 years of being disease-free, especially in the nodular lymphocyte-predominant subtype of Hodgkin's lymphoma.
Patients who are cured of their Hodgkin's disease can be expected to live many decades after their treatment. However, this means that some late effects of treatments can be seen. There is little to no evidence showing that specific surveillance measures improve long-term outcomes. The following are guidelines for your continued treatment; your team will create a plan with you specific to your needs.
After completing treatment for Hodgkin's lymphoma, you should see a physician every 3-6 months for the first two years, then every 6-12 months until year 3, and annually thereafter.
Ask your oncology team if you have any questions about reproduction or fertility, general health habits, or psychosocial issues.
A common side effect of treatment for Hodgkin's lymphoma is secondary cancer. For this reason, it is recommended that Hodgkin's survivors have earlier and more frequent cancer screening.
It is well demonstrated that survivors of Hodgkin's lymphoma have higher rates of cardiovascular disease and are at increased risk of death from heart attack and stroke. The factors that lead to higher risk of heart attack and heart disease in cancer survivors are many, but include chemotherapy, radiation, high levels of stress on the body and changes in the body's metabolic systems. The risk of heart disease is even higher if you have a family history of heart disease or have other risk factors for heart disease, like smoking, obesity, or diabetes. Symptoms from heart disease can begin quite early after cancer treatment and can be life-threatening. One of the most important things patients can do to reduce the risk of cardiovascular disease is to live a healthy lifestyle – engage in regular exercise, maintain a healthy body weight, and quit smoking.
Beginning five years after finishing treatment, your physician should check your blood pressure and cholesterol levels at least once per year. If they are abnormal, your provider should start you on medication to lower them to the recommended range. Additionally, the NCCN recommends a baseline stress test or echocardiogram at 10 years. This will look for problems with the valves, how well the heart is pumping, and whether the arteries to the heart are clogged. Finally, if you received radiation to the neck, you may have a higher risk of stroke due to problems with the large blood vessels in the neck. It is controversial whether specific imaging of these blood vessels is indicated, but professionals agree that risk factors for stroke, like high blood pressure, high cholesterol, and diabetes, should be controlled.
The thyroid gland is located in the neck and can be affected by radiation therapy. If you received radiation to the neck, you should receive yearly thyroid tests to monitor for poor thyroid function. Symptoms of low thyroid levels (hypothyroidism) include fatigue, weight gain, decreased appetite, dry skin, constipation, depression, and brittle hair or nails. If you have these symptoms, ask your provider if he or she recommends a thyroid test.
Fear of recurrence, financial impact of cancer treatment, employment issues, and coping strategies are common emotional and practical issues experienced by Hodgkin's lymphoma survivors. Cancer survivorship is a relatively new focus of oncology care. With over 15 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.
Leukemia and Lymphoma Society
Provides disease information and support resources. www.lls.org
Lymphoma Research Foundation
Offers education and patient services, information on research and stories of hope. www.lymphoma.org
American Society of Hematology
The official website of providers who treat blood disorders such as lymphoma. www.hematology.org/Patients/Cancers/Lymphoma.aspx
Aim to bring people together around lymphoma-related issues by providing concise, up-to-date information and a meeting place for lymphoma patients and those who care about them. www.lymphomainfo.net
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Found at: http://seer.cancer.gov/statfacts/html/hodg.html