Hodgkin's Lymphoma

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Original Editors - Ann Bedwell from Bellarmine University's Pathophysiology of Complex Patient Problems project.

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Definition/Description

Hodgkin’s Lymphoma, also known as Hodgkin’s disease, is a “chronic, progressive, neoplastic disorder of lymphatic tissue characterized by the painless enlargement of lymph nodes with progression to extralymphatic sites such as the spleen and liver.” It may also metastasize to bone marrow and other organs. The sites initially affected are the lymph glands in the neck or groin, usually on one side.                        

                                                                                                                                                               

This type of cancer is malignant and may  travel to other parts of the body. As it progresses, it may compromise the body’s ability to fight infection since it is attacking the immune system.

Hodgkin’s lymphoma is differentiated from other cancers and Non-Hodgkin’s lymphoma by the type of cell involved. The Reed-Sternberg cell is “part of the tissue macrophage system and have twin nuclei and nucleoli that give them the appearance of owl eyes.”   There are two subtypes of Hodgkin’s lymphoma, classic and nodular lymphocyte-predominant. Classic Hodgkin’s lymphoma is further divided into four categories based on what the cell looks like under a microscope. These are Lymphocyte-rich classical Hodgkin lymphoma, Nodular sclerosis Hodgkin lymphoma, Mixed cellularity Hodgkin lymphoma, Lymphocyte-depleted Hodgkin lymphoma.

Prevalence

In 2007, there were approximately 164,273 persons in the United States with a history of Hodgkin’s lymphoma. Based on rates from 2005-2007, “1 in 428 men and women will be diagnosed with Hodgkin lymphoma during their lifetime.”

Incidence Rates by Race

Race/Ethnicity	Male	Female
All Races	3.2 per 100,000	2.5 per 100,000
White	3.4 per 100,000	2.7 per 100,00
Black	3.0 per 100,000	2.3 per 100,000
Asian/Pacific Islander	1.5 per 100,000	1.1 per 100,000
American India/Alaska Native
Hispanic	2.8 per 100,000	2.0 per 100,000

Hodgkin’s can occur in children and adults at any age, but peaks around age 25-30 years and after 55 years. Men are typically diagnosed with Hodgkin’s more than women. “Children younger than 5 years rarely develop this disease, while only 10% of HL cases occur in children 16 years old and younger.” The nodular lymphocyte-predominant Hodgkin’s lymphoma (LPHL), has a peak incidence around the fourth decade of life.

Approximately 7800 cases of HL are diagnosed in the United States each year.

“Estimated new cases and deaths from Hodgkin’s lymphoma in the United States in 2010:
New cases: 8490
Deaths: 1320”

Characteristics/Clinical Presentation

Signs:

•  Painless, unilateral, enlargement of nymph node usually in the neck, underarm or groin

                   o The lymph nodes should be examined based on the size, mobility, consistency and tenderness. A lymph node that is “over 1 centimeter in diameter and firm or rubbery consistency or tender are considered suspicious

                   o Lymph nodes that are soft and tender to touch are usually indicative of infection.
                   o Any changes in the shape, size, consistency, or mobility are red flags and should be reported to a physician immediately.

Symptoms:

•  Fatigue
•  Fever and chills that come and go

                   o Typically peaks in the late afternoon

•  Itching all over the body that cannot be explained

                   o Itching occurs mostly at night

•  Loss of appetite
•  Soaking night sweats
• Painless swelling of the lymph nodes in the neck, armpits, or groin (swollen glands)
•  Weight loss that cannot be explained

Other symptoms that may occur with this disease:

•  Coughing, chest pains, or breathing problems if there are swollen lymph nodes in the chest
•  Excessive sweating
•  Pain or feeling of fullness below the ribs due to swollen spleen or liver
•  Pain in lymph nodes after drinking alcohol
•  Skin blushing or flushing
•  Malaise
•  Anorexia
•  Symptoms may occur due to the obstruction or compression of structures by the enlarged lymph nodes. This may cause edema in the neck, face or right arm due to blockage of the superior vena cava or renal failure from blockage of the urethra.
•  Obstruction of bile ducts results in liver damage or jaundice, which will present as a yellowish color to the skin
•  “Mediastinal lymph node enlargement with involvement of lung parenchyma and invasion of the pulmonary pleura progressing to the parietal pleura may result in pulmonary symptoms, including nonproductive cough, dyspnea, chest pain and cyanosis.”
•  Nerve root pain and paraplegia could occur if the cancer spreads to the bones
•  Invasion pericardium caused by enlarged “penetrating lymph nodes adjacent to the heart”
•  Hepatoslenomegaly

Many of these signs and symptoms may be due to other health problems.

Associated Co-morbidities

No associated co-morbidities were found although there are risks associated with chemotherapy and radiation therapy described further in the Medications section.

Medications

There are several treatments used in patients with Hodgkin’s lymphoma which are discussed in the Medical Management section. Below is a list of medications that are used during chemotherapy.

Chemotherapy

Chemotherapy is a mix of specific drugs that are introduced through the bloodstream to kill tumor cells. Most of the drugs are given intravenously, but some can also be given orally. Chemotherapy is given in cycles with a rest period. The amount of time spent in each cycle is determined by the type of drug used and stage of cancer.

•  Children

            o Health professionals, such as oncologists, agree that the use of chemotherapy and radiation has different effects on children than it does on adults. Most all children patients are treated with chemotherapy with or without radiation unless the patient has “stage I, completely resected, nodular lymphocyte-predominant Hodgkin lymphoma, Hodgkin’s lymphoma.” These patients may receive surgery only. Radiation dosed for an adult can cause profound harm to musculoskeletal growth and increase risk for cardiovascular disease in children. There are also gender differences for treatment in children.
            o Drugs that are used for children in childhood or adolescence are:
                     •Alkylating Agents: Some have been “shown be to associated with an increased risk for therapy-related leukemia.” Therefore nonalkylating agents were developed, including ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).
                               • Cyclophosphamide
                               • Mechlorethamine
                               • Procarbazine: causes long term gonadal toxicity in males
                     • Vinca Alkaloids                                                                                                                          
                               • Vincristine

Chemotherapy

                               • Vinblastine
                     • Steriods
                               • Prednisone
                               • Dexamethasone
                     • Antimetabolites
                               • Methotrexate
                               • Cytosine arabinoside
                     • Other Agents
                               • Doxorubicin: associated with cardiac damage
                               • Bleomycin: associated with pulmonary fibrosis
                               • Dacarbazine
                               • Etopside: developed to decrease male infertility                

Combination Chemotherapy Regimens Commonly Used for Children and Yound Adults with Hodgkin Lymphoma

Chemotherapy Regimen	Agents
ABVD	doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine
ABVE	doxorubicin (Adriamycin), bleomycin, vincristine, etoposide
VAMP	vincristine, doxorubicin (Adriamycin), methotrexate, prednisone
OPPA+/-COPP (females)	vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine
OEPA+/-COPP (males)	vincristine (Oncovin), etoposide, prednisone, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine
COPP/ABV	cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin), bleomycin, vinblastine
BEACOPP (advanced stages)	bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine
COP(P) with or without prednisone	cyclophosphamide, vincristine (Oncovin), ± prednisone, procarbazine
CHOP	cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin), prednisone
ABVE-PC	doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone, cyclophosphamide
MOPP/ABV	mechlorethamine, vincristine (Oncovin), procarbazine, prednisone, doxorubicin (Adriamycin), bleomycin, vinblastine

•  Adults:

              o Adults in early stages of Hodgkin’s lymphoma may receive chemotherapy, combined modality therapy or radiation therapy alone. Usually these patients “receive either four courses of ABVD or two courses of ABVD plus radiation.” Adults with stage III or IV Hodgkin’s lymphoma with favorable prognosis will receive six courses of ABVD while patients with unfavorable prognosis will receive BEACOPP.
               o Combinations of drugs used in chemotherapy for adults consist of:
                         • ABVD: doxorubicin, bleomycin, vinblastine and dacarbazine
                         • BEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone9
                         • MOPP: mechlorethamine, vincristine, procarbazine and prednisone.

Pregnant Women: Each patient must be looked individually when they present with Hodgkin’s lymphoma and are pregnant. If the HL is in the early stages and appears to be growing slowly, “patients can be followed carefully with plans to induce delivery early and proceed with definitive therapy.” These patients can also receive radiation therapy if shielded properly. “Investigators at M.D. Anderson reported no congenital abnormalities in 16 babies delivered after the mothers had received supradiaphragmatic radiation while shielding the uterus with five half-value layers of lead.” There are, however, risks that minimal scattered radiation could occur outside the radiation field and cause future malignancies in the baby.

“Chemotherapy that is administered in the first trimester has been associated with congenital abnormalities in as many as 33% of infants. However, in one series, there were no adverse effects in 14 children of mothers who received a combination of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or a combination of doxorubicin, plus bleomycin, plus vinblastine, and dacarbazine (ABVD) during gestation, five of whom began treatment during the first trimester.”

When a patient has HL in the 2nd half of their pregnancy, the cancer must be monitored carefully until they are induced into labor. If the patient is in a more advanced stage of cancer, vinblastine alone can be used because it has no associated fetal abnormalities with it. “Steroids are employed both for their antitumor effect and for hastening fetal pulmonary maturity.” Also, a combination of ABVD seems to be safe to use in the second half of the pregnancy. A combination of drugs is usually recommended over a single drug.

Side Effects of Chemotherapy:

•  Increase risk for infection, bruising or bleeding
•  Weakness and fatigue
•  Hair loss
•  Poor appetite
•  Nausea and vomiting
•  Diarrhea
•  Mouth and/or lip sores
•  Infertility
•  Heart disease
•  Bone marrow diseases
•  Lung problems
•  Other cancers 
• Thyroid problems

Diagnostic Tests/Lab Tests/Lab Values

File:Lymph node exam.jpg

Hodgkin’s lymphoma presents like many other disorders, so it is hard to differentiate and diagnose. The following tests and procedures are taken to positively diagnose Hodgkin’s lymphoma:

• “Physical exam: Your doctor checks for swollen lymph nodes in your neck, underarms, and groin. Your doctor also checks for a swollen spleen or liver.”
• Biopsy of lymph tissue that looks be involved and bone marrow. Once the sample is taken, it is checked for Reed-Sternberg cells that indicate Hodgkin’s lymphoma.
• Blood Chemistry Tests: check protein levels, liver function tests, kidney function tests and uric acid levels

•  CT Scans: chest, abdomen and pelvis
•  X-Rays: show swollen lymph nodes
•  PET Scan: glucose is injected in the patient’s veins and be will more concentrated around cancerous cells
•  MRI

Once tests reveal that a patient has Hodgkin’s lymphoma, additional tests will be done to see if the cancer has spread therefore finding out what stage the cancer is in. Once the cancer stage has been found, future treatments can be planned and initiated.

Etiology/Causes

The exact cause of Hodgkin’s lymphoma is unknown. HL begins with an abnormal B cell, which is a type of lymph cell that is important in the body’s response to foreign intruders. When these B cells become abnormal they are called Reed-Sternberg cells. This cell continues to divide and make copies, but unlike normal cells, it does not die. “The genes have the ability to mimic transmembrane receptors and activate the transcription factor NF-кB. NF-кB, through its function of regulating dozens of genes within the cell, plays a key role in the proliferation and survival of the malignant clones.” Products of these genes include cytokines and chemokines. Most cytokines, mostly interleukins produce an environment where the Reed-Sternberg cells can flourish. These interleukins may attract inflammatory cells to survive as it is shown in the lab that they cannot survive without the inflammatory cells. Other interleukins restrain the activation of T cells that are normally used to destroy any unusual cell, while others “act as growth factors, encouraging proliferation, metastasis and angiogensis.” The abnormal B cell is unable to die due to a protein called c-FLIP that usually signals cell death but is not able to function in the circumstances. Therefore the abnormal B cell is undying.

The cells build up while attracting normal immune cells to cause tissue growth in the lymph nodes.This mass of tissue growth is called the tumor. The reason that these B cells are malignant is unknown, but recent evidence implies that it begins from an infection or inflammation. Genes from a virus called Epstein-Barr have been found in half of all HL cases.                                                                                                            

Once the lymphoma begins in the lymph nodes, typically the neck, axilla or groin, it can travel to all other lymph nodes in the body then spread outside of the lymph nodes into any part of the body.                                                                                   

Systemic Involvement

Hodgkin’s lymphoma primarily affects the lymph nodes in the neck, axillas, and groin but can also affect and grow to the spleen, liver, tonsils, thymus and bone marrow, which are all part of the lymphatic system.  The spleen, composed of blood and lymphoid tissue, is where the final destruction of red blood cells, filtration and storage of blood takes place as well as production of lymphocytes. The liver is a vascular, glandular organ that secretes bile to aid in digestion and changes substances in blood that passes through it. The tonsils are masses of lymphoid tissue near on either side of the throat. The thymus gland is composed of lymph tissue and functions in cell-mediated immunity by developing T cells. This gland is highly active in the younger population, then disappears with age. Bone marrow is the inner part of the bone where blood cells are made. B cells, which are white blood cells that help to aid in fighting infection. These B cells are the particular cells in Hodgkin’s lymphoma that become abnormal and begin the multiply to form a tumor.

Other organs and systems can be involved by way of metastasis. Hodgkin’s lymphoma can metastasize to all tissues of the body due to the lymphoreticular cells inhabiting all types of tissue except the central nervous system. “Hematological spread may also occur, possibly by means of direct infiltration of blood vessels.”

Medical Management (current best evidence)

Management of Hodgkin’s lymphoma is done by chemotherapy or a combination of chemotherapy and radiation. The different medications used in chemotherapy are listed above under the Medications section. However, treatment does depend on several different factors:

•  The type of Hodgkin's lymphoma (most people have classic Hodgkin's)
•  The stage at which the cancer is at as well as number of lymph nodes involved
•  The size of the tumor

                  o “A staging evaluation is necessary to determine the treatment plan”
                            • Stage I: one lymph node region involved
                            • Stage II: two lymph node regions on the same side of the diaphragm involved
                            • Stage III: lymph node regions are involved on both sides of the diaphragm
                            • Stage IV: cancer is found outside the lymph nodes (i.e. bone)

•  The patient's age and co-morbidities
•  “Other factors, including weight loss, night sweats, and fever”
•  Age of patient
•  Whether the patient is pregnant or not

Treatment is different for patients in a certain stage and age:

•  Stages I and II: treated with local radiation therapy, chemotherapy, or both.
•  Stage III: “treated with chemotherapy alone or a combination of radiation therapy and chemotherapy.”
•  Stage IV: usually treated with chemotherapy alone

Surgery: There are several different types of surgery that may be performed to decrease or rid of any tumor. These are:

• Partial resection or debulking: used when only part of the tumor can be removed.
• Complete resection: the whole tumor is removed.
• Mohs surgery: each layer of the tumor is removed until it is completely gone
• Lymph node dissection
• Implantation of radioactive beads (brachytherapy)
  
  

Chemotherapy: Chemotherapy is a mix of specific drugs that are introduced through the bloodstream to kill tumor cells. Most of the drugs are given intravenously, but some can also be given orally. Chemotherapy is given in cycles with a rest period. The amount of time spent in each cycle is determined by the type of drug used and stage of cancer.

Radiation Therapy

Radiation therapy uses high energy x-rays to kill cancer cells and decrease pain. The duration of radiation therapy depends on what stage the cancer is in. Radiation is confined to a certain area, killing the cells in only that area. It is usually combined with chemotherapy and rarely used by itself. Most children who receive radiation are given a low-dose.

Side Effects of radiation therapy:

•  Increased risk of heart disease
•  Stroke
•  Thyroid problems
•  Infertility
•  Other forms of cancer
•  Red, dry tender skin
•  Fatigue

                                                                                                                 

Biotherapy or tumor immunotherapy uses a pharmacological approach to genetically engineer antibodies that specifically attack antigens on cancer cells.

Bone marrow or stem cell transplantation may be used if the cancer returns or if the patient is not responding to treatment. Bone marrow or stem cells are taken from the patient, frozen and stored. The patient then receives high dose chemotherapy to destroy all the cancerous cells. Then the frozen marrow or stem cells are injected into the body through the patient’s veins.

Additional treatments may be used due to symptoms:

•  Blood transfusion to fight low platelet counts
•  Antibiotics to fight infection
  

Physical Therapy Management (current best evidence)

Physical therapy for patients with Hodgkin’s lymphoma focuses on cardiovascular and pulmonary health, strength, and flexibility in order to improve quality of life and reduce symptoms produced from the cancer and treatments. Most physical therapy sessions focus on activities of daily living, but also focus on the ability to reduce fatigue. The ability to improve cardiovascular and pulmonary health along with strength and flexibility will allow patients the ability to help their tolerance to chemotherapy and radiation while maintaining or improving their ability to do everyday activities. In a literature review by Courneya and Friedenreich, 24 empirical studies that were published between 1980 and 1997 showed that physical exercises and activity has a positive effect on quality of life in patients with cancer. Physical activity is able to increase functional health as well as psychological and emotional welfare.

Alternative/Holistic Management (current best evidence)

“There are no alternative medicine treatments that can cure Hodgkin's lymphoma, but some alternative and complementary therapies can reduce symptoms or relieve side effects from treatment.” Following some of these therapies will help the patient reduce stress and anxiety to help improve their quality of life. Some therapies are:

•  Relaxation techniques such as meditation and yoga
•  Acupuncture will help treat nausea from the chemotherapy
•  Massage will help decrease stress, anxiety, depression and pain.
•  Aromatherapy will help diminish anxiety, pain, queasiness and depression.
•  Nutrition Therapy
•  Pain Management
•  Naturopathic Medicine
•  Mind Body Medicine
  
•  Spiritual Support
•  Image Enhancement

Nutrition Therapy: Eating right and staying active is another way to help your body feel better and relieve some stress. Patients should try to maintain the correct amount of calories to maintain a good weight, eat enough protein to increase strength and create more energy. Vitamins and minerals may also be used to supplement when a patient is not getting enough in their meals.

Pain Management: Pain management is finding a way of reducing pain or the perception of pain through use of pharmacological agents and non-pharmacological agents. Non-pharmacological agents consist of “behavioral techniques, emotional counseling and support, physical therapy, radiation, neurological and neurosurgical interventions, and traditional nursing and psychosocial interventions.”

Naturopathic Medicine: A central goal of naturopathic medicine is to use the healing power of nature to maintain and restore health. Naturopathic medicine focuses on clinical nutrition, botanical medicine, physical medicine, Chinese medicine, psychological medicine and homeopathic medicine. “Naturopathic practice also includes the use of any medical substances that contain elements that are components of bodily tissues, or can be employed by the body, for the maintenance of life and the repair of tissues. This also encompasses methods of diagnostic testing and imaging, including X-ray and ultrasound.”

Mind Body Medicine: Mind body medicine is based on psychoneuroimmunology which influences your mind over your body.

Spiritual Support

Image Enhancement: image enhancement through beauticians, cosmetologists and salon personnel can help improve a patient’s well-being and self-confidence.

To read more about these therapies offered go to Cancer Treatment Centers of America

Differential Diagnosis

Differential Diagnoses include:

• Actue lymphoblastic leukemia
• lymphadenopathy
• brucellosis
• lymphoproliferative disorders
• catscratch disease
• mononucleosis and Epstein-Barr virus infection
• cytomegalovirus infection
• non-Hodgkin lymphoma
• histoplasmosis
• toxoplasmosis
• lymph node disorder
• tuberculosis
• lymphadenitis
• fibrosing mediastinitis
• atypical mycobasteria
• AIDS
• human immunodeficiency virus
• systemic lupus erythmatosus

Case Reports/ Case Studies

add links to case studies here (case studies should be added on new pages using the case study template)

Hodgkin's lymphoma masquerading as vertebral osteomyelitis in a man with diabetes: a case report

Hodgkin's lymphoma presenting with heart failure: a case report

A case of nodular sclerosis Hodgkin’s lymphoma repeatedly relapsing in the context of composite plasma cell-hyaline vascular Castleman’s disease: successful response to rituximab and radiotherapy

Resources

What you need to know about^TM Hodgkin Lymphoma

Lymphoma Research Foundation: resources for facts, information and support groups

Recent Related Research (from Pubmed)

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References

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