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40 years!
Last updated:
October 18, 2018
Years published: 1989, 1996, 1997, 1998, 2002, 2003, 2007, 2013
NORD gratefully acknowledges Javier Munoz, MD, FACP, Hematology and Oncology, Banner MD Anderson Cancer Center, Gilbert, Arizona, for assistance in the preparation of this report.
General Discussion
Summary
Cutaneous T-cell lymphomas (CTCLs) are a group of disorders characterized by abnormal accumulation of malignant T-cells in the skin potentially resulting in the development of rashes, plaques and tumors. CTCLs belong to a larger group of disorders known as non-Hodgkin’s lymphomas (NHLs), which are related malignancies (cancers) that affect the lymphatic system (lymphomas).
Introduction
Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.
There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes. CTCLs result from errors in the production of T-lymphocytes or transformation of T-lymphocytes into malignant cells. In CTCLs, abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-lymphocytes result in accumulation of these lymphocytes in the skin. In some cases, malignant lymphocytes may spread to affect the lymph nodes and eventually to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from case to case, depending upon the extent and region(s) of involvement, the specific type of CTCL present, and various additional factors.
Non-Hodgkin’s lymphomas, such as CTCLs, may also be categorized based upon certain characteristics of the cancer cells as seen under a microscope and how quickly they may tend to grow and spread. For example, CTCLs may be characterized as “low-grade” (or indolent) lymphomas, which tend to grow slowly and result in few associated symptoms, or “intermediate-grade” or “high-grade” (aggressive) lymphomas, which typically grow rapidly, requiring prompt treatment. Most cases of CTCL, especially the classic form (mycosis fungoides), are slow-growing (indolent) lymphomas.
The signs and symptoms associated with cutaneous T-cell lymphomas vary greatly from case to case, depending upon the specific type of lymphoma present and how far the disease has progressed (i.e., staging). (For further information on stages, please see the section entitled “Standard Therapies: Diagnosis” [Staging] below.)
The most common type and classic presentation of CTCL is known as mycosis fungoides and usually progresses slowly over many years. The associated skin symptoms of mycosis fungoides progress through three separate phases. Affected individuals may first develop a red rash or dry, red, scaly patches of skin that most often affect the buttocks and trunk (premyotic phase). These patches may remain unchanged, spontaneously go away, or slowly grow larger. The skin lesions associated with the initial phase of mycosis fungoides are termed “nonspecific” because they cannot be differentiated from skin lesions associated with other, more common, skin disorders such as psoriasis. This initial phase of mycosis fungoides may persist for months, years, or decades.
In the second phase of mycosis fungoides, slightly-elevated, reddish-brown, scaly bumps (plaques) develop on the skin (mycotic stage). These plaques may develop from existing patches or spontaneously in unaffected areas. Eventually, these plaques may expand and grow together (coalesce) forming larger plaques. Any area of the body may be affected.
The skin lesions associated with the first two phases of mycosis fungoides may not be associated with other symptoms (asymptomatic) or may occur along with itchiness (pruritis) and pain. In rare cases, affected individuals may experience difficulty sleeping due to severe itchiness.
The third phase of mycosis fungoides is characterized by the development of mushroom-shaped tumors. In some cases, the tumors may become ulcerated and infected. Some individuals may not progress beyond the plaque phase of mycosis fungoides and do not develop tumors. Other individuals may develop tumors without first developing the patches or plaques associated with the early stages of mycosis fungoides (tumeur d’ emblee variant).
In approximately 10 percent of individuals with the classic mycosis fungoides presentation of CTCL, malignant lymphocytes may spread beyond the skin to affect the lymph nodes and major organs of the body including the liver, spleen and gastrointestinal system. Depending upon specific sites and extent of involvement, disease management, and additional factors, disease progression may eventually lead to life-threatening complications. (For more information on this disorder, choose “mycosis fungoides” as your search term in the Rare Disease Database.)
In rare cases, affected individuals may develop Sezary syndrome, a form of CTCL that is considered the leukemic variant of mycosis fungoides. It is characterized by a widespread red rash that may cover most of the body (generalized erythroderma), the presence of specific malignant lymphocytes (Sezary cells) in the blood, and abnormally enlarged lymph nodes (lymphadenopathy). Individuals with Sezary syndrome may experience intense itchiness (pruritis) and thickening, scaling, and peeling (exfoliation) of the skin. Additional symptoms associated with Sezary syndrome include outward turning of the eyelids (ectropion); abnormally thick, rough skin on the palms of the hands and the soles of the feet (palmoplantar keratoderma); malformation of the nails (onychodystrophy); and abnormal enlargement of the liver and/or spleen (hepatosplenomegaly). General symptoms associated with Sezary syndrome include fevers, weight loss, bald patches on the scalp (alopecia), and a general feeling of ill health (malaise).
Granulomatous slack skin is a rare form of CTCL characterized by areas (folds) of lax, reddened skin. The underarms, groin, and stomach are most often affected. Granulomatous slack skin is usually a benign, slow-growing (indolent) form of CTCL. In some cases, affected individuals may develop a more serious form of CTCL, such as mycosis fungoides, later during life.
Primary cutaneous anaplastic large cell lymphomas represent a subgroup of CTCL characterized by positive expression of the CD30 (Ki-1) antigen. Affected individuals develop tumors on the skin. The tumors may become ulcerated or infected. In some cases, the lesions or tumors go away without treatment (spontaneous regression). However, lesions often return (relapse). In rare cases, other organ systems of the body may become involved.
Lymphomatoid papulosis is a rare skin disorder that some researchers believe is an early from of CD30+ lymphoma. The disorder is characterized by groups of slightly-elevated, reddish-brown bumps (nodules or papules) that most often affect the trunk, face, and arms and legs. These lesions often become crusted or ulcerated, sometimes leaving a scar. Approximately 5-20 percent of individuals with lymphomatoid papulosis develop CTCL. Other researchers believe that lymphomatoid papulosis is a similar, yet distinct, “premalignant” condition and not a form of CTCL.
Subcutaneous pannulitic T-cell lymphoma is a rare variant of CTCL. Affected individuals may have multiple, tender, bumps (nodules) just under the surface of the skin of various areas of the body especially the arms and legs (extremities). These nodules may lead to inflammation of the subcutaneous layer of fat (panniculitis). Affected individuals may also experience weight loss, fevers, and joint pain (arthralgia). Unlike mycosis fungoides, this form of CTCL is often aggressive may lead to the involvement of other organ systems and, potentially, life-threatening complications.
Pagetoid reticulosis (PR), also known as Woringer-Kolopp disease, is a rare skin condition characterized by a solitary lesion that usually affects the arms or legs and may grow slowly. The lesion is similar in appearance to the lesions associated with mycosis fungoides. In addition, there are also microscopic similarities between the skin lesions in mycosis fungoides and pagetoid reticulosis. Consequently, most researchers believe that PR is a slow-growing variant of CTCL.
According to the medical literature, cases have been reported in which individuals developed more than one form of CTCL at the same time.
The exact underlying cause of cutaneous T-cell lymphomas is unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; bacterial skin infections, etc.), diet, stress, and/or additional factors may play varying contributing roles in causing specific types of cancer. Investigators at the National Institutes of Health (NIH)/National Cancer Institute, across the United States, and around the world are conducting ongoing basic research to learn more about the many factors that may result in cancer. (The National Cancer Institute is listed in the “Resources” section of this report below.)
In individuals with cancer, including CTCLs, malignancies may develop due to abnormal changes in the structure and orientation of certain cells (e.g., T-lymphocytes). As mentioned above, the specific cause of such changes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically), such as due to exposure to certain environmental factors, or, more rarely, may be inherited.
The symptoms of CTCLs result from abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-lymphocytes, which results in accumulation of these lymphocytes in the skin and, in some cases, other organ systems of the body. There are two types of T-lymphocytes known as CD4 and CD8. CD4s (helper cells) help regulate functions of the immune system. CD8s (killer cells) breakdown or rid the body of foreign substances. In most cases of CTCL, CD4s are the cells that become malignant.
According to the medical literature, CTCL affects males twice as often as females. In the majority of cases, diagnosis is made between 40 and 60 years of age. One study estimated that from .5 to 5 percent of all CTCLs occur in children. CTCLs occur twice as often in individuals of African-American descent as in individuals of European or Asian descent.
There are approximately 1,000 new cases of skin lymphoma each year in the United States. Approximately 16,000-20,000 Americans have the classic presentation of CTCL known as mycosis fungoides. One estimate placed the incidence of mycosis fungoides at one case per 1,000,000 people in the United States.
The diagnosis of cutaneous T-cell lymphomas is based upon a thorough clinical evaluation, detection of certain symptoms and physical findings, a detailed patient history, and a variety of specialized tests. Such testing is necessary to confirm the specific type (and subtype) of CTCL, to assess the nature and extent of the disease, and to determine the most appropriate treatments.
For those with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. These may include biopsies, blood tests, specialized imaging tests, and/or additional tests.
Biopsies typically involve surgical removal and microscopic examination (i.e., histologic) of small samples of tissue cells gathered from CTCL skin lesions. A biopsy may confirm a diagnosis of CTCL. However, the skin lesions associated with the early stages of CTCL are difficult to distinguish from other skin conditions such as psoriasis. Consequently, several biopsies performed over an extended period of time may be necessary to detect characteristic microscopic changes associated with CTCL. A separate test that is often used to help diagnose early stage CTCL is T-cell receptor gene rearrangement analysis (TCRGR). This test can help identify specific rearrangements of particular T-cell gene segments that are characteristic of most individuals with CTCL. The presence of identical twin T-cells may support the diagnosis of CTCL.
Blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.) Blood tests may also be performed to detect the presence of characteristic cells (Sezary cells) in individuals with suspected Sezary syndrome.
To determine the extent of the disease, various specialized imaging procedures may also be recommended, such as standard x-ray imaging and computed tomography (CT) scanning. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. For those with suspected or diagnosed CTCL, CT scans may be taken of the neck, chest, abdominal, and/or pelvic regions to help detect enlargement of certain lymph nodes or spread of the malignancy to certain organs.
A procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. During this procedure, a sample of bone marrow is obtained, usually from the hipbone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.
In some cases, physicians may recommend other testing procedures to help assess the extent of disease and to follow treatment. In addition, tests may be required to help evaluate the health and functioning of certain organs that may potentially be adversely affected due to certain treatments (e.g., particular anticancer [chemotherapeutic] drugs]). For example, such tests may include certain procedures to evaluate functioning of the heart and lungs.
Staging
When an individual is diagnosed with a CTCL, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help determine how far the disease has spread, characterize the potential disease course, and determine appropriate treatment approaches. Some of the same diagnostic tests described above may be used in staging a CTCL (e.g., blood tests, CT scanning, gallium scanning, bone marrow biopsy). In addition, in some cases, additional biopsies may be obtained to assist in lymphoma staging.
Different staging systems have been proposed for CTCLs. The most accepted and widely used system is the tumor-node-metastasis (TNM) system. It includes the following stages:
Stage I indicates the presence of red, scaly patches or plaques of skin on the body. There is no involvement of the lymph nodes, blood, or additional organ systems.
Stage II indicates either of the following: IIA: the presence of red, scaly patches of skin, but no tumors. The lymph nodes are enlarged, but without the presence of cancer cells; or IIB: tumors are present. Lymph nodes may be enlarged, but without the presence of cancer cells.
Stage III indicates that nearly all of the skin is red and scaly. Lymph nodes may be enlarged, but without the presence of cancer cells.
Stage IV indicates that individuals have red, scaly skin and involvement of lymph nodes or additional organ systems (e.g., liver, lungs, spleen).
Treatment
In 2006, the U.S. Food and Drug Administration (FDA) approved vorinostat (Zolinza) for the treatment of cutaneous T-cell lymphoma. Zolinza is to be used when the disease persists or returns after treatment by other medicines. For information, contact the sponsor, Merck & Co., or go to https://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_ppi.pdf .
In 2018, Poteligeo (mogamulizumab-kpkc) injection was approved for the treatment of adult patients with Sezary Syndrome (SS) after at least one prior systemic therapy. This approval is the first FDA approval of a drug specifically for SS. Poteligeo is manufactured by Kyowa Kirin, Inc.
The diagnosis and therapeutic management of cutaneous T-cell lymphomas may require the coordinated efforts of a team of medical professionals, such as specialists who diagnose and treat skin disorders (dermatologists); physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific subtype of CTCL; the presence or absence of certain symptoms; individual’s age and general health; and/or additional elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
A wide variety of treatment options exist for individuals with CTCL including topical chemotherapy, radiation therapy, photochemotherapy, vitamin A derivatives (retinoids), and chemotherapy. These treatments may be used alone or in varied combination.
During the early stages of CTCLs, conservative topical treatment may be recommended. Early-stage disease confined to the skin often responds extremely well to skin-directed therapies. Such therapies include topical chemotherapy, radiation therapy, and a procedure known as phototherapy. Chemotherapy is treatment with certain anticancer drugs. Specific topical chemotherapies used to treat individuals with early-stage CTCL include mechlorethamine (nitrogen mustard) or carmustine (BCNU). These drugs may be administered as an ointment or watery solution.
In 2013, the FDA approved mechlorethamine gel for the topical treatment of stage IA-IB mycosis fungoides-type cutaneous T-cell lymphoma (CTCL). The mechlorethamine gel is applied once per day on the affected skin.
Radiation therapy is a treatment method that uses radiation to destroy cancer cells. Radiation therapy may be used to treat specific lesions on the skin. During the early stages of CTCL, electron beam radiation therapy (EBRT), which uses energy rays containing electrons to destroy cancer cells, may be used to treat specific skin lesions. The procedure can treat the entire surface of the skin (total electron beam radiation therapy) without affecting internal organs. Another form of radiation treatment uses conventional x-rays to treat individuals with CTCLs. The x-rays are directed at specific skin lesions. Radiation therapy is effective in treating individuals with early stage and tumor stage CTCL.
A procedure known as psoralen plus ultraviolet A phototherapy (PUVA) may also be used to treat individuals with early state CTCL. During this procedure, affected individuals take the drug psoralen, which binds to the DNA in cancer cells making the cells extra sensitive to light. Affected individuals are then exposed to ultraviolet A light, which activates the drug, damages the DNA and ultimately destroys the cancer cells. PUVA therapy has been effective in treating individuals with early stage CTCL and in sustaining remission with long-term maintenance therapy. Another form of phototherapy using ultraviolet B light is effective in treating early patch stage disease.
In some cases, a procedure known as extracorporeal photochemotherapy or photopheresis is used to treat individuals with CTCL. In this procedure, the drug psoralen is added to a concentrated blood sample, removed from the body, run under ultraviolet light and, ultimately, returned to the body. This procedure is often used for individuals with the Sezary syndrome variant of CTCL.
In some case, individuals with CTCL may be treated with topical and oral retinoids. The FDA has approved bexarotene (Targretin), in both capsule and gel form, for the treatment of individuals with CTCL who have not responded to at least one other systemic treatment.
The FDA has also approved a fusion toxin protein, denileukin diftitox (Ontak), for the treatment of individuals with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2 receptor.
In individuals with advanced CTCL that has spread to other organ systems of the body or resists standard treatments, a regimen of high-doses of single or multiple anticancer drugs (e.g., methotrexate) may be administered (systemic chemotherapy).
Because certain therapies directed against destroying cancer cells may also damage healthy cells, many of these therapies may be associated with various side effects. Therefore, affected individuals should ask their physicians about the specific effects that may be associated with certain treatments. In addition, physicians and other members of the health care team may be able to take certain steps during and following treatment and may advise affected individuals to take particular precautions during therapy that may help to alleviate or prevent certain side effects.
Response to standard treatments varies widely; some individuals will respond favorably to certain treatments while other will not. Some individuals with CTCL may have insufficient response to standard therapies or may experience relapses. In some cases, the disease may become resistant (refractory) to standard treatments, potentially leading to life-threatening complications. Therefore, researchers are exploring the potential effectiveness of differing combinations of various chemotherapeutic drugs, high-dose chemotherapy regimens followed by stem cell/bone marrow transplantation, and/or other investigational therapies that may be warranted for selected individuals, possibly at the time of diagnosis, following certain standard therapies, and/or for those with refractory disease or relapse. They are also investigating appropriate ways in which to combine various therapies and to reduce potential side effects. (For further information, please see the “Investigational Therapies” section below.)
Other standard therapies for individuals with CTCL include symptomatic and supportive measures (e.g., antibiotics for infection or antihistamines for severe itching).
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Many researchers are evaluating the safety and effectiveness (efficacy) of high-dose therapy with certain chemotherapeutic drugs, possibly in combination with radiation therapy and/or other treatments, followed by stem cell/bone marrow transplantation to help restore healthy bone marrow. The latter may consist of transplantation using the affected individual’s own stem cells isolated earlier from circulating blood (peripheral blood) or bone marrow (autologous transplantation), or using stem cells obtained from a matched donor’s bone marrow or blood (allogeneic transplantation).
Researchers are also investigating the use of certain biological therapies known as immunotherapies that may use the body’s immune system directly or indirectly to treat the malignancy and/or reduce certain side effects caused by other treatments. For example, investigators are evaluating a therapy with antibodies known as monoclonal antibodies. One form of monoclonal antibody known as alemtuzumab has led to improvement in at least half of patients with advanced disease. In one reported case, a patient with cutaneous mycosis fungoides showed dramatic improvement of skin lesions after treatment with alemtuzmab and gemcitabine.
The use of interferon (e.g., alpha interferon) in association with or following chemotherapy is also under evaluation, such as for individuals who have had insufficient response to standard therapies. Interferons are proteins that are naturally produced by the body in response to certain infections, the presence of cancer cells, or other stimuli. Interferon may also be produced artificially in the laboratory for the purposes of immunotherapy. This drug was granted orphan drug status by the FDA in 1991.
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., etc.)
TEXTBOOKS
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Champion RH, et al., eds. Textbook of Dermatology. 5th ed. Cambridge, MA: Blackwell Scientific Publications; 1992:2119-29.
DeVita Jr VT, et al., eds. Cancer Principles and Practice of Oncology. 5th Ed. New York, NY: J.B. Lippincott Company; 1997:2220-30.
Raghavan D., ed. Textbook of Uncommon Cancer, 2nd ed. New York, NY: John Wiley & Sons, Ltd; 1999:634.
JOURNAL ARTICLES
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Pichardo D, et al. Cutaneous T-cell lyphoma: a paradigm for biological therapies. Leuk Lymphoma. 2004;45:1755-65.
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Suchin KR, et al. Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol. 2002;138:1054-60.
Bassiri-Tehrani S, et al. Treatment of cutaneous T-cell lymphoma with alitretinoin gel. Int J Dermatol. 2002;41:104-6.
Apisarnthanarax N, et al. Treatment of cutaneous T-cell lymphoma: current status and future directions. Am J Clin Dermatol. 2002;3:193-215.
Duvic M, et al. Quality-of-life improvements in cutaneous T-cell lymphoma patients treated with denileukin diftitox (ONTAK). Clin Lymphoma. 2002;2:222-8.
LiuV, McKee PH. Cutaneous T-cell lymphoproliferative disorders: approach for the surgical pathologist: recent advances and clarification of confused issues. Adv Anat Pathol. 2002;9:79-100.
Breneman D, et al. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol. 2002;138:325-32. Comment In: Arch Dermatol. 2002;138:398-99.
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Bouwhuis SA, et al. Sustained remission in Sezary syndrome. Eur J Dermatol. 2002;12:287-90.
Kang SK, et al. Coexistence of CD30-positive anaplastic large cell lymphoma and mycosis fungoides. Clin Exp Dermatol. 2002;27:212-15.
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Cerroni L, et al. Follicular mucinosis: a critical reappraisal of clinicopathologic features and association with mycosis fungoides and Sezary syndrome. Arch Dermatol. 2002;138:182-9. Comment In: Arch Dermatol. 2002;138:244-46.
Dahmoush L, et al. Adult T-cell leukemia/lymphoma: a cytopathologic, immunocytochemical, an dflow cytometric study. Cancer. 2002;96:110-16.
Bouwhuis S, Davis MD Sezary syndrome: a summary. Dermatol Nurs. 2001;13:205-7, 230.
Schmook T, et al. Granulomatous slack skin: partial remission following intralesional administration of interferon-alpha and PUVA. Hautarzt. 2001;52:985-88.
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