Key Terms: Alkylating agent, Erythroderma, Mycosis fungoides, Retinoids, Sézary syndrome, T-helper cells.
Definition
Cutaneous T-cell lymphoma (CTCL) is a malignancy of the T helper (CD4+) cells of the immune system.
Description
CTCL is a cancer of the white blood cells that primarily affects the skin and only secondarily affects other sites. The disease usually develops slowly, advancing from itchy dark patches on the skin to mushroom shaped tumors, a condition known as mycosis fungoides. This disease involves the uncontrollable proliferation of T-lymphocytes known as T helper cells, so named because of their role in the immune response. T-helper cells are characterized by the presence of a protein receptor on their surface called CD4. Accordingly, T-helper cells are said to be CD4+.
The proliferation of T-helper cells results in the penetration, or infiltration, of these abnormal cells into the epidermal layer of the skin. The skin reacts with slightly scaling lesions that itch, although the sites of greatest infiltration do not necessarily correspond to the sites of the lesions. The lesions are most often located on the trunk, but can be present on any part of the body. In the most common course of the disease, the patchy lesions progress to palpable plaques that are deeper red and have more defined edges. As the disease worsens, skin tumors develop that are often mushroom-shaped, hence the name mycosis fungoides (the name was not meant to imply that a fungus is involved in the disease). Finally, the cancer progresses to extracutanous involvement, often in the lymph nodes or the viscera.
The progression of the disease is often not linear, although the probability of spread to the viscera (internal organs in the abdomen) is directly related to the amount of skin involvement. Visceral involvement is almost never seen with minimal skin involvement. About 8% of those with generalized plaques have extracutaneous spread, while 30% with tumors have viscera involved. Overall, visceral involvement occurs with only 15 to 20% of all patients diagnosed with the disease.
Some patients present with an overall redness of the skin, with or without overlying plaques or tumors. The skin can be atrophic (shrunken) or lichenified (having small, firm bumps, close together), with cold intolerance and intense itching. These patients have swollen lymph nodes and large numbers of abnormal cells circulating the blood. This particular manifestation of CTCL is known as Sézary syndrome.
Demographics
CTCL is a rare disease, with an annual incidence of about .29 cases per 100,000 persons in the United States. It is about half as common in Eastern Europe. However, this discrepancy may be attributed to a differing physician awareness of the disease rather than a true difference in occurrence. In the U.S., there are about 500 to 600 new cases a year and about 100 to 200 deaths. Usually seen in older adults, CTCL strikes twice as many men as women and the median age at diagnosis is 55 to 60 years.
Causes and Symptoms
The cause of CTCL is unknown. Exposure to chemicals or pesticides has been suggested but the most recent study on the subject failed to show a connection between exposure and development of the disease. The ability to isolate various viruses from cell lines grown from cells of CTCL patients raises the question of a viral cause, but studies have been unable to confirm these suspicions.
The symptoms of CTCL are seen primarily in the skin, with itchy red patches or plaques and, usually over time, mushroom-shaped skin tumors. Any part of the skin can be involved and the extent and distribution of the rash or tumors vary greatly from patient to patient. The only universal symptom of the disease is the itch and this symptom is usually what brings the patient to the doctor for treatment. If the disease spreads outside of the skin, the symptoms include swelling of the lymph nodes, usually most severe in those draining the areas with skin involvement. Spread to the viscera is most often manifested as disorders of the lungs, upper digestive tract, central nervous system, or liver but virtually any organ can be shown to be involved at autopsy.
Diagnosis
Diagnosis of CTCL is often difficult in the early stages because of its slow progression and ability to mimic many other benign skin conditions. The early patches of CTCL resemble closely the rashes of eczema, psoriasis, and contact dermatitis. In a further complication, the early manifestations of the disease can respond favorably to the topical corticosteroid treatments prescribed for these skin disorders. This has the unfortunate result of the disease being missed and the patient remaining untreated for years. CTCL is most likely discovered when a physician maintains a suspicion about the disease, performs multiple skin biopsies, and provides close follow-up after the initial presentation.
Skin biopsies showing penetration of abnormal cells into the epidermal tissue are necessary to make a firm diagnosis of CTCL. Several molecular studies can also help support the diagnosis. The first looks at the cellular proteins seen on the surface of the abnormal cells. Many cases of CTCL show the retention of the CD4+ protein, but the loss of other proteins usually seen on the surface of mature CD4+ cells, such as Leu-8 or Leu-9. The abnormal cells also show unusual rearrangements at the genetic level for the gene that encodes the T-cell receptors. These rearrangements can be identified using Southern blot analysis. The information from the molecular tests, combined with the presence of abnormal cells in the epidermis, strongly supports the CTCL diagnosis.
Treatment Team
This disease is treated by a dermatologist, a medical oncologist, and, if radiation therapy is used, a radiation oncologist.
Clinical Staging, Treatments, and Prognosis
The current staging of this disease was first presented at the International Consensus Conference on CTCL in 1997. This staging attempts to show the complex interaction between the various outward symptoms of the disease and prognosis. The system has seven clinical stages based on skin involvement (tumor = T), lymph node involvement (LN), and presence of visceral metastases (M).
The first stage, IA, is characterized by plaques covering less than 10 percent of the body (T1) and no visceral involvement (M0). Lymph node condition at this stage can be uninvolved, reactive to the skin disease, or dermatopathic (biopsies showing CTCL involvement) but not enlarged (LN0-2). The shorthand expression of this stage is therefore T1, LN0-2, M0. Prognosis is very good if the disease has only progressed this far, with an average survival of 20 or more years. Most deaths occurring to persons in this group are unrelated to CTCL.
The next stage, IB, differs from IA in that greater than 10 percent of the body is covered by plaques (T2, LN0-2, M0). Stage IIA occurs with any amount of plaques in addition to the ability to palpate the lymph node and the lymph uninvolved, reactive, or dermatopathic (T1-2, LN0-2, M0). Average survival for patients in stages IB and IIA is about 12 years.
Treatments applied to the skin are preferred for patients having these preliminary stages of the disease. These commonly include topical chemotherapy with mechlorethamine hydrochloride (nitrogen mustard) or phototherapy of psoralen plus ultraviolet A (PUVA). Topical chemotherapy involves application to the skin of nitrogen mustard, an alkylating agent, in a concentration of 10 to 20 mg/dL in an aqueous or ointment base. Treatment of affected skin is suggested at a minimum and application over the entire skin surface is often recommended. Care needs to be taken that coverage of involved skin is adequate, as patients who self-apply the drug often cannot reach all affected areas. The most common side effect is skin hypersensitivity to the drug. Nearly all patients respond favorably to this treatment, with a 32 to 61% complete response rate, based on amount of skin involvement. Unfortunately, only 10 to 15% of patients maintain a complete response rate after discontinuing the treatment.
Phototherapy involves treatment with an orally administered drug, 8-methyloxypsoralen, that renders the skin sensitive to long-wave ultraviolet light (UVA), followed by controlled exposure to the radiation. During the initial treatment period, which may last as long as 6 months, patients are treated two to three times weekly. This is reduced to about once monthly after initial clearing of the lesions. Redness of the skin and blistering are the most common side effects of the treatment and are much more common in patients presenting with overall skin redness, or erythroderma, so lower intensities of light are usually used in this case. About 50% of all patients experience complete clearance with this treatment. Some patients with very fair skin and limited skin involvement can successfully treat themselves at home with special lamps and no psoralen.
The next stage, IIB, involves one or more cutaneous tumors, in combination with absent or present palpable lymph nodes, lymph uninvolved, reactive, or dermatopathic, and no visceral involvement (T3, LN0-2, M0). Stage III is characterized by erythroderma, an abnormal redness over widespread areas of the skin (T4, LN0-2, M0). The disease in both of these stages involves intermediate risk to the patient.
For more extensive disease, radiation therapy is an effective treatment option. It is generally used after the topical treatments have proven ineffective. Individual plaques or tumors can be treated using electrons, orthovoltage x rays, or megavoltage photons with exposure in the range of 15 to 25 Gy. Photon therapy has proven particularly useful once the lymph nodes are involved. Another possibility is total-skin electron beam therapy (TSEB), although the availability of this treatment method is limited. It involves irradiation of the entire body with energized electrons. Side effects of this treatment include loss of finger and toe nails, acute redness of the skin, and inability to sweat for about 6 to 12 months after therapy. Almost all patients respond favorably to radiation treatment and any reoccurrence is usually much less severe.
Combinations of different types of treatments is a very common approach to the management of CTCL. Topical nitrogen mustard or PUVA is often used after completion of radiation treatment to prolong the effects. The addition of genetically engineered interferon to PUVA therapy significantly increases the percentage of patients showing a complete response. Furthermore, although treatments using chemotherapy drugs alone, such as deoxycofomycin or etretinate, have been disappointing for CTCL, combining these drugs with interferon has shown promising results. Interferon has also been combined with retinoid treatments, although the mechanism of action of retinoids (Vitamin A analogues) against CTCL is unknown.
The final two stages of the disease are IVA and IVB. IVA presents as any amount of skin involvement, absent or present palpable lymph nodes, no visceral involvement, and lymph that contains large clusters of convoluted cells or obliterated nodes (T1-4, LN3-4). Patients in stage III and IVA have an average life expectancy of about five years. IVB differs in the addition of palpable lymph nodes and visceral involvement (T1-4, LN3-4, M1). At these stages the disease is high risk, with most deaths occurring by infection, due to the depleted immune system of the later stage patient. Once a patient has reached stage IVB, the average life expectancy is one year. All of the treatment methods described above are appropriate for the final two stages of the disease.
Alternative and Complementary Therapies
Itching of the skin is one of the most troublesome symptoms of CTCL. One alternative treatment for itchiness is the application of a brewed solution of chickweed that is applied to the skin using cloth compresses. Another suggested topical application is a mixture of vitamin E, vitamin A, unflavored yogurt, honey, and zinc oxide. Evening primrose oil applied topically may also reduce itch and promote healing.
Coping With Cancer Treatment
Topical chemotherapy and radiation treatment of the skin require special care of the areas being exposed to the drug or emission. Use of mild soap and special sensitive formulas for moisturizer and other skin products is suggested. Tight clothing in the area should be avoided. It is important that the treated area is not exposed to the sun during the treatment course. In general, special care to not irritate the area that is being treated will help ease the treatment course.
Clinical Trials
Recent clinical trials for CTCL have focused on testing molecular treatment approaches. Anti-T-cell monoclonal antibodies, that would theoretically target the abnormal T cells for destruction by the patient's own immune system, have been tried. Unfortunately, the responses to this treatment have been brief and limited by the development of an immune reaction against the antibodies themselves (which are made in mouse cells and therefore seen as foreign by the patient's immune system). Studies continue using newly developed, more specific antibodies and radiolabeled antibodies (to target radiation therapy to the T-helper cells).
Genetically engineered fusion proteins that link diphtheria toxin (a protein that kills cells) with interleukin-2 (a protein that binds to T-helper cells through a receptor on its surface) have also been administered intravenously to CTCL patients. The toxin was taken into the abnormal cells and did kill them. Three out of five patients in a phase I trial achieved significant tumor response to this novel therapy.
As of 2003, other experimental treatments for CTCL include imiquimod, an immune response modifier available as a topical cream; denileukin-diftitox (Ontak), a drug given by injection; doxorubicin; and various combinations of these agents.
Additional new approaches to the treatment of CTCL include vaccine therapy and stem cell transplantation. A group of researchers in Japan is currently testing various peptides introduced through the skin as a possible form of immunization against CTCL, while German and American researchers are investigating the potential of stem cell transplantation in the treatment of CTCL. As of late 2003, bone marrow transplants from unrelated donors offer the best hope of a curative treatment for CTCL.
Prevention
Studies have been unable to link CTCL to any environmental or genetic factors, so prevention is not possible as of the early 2000s.
Questions to Ask the Doctor
- What is the stage of the disease at this point and what is the prognosis?
- What are the treatment options and what side effects can be expected?
- Is total-skin electron beam therapy (TSEB) available and is this a treatment that should be considered?
- What are the chances of complete clearance of the disease?
Special Concerns
Because the initial diagnosis of CTCL can be difficult, any dermatitis-like or eczema-like rash that does not respond to treatment or recurs after running the full course of topical corticosteroids should be brought to the attention of a doctor. This is particularly important given the good prognosis with early diagnosis and treatment of CTCL but rapidly worsening prognosis with progression of the disease.
Resources
Books
Beers, Mark H., MD, and Robert Berkow, MD, editors. "Mycosis Fungoides." Section 11, Chapter 139 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2002.
Hoppe, Richard, T. "Mycosis Fungoides and Other Cutanous Lymphomas." In The Lymphomas, edited by George P. Canellos, et al. Philadephia: W.B. Saunders Co., 1999, pp. 495–406.
Wilson, Lynn D., et al. "Cutaneous T-Cell Lymphomas." In Cancer Principles & Practice of Oncology, edited by Vincent T. DeVita, et al. Philadelphia: Lippincott Williams & Wilkins, 2001, pp. 2316–2329.
Periodicals
Beyeler, M., and R. Dummer. "Standard and Experimental Therapy of Cutaneous T-cell Lymphoma." [in German] Hautarzt 54 (December 2003): 1177–1184.
Dippel, E., C. D. Klemke, and S. Goerdt. "Current Status of Cutaneous T-cell Lymphoma: Molecular Diagnosis, Pathogenesis, Therapy and Future Directions." Onkologie 26 (October 2003): 477–483.
Kempf, W., N. Kettelhack, M. Duvic, and G. Burg. " Topical and Systemic Retinoid Therapy for Cutaneous T-cell Lymphoma." Hematology/Oncology Clinics of North America 17 (December 2003): 1405–1419.
Oyama, Y., J. Guitart, T. M. Kuzel, et al. "High-Dose Therapy and Bone Marrow Transplantation in Cutaneous T-cell Lymphoma." Hematology/Oncology Clinics of North America 17 (December 2003): 1475–1483.
Seo, N., F. Furukawa, Y. Tokura, and M. Takigawa. "Vaccine Therapy for Cutaneous T-cell Lymphoma." Hematology/Oncology Clinics of North America 17 (December 2003): 1467–1474.
Organizations
National Cancer Institute. Building 31 Room 10A31 31 Center Drive MSC 2580 Bethesda, MD 20892-2580. (800)4-CANCER. .
—Michelle Johnson, M.S., J.D.; Rebecca J. Frey, PhD
