Lymphoma

More than 60,000 Americans were diagnosed with some form of lymphoma in 2004, and more than 20,000 died from their disease. Lymphomas are linked to a variety of risk factors, including diet, medical history, environmental exposure to chemicals, and infections. To date, conventional medical treatment for lymphoma has been based on combinations of chemotherapy, radiotherapy, and stem cell therapy. However, new treatments for lymphoma now add to these traditional therapies the use of substances that can specifically target the delivery of radiotherapy to lymphoma cells (radioimmunotherapy) or activate the immune system to kill lymphoma cells (chemoimmunotherapy).

Nutritional supplements with demonstrated activity against lymphoma cells include curcumin, genistein from soy extract, vitamins A, C, D, and E, green tea, resveratrol, ginger, fish oil, and garlic. These supplements can be used to complement conventional drugs, and they can be closely monitored for effectiveness with a range of blood tests and diagnostic procedures described in this protocol.

What Is Lymphoma?

The lymphatic system consists of organs such as the lymph nodes, the thymus gland, the spleen, and bone marrow, which participate in the production and storage of infection-fighting white blood cells (lymphocytes), as well as in the network of vessels that carry these white blood cells around the body. Lymphomas are cancers of the white blood cells (lymphocytes) within the lymphatic system.

There are two types of lymphoma (Hansmann ML et al 1996):

• Hodgkin’s lymphoma, also known as Hodgkin’s disease (HD)
• Non-Hodgkin’s lymphoma (NHL).

The diagnosis, staging (Lister TA et al 1989), and general symptoms (Jose BO et al 2005) of lymphoma are summarized in Table 1.

Table 1. Lymphoma: symptoms, diagnosis, and staging

Hodgkin's lymphoma begins in the lymph nodes and is characterized by the presence of Reed-Sternberg cells, which are large, cancerous cells that increase in number with disease progression (Harris NL 1999; Kuppers R et al 2002). Evidence suggests that B lymphocytes (B-cells), the infection- and tumor-fighting cells that produce antibodies, produce Reed-Sternberg cells (Brauninger A et al 1999; Harris NL 1999; Kuppers R et al 2002). However, T lymphocytes (T-cells) have also been implicated in rare cases (Kuppers R et al 2002).

Although it can affect any lymph tissue, HD most commonly affects the supraclavicular, high-cervical, or mediastinal lymph nodes (Jose BO et al 2005). There are five different types of Hodgkin's lymphoma.

Non-Hodgkin's lymphoma describes all lymphoma types without Reed-Sternberg cells (Coffey J et al 2003; Jimenez-Zepeda VH et al 1998). NHL develops as a result of malignant B and T lymphocytes (white blood cells). B-cell lymphomas are more common and account for over 85 percent of NHL cases (Coffey J et al 2003). There are at least 29 different types of NHL; the main types, which can be further classified into subtypes, are summarized in Table 2.

Table 2. Different types of Non-Hodgkin’s lymphoma and MALT (mucosa-associated lymphoid tissue) lymphoma

Lymphoma Occurrence

New cases of Hodgkin’s lymphoma represent less than 1 percent of all cancer cases in the United States. By contrast, non-Hodgkin’s lymphoma is the fifth most common cancer after lung, breast, colorectal, and prostate cancers (Groves FD et al 2000). Moreover, NHL is among the top five causes of cancer-related death (Fisher SG et al 2004; Hauke RJ et al 2000) and is the leading cause of cancer death in males aged 15-54 (Mohammad RM et al 2003). US cases of lymphoma for 2004 are summarized in Table 3 (Baris D et al 2000).

Table 3. Lymphoma cases in the US in 2004 (US National Cancer Institute SEER data)

Lymphoma is generally more common in men than in women (Cartwright RA et al 2002; Groves FD et al 2000). The incidence of lymphoma also varies by race. Statistics indicate that African-Americans are less likely to develop lymphoma than Caucasians (Glaser SL 1991; Groves FD et al 2000).

Genetic Abnormalities in Lymphoma

Like all cancers, lymphoma begins with damage to the cell’s deoxyribonucleic acid (DNA), the molecules containing all the information that determines the structure and function of cells. Within each cell, DNA is housed in structures known as chromosomes, which are made up of sections called genes.

The development of lymphoma begins with damage to the DNA of T-cells and B-cells (lymphocytes), immune cells that protect the body from infections (Coffey J et al 2003; Kuppers R et al 2002). DNA damage that can start cancer development occurs in genes called oncogenes or tumor-suppressor genes, which play important roles in maintaining a balance between cell death and cell growth.

Excessive cell growth occurs in lymphoma as a result of malfunction of the proteins that control cell growth (leading to permanent cell division) and cell death (making the cell insensitive to normal signals to die). Numerous genetic abnormalities have been implicated in the malfunction of cell controls. Two critical proteins involved in lymphoma development are bcl-2 and bcl-6.

The identification of these genetic irregularities has important implications for treating lymphoma, as it indicates potential targets for manipulation with pharmaceutical drugs or nutritional supplements. For example, pharmacological agents capable of inactivating bcl-6 can cause increased cell death (apoptosis) in lymphoma cells (Pasqualucci L et al 2003). Furthermore, in clinical studies, an agent that targets bcl-2 has also been shown to have efficacy in non-Hodgkin’s lymphoma patients (Chanan-Khan A 2004).

What Causes Lymphoma?

The cause of lymphoma is still a subject of much debate, and many lymphoma patients do not have obvious risk factors.

Hodgkin’s Lymphoma

Epstein Barr and Herpes Viruses. The Epstein Barr virus is thought to cause one third of all HD cases (Jarrett RF 2003). In addition, HD patients often show high numbers of herpes-infected cells (Krueger GR et al 1994). These viruses are thought to contribute to the development of lymphoma (Krueger GR et al 1994), and are also linked to the development of NHL (Danese C et al 2004; Muller AM et al 2005).

Weakened Immune System. Individuals with suppressed immune systems associated with HIV infection appear to be at higher risk of developing HD (Lim ST et al 2005; Thompson LD et al 2004).

Non-Hodgkin’s Lymphoma

Factors that play a role in susceptibility to non-Hodgkin’s lymphoma include nutrition, medical history, environment, and use of medications.

Diet/Nutrition. NHL is more common in individuals with weakened immune systems (Zhang S et al 1999; Zhang SM et al 2000). Clinical studies have now shown that diets rich in animal protein and fats, which are thought to diminish immune function (Calder PC et al 2002; Jones DE 2005; Plat J et al 2005), are associated with an increased risk of developing NHL (Chang ET et al 2005; Chiu BC et al 1996; De SE et al 1998; Zhang S et al 1999). Clinical studies have also shown that diets rich in fruits and vegetables, which are thought to enhance immune cell function (Gaisbauer M et al 1990; Rossing N 1988; Loghem JJ 1951), are associated with a reduced risk of developing NHL (Zhang SM et al 2000; Zheng T et al 2004).

Medical History. Evidence suggests that some medical conditions or procedures, especially those that reduce immune system activity, increase the risk of developing non-Hodgkin’s lymphoma. These include:

• Blood transfusions and organ transplantation
• Diabetes
• Celiac disease
• Hepatitis C
• Epstein Barr virus
• Gastric ulcers (Helicobacter pylori)
• HIV
• HTLV (human T-lymphotropic virus)
• Herpes.

Numerous studies have examined the link between blood transfusions and the development of NHL. However, the data are conflicting, with some studies showing that allogeneic blood transfusions (i.e., from other people/donors) are associated with a twofold increase in the risk of developing NHL (Cerhan JR 1997a; Vamvakas EC 2000). Similarly, the risk of NHL is thought to increase in organ transplant patients (Vamvakas EC 2000), most likely as a result of post-transplant immunosuppression.

In older women, adult-onset (type II) diabetes of long duration has also been shown to increase the risk of developing NHL (Cerhan JR et al 1997b). Other clinical studies have also shown that diabetes sufferers are at greater risk of developing NHL (Natazuka T et al 1994), presumably because diabetes impairs the efficiency of the immune system (Jackson RM et al 1987; Kohn LD et al 2005).

Celiac disease, a condition characterized by inflammation of the intestinal lining due to sensitivity to a protein called gluten (found in wheat and rye), is also associated with increased risk of developing NHL, particularly localized in the gut (Catassi C et al 2002; Smedby KE et al 2005; Sonet A et al 2004).

Hepatitis C virus, a common infection in the US, is linked to the development of B-cell NHL (Fiorilli M et al 2003; Vallisa D et al 2005), MALT lymphoma (Seve P et al 2004), and a rare type of NHL known as primary hepatic lymphoma (Noronha V et al 2005). Interestingly, this association appears to have some geographical variations, although some studies do not support it (Giannoulis E et al 2004; Morgensztern D et al 2004).

Helicobacter pylori infection, normally associated with peptic ulcers, is also linked to the development of gastric MALT lymphomas (Franco M et al 2005; Wotherspoon AC 1998).

The immunosuppression caused by infection with the human immunodeficiency virus (HIV) is associated with a greater risk of developing NHL (Irwin D et al 1993; Kaplan LD 1990; Tulpule A et al 1999). The incidence of NHL in HIV-positive individuals is 60 times greater than that observed in the general population (Tulpule A et al 1999).

The human T-lymphotropic virus, a close relative of HIV, is also known to cause T-cell lymphomas (Nicot C 2005).

Environment. Exposure to pesticides and herbicides is associated with an increased risk of developing non-Hodgkin’s lymphoma, particularly in rural farming communities where these substances are used routinely (Quintana PJ et al 2004; Waddell BL et al 2001; Weisenburger DD 1990). Asthmatics exposed to pesticides have a higher risk of developing NHL compared to non-asthmatics (Lee WJ et al 2004). Chemicals known as dioxins, which are emitted from solid waste incinerators, are thought to increase the risk of non-Hodgkin’s lymphoma (Floret N et al 2003). Contamination of drinking water with nitrates is also thought to increase the risk of developing NHL (Ward MH et al 1996), though other studies show that contamination levels would have to be very high to pose this risk (Freedman DM et al 2000).

Medications. Long-term use of medications such as conventional hormone replacement therapy (primarily unopposed estrogens with synthetic, equine-derived estrogens), certain antibiotics, and pain relievers is associated with an increased risk of certain types of NHL (Cerhan JR et al 2002; Kato I et al 2002; Kato I et al 2003). In particular, individuals with rheumatoid arthritis who are long-term users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have a greater risk of developing NHL (Cerhan JR et al 2003).

Conventional Therapy

Currently, medical treatment for lymphoma revolves around the following therapies:

• Chemotherapy
• Radiotherapy
• Stem cell therapy.

A discussion of how chemotherapy and radiotherapy agents kill blood cancers, and the use of stem cell therapy, is available in the Leukemia protocol.

The standard chemotherapy regimen for NHL, known as CHOP, combines four agents: cyclophosphamide, doxorubicin, vincristine, and prednisone (Canellos GP 2004; Escalon MP et al 2005; Younes A 2004). Although CHOP has been the accepted “gold standard” for NHL chemotherapy treatment for the past 30 years, its delivery was recently optimized with a change to a 14-day dose-dense schedule, which increased clinical responses compared to the traditional 21-day schedule (Younes A 2004). A recent study showed the effectiveness of another chemotherapy combination (carmustine, doxorubicin, etoposide, vincristine, and cyclophosphamide, plus mitoxantrone, cytarabine and methotrexate with a factor known as BAVEC-MiMA) for NHL treatment (Rigacci L et al 2005).

The standard chemotherapy combination for HD is known as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (Canellos GP 2004).

The use of these chemotherapy agents is often combined with radiotherapy (Mukai HY et al 2003) and stem cell therapy (Lavoie JC et al 2005).

Side Effects of Conventional Therapy

Chemotherapy often has a side effect of reducing white blood cell count to very low levels, thereby leaving the patient vulnerable to infections (Lyman GH 2000). As with other cancers, the risk of developing lymphoma increases sharply with increasing age (Holmes FF et al 1991). Changes in the aging body reduce the patient’s ability to tolerate standard chemotherapy and radiotherapy regimens that are often better suited to the relatively more robust immune systems of young adults.

In particular, the aging body experiences a decline in its ability to make new white blood cells (Chatta GS et al 1996). The use of chemotherapy in elderly patients therefore aggravates this problem because it destroys patients’ normal white blood cells, leaving them prone to infections. Readers should refer to the Cancer Chemotherapy protocol for a range of prescription drugs that can be taken to reduce this negative side effect of chemotherapy. Readers should also refer to the protocol on Blood Disorders: Anemia, Leukopenia, and Thrombocytopenia for other practical guidelines on dealing with reduced white and red blood cells.

Heart disease (cardiomyopathy) is the most important long-term toxicity of Adriamycin® (doxorubicin) administration, which is used to treat both NHL and HD. Several clinical studies suggest that some changes in the heart’s electrical activity caused by Adriamycin® may be prevented by coenzyme Q10 supplementation (Tajima M 1984; Tsubaki K et al 1984). Coenzyme Q10 supplementation has a protective effect on cardiac function during therapy with Adriamycin® in lymphoma patients (Iarussi D et al 1994; Wang SQ 1991). Some investigators believe that simultaneous coenzyme Q10 and vitamin E supplementation is indicated during Adriamycin® therapy in order to reduce its toxicity and prevent fatal congestive heart failure (Wang SQ 1991).