Cutaneous T-Cell Lymphoma

Cutaneous T-Cell Lymphoma 

Definition

Cutaneous T-cell lymphoma (CTCL) is a malignancy of the T-helper (CD4+) cells of the immune system.

Description

CTCL, also known as mycosis fungoides, is a cancer of the white blood cells that primarily affects the skin and only secondarily affects other sites. 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. Finally, the cancer progresses to extracutanous involvement, often in the lymph nodes or the viscera.

CTCL is a rare disease, with an annual incidence of about 0.29 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 United States, there are about 500-600 new cases a year and about 100-200 deaths. CTCL is usually seen in older adults; the median age at diagnosis is 55-60 years. It strikes twice as many men as women. The average life expectancy at diagnosis is 7-10 years, even without treatment.

Causes and symptoms

The cause of CTCL is unknown. Exposure to chemicals or pesticides has been suggested; however, 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 really 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.

Some patients with CTCL develop a leukemic phase of the disorder known as Sézary syndrome, which is characterized by the appearance of malignant T cells in the bloodstream. It is named for the French dermatologist who first identified the abnormal T cells.

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 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

Treatment of CTCL depends on the stage of the disease. The current staging of this disease was first presented at the International Consensus Conference on CTCL in 1997. The 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% 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. The next stage, IB, differs from IA in that greater than 10% 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).

Treatments applied to the skin are preferred for patients having these preliminary stages of the disease, commonly 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 10-20 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 32-61% complete response rate, based on amount of skin involvement. Unfortunately, only 10-15% 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 six 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).

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 six to 12 months after therapy. Almost all patients respond favorably to radiation treatment and any reoccurrence is usually much less severe.

Combination 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). IVB differs in the addition of palpable lymph nodes and visceral involvement (T1-4, LN3-4, M1). All of the treatment methods described above are appropriate for the final two stages of the disease.

A newer drug that has been used to treat CTCL is bexarotene, a topical gel that is a synthetic retinoid analog. Bexarotene has been shown to be effective in clinical trials for stage IA or IB CTCL, and has fewer side effects than topical nitrogen mustard or electron beam radiotherapy. Another team of researchers at the University of Pennsylvania reported in 2003 that bexarotene combined with psoralen and UVA therapy is also effective in treating patients with advanced CTCL.

A treatment for advanced CTCL that is considered experimental as of mid-2003 is alemtuzumab, a monoclonal antibody. A Swedish study of 22 patients with advanced CTCL and Sézary syndrome found that alemtuzumab relieved symptoms in 55% of patients, with 32% in complete remission and 23% in partial remission.

Alternative treatment

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 is also claimed to reduce itch and promote healing.

Key terms

Alkylating agent — A chemical that alters the composition of the genetic material of rapidly dividing cells, such as cancer cells, causing selective cell death; used as a topical chemotherapeutic agent to treat CTCL.

Cutaneous — Pertaining to the skin.

Erythroderma — An abnormal reddening of the entire skin surface.

Monoclonal antibody — An antibody produced by the identical offspring of a single cloned antibody-producing cell.

Mycosis fungoides — Another name for cutaneous T-cell lymphoma.

Sézary syndrome — A leukemic phase of CTCL that develops in some patients, characterized by the appearance of malignant T cells in the peripheral blood and sometimes in the lymph nodes. The syndrome is named for Alfred Sézary (1880–1956), a French dermatologist.

T-helper cells — A cellular component of the immune system that plays a major role in ridding the body of bacteria and viruses, characterized by the presence of the CD4 protein on its surface; the type of cell that divides uncontrollable with CTCL.

Total-skin electron beam therapy — A method of radiation therapy used to treat CTCL that involves bombarding the entire body surface with high-energy electrons.

Prognosis

The prognosis for CTCL is dependent on the stage of the disease. Prognosis is very good if the disease has only progressed to Stage IA, with a mean survival of 20 or more years. At this point, the disease is a very low mortality risk to the patient, with most deaths occurring to persons in this group unrelated to CTCL. For patients diagnosed at stages IB and IIA, the median survival is about 12 years. The disease in both of these stages involves intermediate risk to the patient. Patients in stage III and IVA have a mean life expectancy of about five years. At these later 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 mean life expectancy is one year.

Prevention

Studies have been unable to link CTCL to any environmental or genetic factors as of 2003, so prevention at this time is not possible.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Lymphomas: Mycosis Fungoides." Section 11, Chapter 139 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Hoppe, Richard T. "Mycosis Fungoides and Other Cutanous Lymphomas." In The Lymphomas, edited by George P. Canellos, et al. Philadelphia: W.B. Saunders Co., 1999.

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.

Periodicals

Dawe, R. S. "Ultraviolet A1 Phototherapy." British Journal of Dermatology 148 (April 2003): 626-637.

Elmer, Kathleen B., and Rita M. George. "Cutaneous T-Cell Lymphoma Presenting as Benign Dermatoses." American Family Physician 59 (May 1999): 2809-2815.

Kari, L., A. Loboda, M. Nebozhyn, et al. "Classification and Prediction of Survival in Patients with the Leukemic Phase of Cutaneous T Cell Lymphoma." Journal of Experimental Medicine 197 (June 2, 2003): 1477-1488.

Lundin, J., H. Hagberg, R. Repp, et al. "Phase 2 Study of Alemtuzumab (Anti-CD52 Monoclonal Antibody) in Patients with Advanced Mycosis Fungoides/Sézary Syndrome." Blood 101 (June 1, 2003): 4267-4272.

Martin, A. G. "Bexarotene Gel: A New Skin-Directed Treatment Option for Cutaneous T-Cell Lymphomas." Journal of Drugs in Dermatology 2 (April 2003): 155-167.

McGinnis, K. S., M. Shapiro, C. C. Vittorio, et al. "Psoralen plus Long-Wave UV-A (PUVA) and Bexarotene Therapy: An Effective and Synergistic Combined Adjunct to Therapy for Patients with Advanced Cutaneous T-Cell Lymphoma." Archives of Dermatology 139 (June 2003): 771-775.

Organizations

American Academy of Dermatology. 930 N. Meacham Road, P.O. Box 4014, Schaumburg, IL 60168-4014. (847) 330-0230. Fax: (847) 330-0050. http://www.aad.org.

American Cancer Society. 1599 Clifton Road NE, Atlanta, GA 30329. (800) ACS-2345.

National Cancer Institute (NCI). NCI Public Inquiries Office, Suite 3036A, 6116 Executive Boulevard, MSC8332, Bethesda, MD 20892-8322. (800) 4-CANCER or (800) 332-8615 (TTY). http://www.nci.nih.gov.

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lymphoma /lym·pho·ma/ (lim-fo´mah) any neoplastic disorder of lymphoid tissue. Often used to denote malignant l., classifications of which are based on predominant cell type and degree of differentiation; various categories may be subdivided into nodular and diffuse types depending on the predominant pattern of cell arrangement.

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adult T-cell lymphoma , adult T-cell leukemia/lymphoma see under leukemia.

B-cell lymphoma  any in a large group of non-Hodgkin's lymphomas characterized by malignant transformation of the B lymphocytes.

B-cell monocytoid lymphoma  a low-grade lymphoma in which cells resemble those of hairy cell leukemia.

Burkitt's lymphoma  a form of small noncleaved-cell lymphoma, usually occurring in Africa, manifested usually as a large osteolytic lesion in the jaw or as an abdominal mass; Epstein-Barr virus has been implicated as a causative agent.

centrocytic lymphoma  mantle cell l.

convoluted T-cell lymphoma  lymphoblastic lymphoma with markedly convoluted nuclei.

cutaneous T-cell lymphoma  a group of lymphomas exhibiting (1) clonal expansion of malignant T lymphocytes arrested at varying stages of differentiation of cells committed to the series of helper T cells, and (2) malignant infiltration of the skin, which may be the chief or only manifestation of disease.

diffuse lymphoma  in an older classification method, malignant lymphoma in which the neoplastic cells diffusely infiltrate the entire lymph node, without any definite organized pattern.

follicular lymphoma  any of several types of non-Hodgkin's lymphoma in which the lymphomatous cells are clustered into nodules or follicles.

follicular center cell lymphoma  B-cell lymphoma classified by the similarity of the cell size and nuclear characteristics to those of normal follicular center cells; the four previous subtypes are scattered among several types of follicular and diffuse lymphomas.

giant follicular lymphoma  follicular l.

granulomatous lymphoma  Hodgkin's disease.

histiocytic lymphoma  a rare type of non-Hodgkin's lymphoma characterized by the presence of large tumor cells resembling histiocytes morphologically but considered to be of lymphoid origin.

Hodgkin's lymphoma  see under disease.

intermediate lymphocytic lymphoma , lymphocytic lymphoma, intermediately differentiated mantle cell l.

large cell lymphoma  any of several types of lymphoma characterized by the formation of one or more types of malignant large lymphocytes, such as large cleaved or noncleaved follicular center cells, in a diffuse pattern.

large cell, immunoblastic lymphoma  a highly malignant type of non-Hodgkin's lymphoma characterized by large lymphoblasts (B or T lymphoblasts or a mixture) resembling histiocytes and having a diffuse pattern of infiltration.

Lennert's lymphoma  a type of non-Hodgkin's lymphoma with a high content of epithelioid histiocytes and frequently with bone marrow involvement.

lymphoblastic lymphoma  a highly malignant type of non-Hodgkin's lymphoma composed of a diffuse, relatively uniform proliferation of cells with round or convoluted nuclei and scanty cytoplasm.

malignant lymphoma  a group of malignancies characterized by the proliferation of cells native to the lymphoid tissues, i.e., lymphocytes, histiocytes, and their precursors and derivatives; the group is divided into two major clinicopathologic categories: Hodgkin's disease and non-Hodgkin's lymphoma.

mantle cell lymphoma , mantle zone lymphoma a rare form of non-Hodgkin's lymphoma having a usually diffuse pattern with both small lymphocytes and small cleaved cells.

marginal zone lymphoma  a group of related B-cell neoplasms that involve the lymphoid tissues in the marginal zone, the patchy area outside the follicular mantle zone.

mixed lymphocytic-histiocytic lymphoma  non-Hodgkin's lymphoma characterized by a mixed population of cells, the smaller cells resembling lymphocytes and the larger ones histiocytes.

nodular lymphoma  follicular l.

non-Hodgkin's lymphoma  a heterogeneous group of malignant lymphomas, the only common feature being an absence of the giant Reed-Sternberg cells characteristic of Hodgkin's disease.

plasmacytoid lymphocytic lymphoma  a rare variety of small lymphocytic lymphoma in which the predominant cell type is the plasma cell.

primary effusion lymphoma  a B-cell lymphoma associated with human herpesvirus 8 infection, characterized by the occurrence of lymphomatous effusions in body cavities without the presence of a solid tumor.

small B-cell lymphoma  the usual type of small lymphocytic lymphoma, having predominantly B lymphocytes.

small cleaved cell lymphoma  a group of non-Hodgkin's lymphomas characterized by the formation of malignant small cleaved follicular center cells, with either a follicular or diffuse pattern.

small lymphocytic lymphoma  a diffuse form of non-Hodgkin's lymphoma representing the neoplastic proliferation of well-differentiated B lymphocytes, with focal lymph node enlargement or generalized lymphadenopathy and splenomegaly.

small lymphocytic T-cell lymphoma  small lymphocytic lymphoma that has predominantly T lymphocytes.

small noncleaved cell lymphoma  a highly malignant type of non-Hodgkin's lymphoma characterized by the formation of small noncleaved follicular center cells, usually in a diffuse pattern.

T-cell lymphomas  a heterogeneous group of lymphoid neoplasms representing malignant transformation of the T lymphocytes.

U-cell lymphoma , undefined lymphoma a category of non-Hodgkin's lymphomas that cannot be classified into a definite type by either morphologic or known immunocytochemical markers.

undifferentiated lymphoma  small noncleaved cell l.