Mycosis Fungoides/Sèzary Syndrome
Dealing with a chronic and potentially life-threatening condition can be very difficult. We have prepared this handout specifically for you as the patient, relative, or family friend to better understand what Mycosis Fungoides (MF) is and how the condition may affect your lives. In this handout, you will find information on the history of MF, a discussion of what may cause MF, how the condition is diagnosed, treatment options for MF, and future developments in medical research. We hope we can address all your areas of concern.
What is Mycosis Fungoides?
Lymphomas are cancers of the lymphoid system, and mycosis fungoides is a rare type of lymphoma, which affects the skin. MF was first described by a French physician, Alibert , in 1806. It has many different appearances, including scaly thin red patches of skin, raised and thick skin changes, tumor or nodular skin changes, and/or erythroderma . Approximately 1000 new cases are diagnosed in the U.S. each year. The average age at the time of diagnosis is approximately 55, although cases have been reported in infants and people older than 80.
In MF, the T-cells accumulate abnormally in the skin, growing excessively and uncontrolled. Interactions of these malignant lymphocytes with other cells in the skin cause the visible skin changes. The malignant T-cells may also circulate in the blood, as in Sezary Syndrome (SS), accumulate in lymph nodes, or affect internal organs.
What causes Mycosis Fungoides?
The cause of MF is unknown. Certain events probably occur to make the normal T-cell become cancerous. There are multiple theories of why MF develops. These include genetics, exposure to chemicals, viral infections, and chronic lymphocyte stimulation. NONE of these has been proved to be correct. There are rare instances of familial MF, but there is no single gene, which has been identified as the cause.
How do you diagnose Mycosis Fungoides?
MF is commonly misdiagnosed at first because of its resemblance to common benign skin conditions. MF may be mistaken for psoriasis, chronic dermatitis from allergy or irritants, or chronic fungal infections. The correct diagnosis can be delayed for several years. To confirm the diagnosis of MF, a biopsy of the skin must be obtained in order to analyze it under the microscope for certain characteristic changes. Even with a skin biopsy, the diagnosis of MF is not always easy to establish, so additional tests or biopsies are often necessary. Some patients have repeated biopsies over several years before the diagnosis can be made.
What will happen after the diagnosis is confirmed?
Although one may be managed by a general dermatologist, MF is such a rare disease that treatment by a team of specialists is more appropriate.
At the Stanford University Multidisciplinary Cutaneous Lymphoma Clinic, you will meet physicians from different medical specialties, including dermatologists who specialize in lymphoma, medical oncologists, radiation oncologists, dermatopathologists , and ancillary services including specialized nurse coordinators and personnel involved in clinical trials. Conventional treatments are always available and will be discussed in the following paragraphs, but investigational therapies from on-going research studies at Stanford may be offered to you as well.
The simplest way to think about the multiple treatments available for MF is by dividing them into two categories: skin-directed therapies versus systemic therapies.
Skin-directed therapies are aimed at the skin primarily. The major treatments in this category include topical chemotherapy agents (nitrogen mustard or Mustargen), topical corticosteroids, topical retinoids (Targretin gel), phototherapy (PUVA, UVB), and electron beam radiation.
Systemic therapies are administered by mouth or injection and are aimed at treating the skin and/or internal organs affected or at risk. These include chemotherapy agents and biologic response modifiers (oral retinoids , interferons , fusion proteins, or extracorporal photopheresis).
Commonly, multiple treatments may be used together, which is called Combined Modality Therapy.
For each treatment option, the following paragraphs include information on treatment indications, practical use of the therapy, and potential side effects.
Topical chemotherapy
The most commonly used topical chemotherapy agent is mechlorethamine ( Mustargen or nitrogen mustard). This treatment involves applying the medication to your skin once or twice a day and is commonly applied to the entire body or body regions. This topical ointment needs to be prepared by pharmacies, which specially compound the medication. Room temperature or refrigerated storage is recommended.
Topical chemotherapy is a common first line therapy in patch or plaque lesions.
Side effects of Mustargen may include an allergic contact dermatitis, irritation, and itchiness.
Topical Retinoids
Another skin directed therapy is topical retinoids . Bexarotene (Targretin) gel is a topical medication, which was approved by the Federal Drug Administration (FDA) for use in MF. Bexarotene is a derivative of Vitamin A. It works by changing the growth and maturation pattern of MF cells. Targretin gel is applied only to areas of skin affected by MF once or twice a day.
Targretin gel is most commonly indicated in limited patch or plaque disease. It can also be used in combination with other therapies for lesions, which may be more resistant to therapy.
Side effects include local irritation or itchiness. Extreme redness can be seen, but it is commonly not painful or irritated. This is called retinoid erythema and is a normal manifestation of the treatment that may be seen. Sometimes, discontinuation of the gel is required, so the skin can be evaluated for any residual disease without the redness from the medication confusing the skin appearance. There is no systemic absorption, so the use of contraception in child-bearing women is not required, as it is for the pill form of Targretin. If you were to become pregnant while using Targretin gel, we do recommend contacting your physician immediately.
Topical Corticosteroids
Topical corticosteroids can be used to treat mild, patch stage MF. The mechanism of action is not exactly known, but studies suggest the growth and maturation pattern of MF cells is modified. Topical corticosteroids vary in strength, with Class I (e.g., Ultravate or Lidex ointment) being the strongest to Class VI being the weakest (e.g., Desowen ointment). They come in lotions, creams, or ointments. Choosing the strength of the topical sometimes depends on where it will be applied on the body. In general, a weaker steroid would be used in more sensitive areas, such as the face, axilla , or groin region. They can be applied once to twice a day.
Topical corticosteroids can be used to treat individual skin lesions. Application to the entire skin, as with Mustargen ointment, is not indicated for corticosteroids.
Side effects include thinning of the skin, superficial blood vessels, easy bruising, and possible systemic absorption if used chronically. Long-term use of topical corticosteroids in MF is not recommended secondary to the potential side effects from continual use.
PUVA
PUVA is a therapy where a natural occurring plant product called psoralen ( oxpsoralen) is used in combination with ultraviolet light therapy, specifically the long wavelength form called UVA. Oxpsoralens makes the T-cells of MF more sensitive to ultraviolet light, which enhances the effect of UVA on clearing your skin.
Typically, you will take the oxpsoralen by mouth (which is dosed by your weight) one and a half hours before receiving the light therapy. It is necessary that you protect your eyes and exposed skin areas with UV-wrap around glasses, protective clothing, or sunscreen between ingesting the oxpsoralens and the next 24 hours. The UVA light therapy is delivered in specialized light boxes. The UVA dosage is adjusted according to your skin type, and the length of time in the box ranges from seconds to minutes. You will be required to have an eye exam prior to starting the therapy because of the increased risk of cataracts with long-term exposure to PUVA therapy. A common initial treatment schedule for PUVA is three times a week (three visits to the clinic each week to receive the light therapy). The frequency of therapy can be decreased as the skin improves.
PUVA is used commonly as first line treatment in patch or plaque skin lesions. It is also used commonly in combination with other treatments for more extensive disease.
Possible side effects include nausea and increased risk of cataracts from the psoralen . UVA causes redness of the skin, itchiness, or dry skin. There is an increased risk for developing non-melanoma skin cancers and a possible increased risk of developing melanoma from exposure to PUVA.
Electron Beam Radiation and Local Radiation
Mycosis fungoides is very sensitive to radiation. Electron beam radiation is a form of radiation where the beam does not penetrate deeper than the skin. This is a therapy, which treats the total skin. Patients are placed in multiple positions 10-12 feet from the radiation machine linear accelerator, so all the skin is exposed. Typical treatment schedules last about 10 weeks, 4 times a week. Importantly, this treatment requires a special center with the proper equipment and technique.
Electron beam radiation is a very effective first line treatment for treating patches, plaques, or tumors. Radiation treatment can also be delivered locally to treat specific skin lesions, which have been resistant to other therapies.
Side effects include redness, swelling, temporary nail loss, temporary hair loss, abnormal sweating, chronic dryness, and an increased risk of developing non-melanoma skin cancers.
Oral retinoids
Retinoids are a class of drugs that are derivatives of vitamin A. These medications are effective in MF because they can change the growth and maturation pattern of MF cells.
Bexarotene (Targretin) is the most commonly used oral retinoid for MF. Each capsule is 75 mg. The capsules are usually taken all together, preferably after dinner. Retinoids are used to treat widespread patch, plaque, or tumorous skin lesions. They are also used in combination with other treatment modalities.
Because this is a systemic medication with several potential side effects, close monitoring is required while on the medication. This includes blood tests to monitor liver function, lipid levels, thyroid function, and blood counts. Bexarotene (Targretin) in particular can affect your lipids significantly, and a medication to control triglyceride levels will be required. It can also cause decreased production of thyroid hormone, so commonly, patients are started on supplemental thyroid hormone. Use of these medications for women of childbearing age is contraindicated. Contraception is essential before, during, and for a period of time after the use of oral retinoids .
Other side effects of bexarotene (Targretin) include headache, loss of strength, nausea, rash, itch, skin flushing, dry skin, and dry mouth.
Interferon alpha
Interferon alpha has been shown to be effective in treating patients with MF. It works by altering the immune system response. Interferon alpha is an injection which is given just under the skin, similar to insulin injections. It is typically delivered three times a week with gradual increases in the dose to therapeutic levels.
Interferon is used to treat widespread patch, plaque, or tumorous skin lesions. It is also commonly used in combination with other therapies.
Side effects include flu-like symptoms, fatigue, depression, weight loss. Periodic monitoring of the blood may be required to follow blood counts and thyroid function.
Fusion proteins
In 1999, the FDA approved a recombinant fusion protein called denileukin diftitox (Ontak) as a therapy for MF. It works by killing lymphocytes that have a certain immune receptor. The T-cells of MF often have this receptor. This medication is delivered intravenously typically over a 3 hour period in an outpatient setting. The schedule for this medication is that it is usually given 5 consecutive days every 3 weeks.
Ontak is not typically used as a first line therapy. It is reserved for refractory cases of widespread patch, plaque, or tumorous skin lesions.
Side effects include flu-like symptoms or acute infusion related events, such as transient low blood pressure, muscle aches, or vascular leak syndrome.
Extracorporal photopheresis
Extracorporal photopheresis (ECP) is a way of delivering PUVA-like therapy to the skin, blood, and lymph nodes. As noted previously, PUVA therapy employs an oral medication called psoralen , which works by making the T-cells of MF more sensitive to ultraviolet light, in combination with UVA. ECP utilizes the same principles of treatment, but the UVA portion in ECP is directed at white blood cells, which are collected temporarily outside the body, instead of the skin (as with PUVA therapy). Your blood is extracted intravenously and mixed with a liquid form of psoralens , exposed to UVA light, and returned to your body intravenously again. It is extracted in increments and the whole process takes a few hours each day in a special nursing area. It is usually transfused over a two day period. You are not required to stay overnight in the hospital. The frequency of treatments is initially every 2-4 weeks, then less frequently as the skin improves.
ECP is a first line therapy for treating erythroderma . It is not as effective in treating patches, plaques, or tumors.
Side effects are minimal. These include temporary low-grade fever and slight malaise.
Systemic chemotherapy agents
Systemic chemotherapy agents are usually reserved for MF that have failed skin-directed or systemic biologic therapies or have disease that extended to lymph nodes or other internal organs. Common agents include cyclophosphamide, adriamycin or Doxil, gemcitabine, methotrexate, and pentostatin. Chemotherapy may be given in as a single agent or multi-agent regimen. A detailed discussion of each agent is beyond the scope of this handout. The side effects can be significant. Close monitoring of laboratory studies and general medical condition is necessary.
What new developments are occurring in medical research of Mycosis Fungoides?
On-going research at major medical centers such as Stanford has led to the development of a variety of newer therapies. There are also other treatments in various stages of being approved by the Federal Drug Administration. These include antibodies directed specifically against markers specific to T-cells (anti-CD3 or anti-CD4), proteins, which affect the structure of DNA ( depsipeptide) or modify the immune response against cancer cells (CpG 7909), and the development of vaccines directed against tumor cells. Some antibodies to T-cells, such as anti-CD52 (Campath) have been approved for use in hematolymphoid cancers and may be used in resistant cases of MF.
In addition, combinations of approved individual treatments, such as oral Targretin and PUVA are being evaluated in clinical trials to assess effectiveness and safety when the treatments are used together.
Are there clinical trials in MF available at Stanford?
Yes, the Multidisciplinary Cutaneous Lymphoma Center is very active in all arenas of research for MF, including clinical trials.
