The lymph system is essentially the "housekeeping system" of the body. It is a network of vessels (tubes), which connect the lymph nodes. These nodes can vary in size, but are normally up to about 2 centimeters in width. They contain cells that clear bacteria and other foreign debris from the body. Lymph is a watery liquid that flows between cells in the body, picking up foreign debris and taking it into the lymph node for filtering. From the lymph node, the debris may pass through several more nodes in the system before being dumped into the bloodstream to ultimately be cleared by the liver. The lymph system flows throughout the body, and also includes the spleen and thymus gland.
Lymphocytes are a type of white blood cell. These cells (called B cells and T cells) are important in fighting infection and mount what is called the "immune response". B cells produce proteins called antibodies, which move through the bloodstream and attack a specific target, as directed by the B cell. They start their lives in the bone marrow and then develop fully in the lymph nodes. T cells are developed in the thymus gland and directly attack the cells identified as foreign by the B cells. In addition, both of these cells are able to remember bacteria from previous infections, and thus respond quicker to future infections.
Simply put, the non-Hodgkin's lymphomas (NHLs) are a group of cancers that affect the various parts of the immune system, the very system that is supposed to protect our body against disease. NHLs begin in the lymph nodes and are made up of malignant (cancerous) lymphocytes (either B cells or T cells). In 2001, the World Health Organization developed a comprehensive classification system for the 30+ different types of non-Hodgkin's lymphomas (NHLs), which are then further divided according to the cell type involved (either B cell or T cell). These 30+ types of NHLs are different in their growth rates and aggressiveness, and are often treated differently.
Cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that affect the skin as their primary site and comprise 3.4% of all NHLs. There are multiple types or "classifications" of CTCL (see below), with varying prognoses and appearance under the microscope (histology). Mycosis fungoides is the most common, accounting for about 44% of all CTCLs. This article will focus on mycosis fungoides and Sézary syndrome, the two most common CTCLs. The other subtypes seen in the table below are considered quite rare.
Classification of CTCL by WHO & EORTC
Indolent clinical behavior
Aggressive clinical behavior
Cutaneous B-cell Lymphomas
Willemze R et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105:3768-3785.
Mycosis fungoides (MF) is a slowly progressive disease in which cancerous T cells accumulate in the skin. This causes the red (erythematous) patches or plaques that most patients present with. Patches are flat lesions, whereas a plaque describes a thicker, raised lesion. MF patches or plaques tend appear round or ring shaped, red to pink in color, may be dry, flaky or itchy and typically occur on skin that is not often exposed to sunlight. The lesions may remain the same size for many years, grow slowly or disappear spontaneously. The median time to diagnosis is about 6 years for CTCL, demonstrating that it's benign behavior and appearance may cause the lesions to be ignored by the patient or to go undiagnosed by the physician. In more advanced stages, the skin lesions can form mushroom-appearing tumors (this is called tumor stage MF), which is how the name mycosis fungoides came about.
Sézary syndrome (SS) is a more aggressive form of CTCL and accounts for approximately 3% of all CTCLs. Patients diagnosed with SS have red patches or generalized redness on the skin, but more importantly, cancerous T cells in the bloodstream. These malignant cells can ultimately involve lymph nodes, bone marrow and other organs. SS can be a result of the progression of existing MF or, more commonly, a new diagnosis (called de novo). The diagnosis of SS is made by detecting the presence of abnormal T-cells, called Sézary cells, in the bloodstream. The skin in SS is often very itchy, appears "thickened" and may appear scaly. Palms and soles may be very red and thickened, with cracks in the skin (called fissures). In addition, these patients can have alopecia (hair loss), nail abnormalities and eye changes (blepharoconjunctivitis and ectropion).
Included within the CTCL classifications are the cutaneous B-cell lymphomas (CBCLs), which account for approximately 10% of all CTCLs. The WHO-EORTC classification recognizes 4 types of CBCLs, and each varies in histology, presentation, treatment and prognosis, compared to other CTCLs and the 4 types themselves.
CTCL is twice as common in men than women and more common in blacks than whites. The incidence increases with age, with an average age of diagnosis between 50 and 60. However, childhood cases have been reported. Experts think the cause is related to some type of viral infection resulting in a chronically heightened immune state. Other theories include genetic changes and chemical exposure, but the actual causes remain unknown.
The incidence has increased over the past 30 years, which may, in part, be due to better diagnosis. There is no accurate reporting system for CTCL diagnoses, but experts estimate there are 16,000-20,000 cases in the U.S. This is a rare cancer; therefore screening tests per se do not exist, though a thorough skin exam by the healthcare provider can detect early lesions. A skin biopsy is necessary to determine a CTCL diagnosis, as blood work (including white blood cell counts) will be normal in most patients with CTCL.
MF and SS are staged using a TNM staging system (see below).
TNM Staging for CTCL
Tumor: T stage
Nodal: N stage
Blood: B stage
Organ: M stage
Hwang, ST et al. Mycosis fungoides and Sézary syndrome. Lancet 2008;371:945-957.
The disease often has a long, slow course and remains confined to the skin. In fact, patients with T1 disease have a similar life expectancy compared with same age persons without CTCL. Some patients may have more rapidly progressing CTCL and about 10% of cases will ultimately spread to lymph nodes or other organs. The diseases are often described as chronic, requiring long-term management by an interdisciplinary team of healthcare providers.
T1 and T2 are often referred to as the patch/plaque stage, T3 as the tumor stage and T4 the erythrodermic stage. Those with SS and advanced MF are chronically immunosuppressed due to the disease's affect on T cells. This leads to infections being a chronic problem that can ultimately be the cause of death.
While early stage CTCL is potentially curable, for most patients this is a chronic disease, progressing over many years. There are no less than 30 treatments for CTCLs, with many more possible combinations of these therapies. Unlike some cancers, progression on one therapy does not mean that the same therapy cannot be successful again in the future. While early (patch/plaque) stage disease may respond well to topical therapy alone, more advanced cases may require a combination of topical and systemic therapies to be successful. (See the table at the end of this article for a summary of therapies by stage).
Topical therapies are applied several times a day as an ointment, cream or gel to the affected areas. Corticosteroids of varying strengths can be used to treat small areas with few side effects, but are not usually applied to the entire body. Nitrogen Mustard and carmustine (CCNU), both chemotherapy agents, can be incorporated into an ointment for application to large areas of the skin. Nitrogen Mustard can cause itching, redness or rash, while topical CCNU can cause myelosuppression (low blood counts).
Bexarotene (Targretin®) is a retinoid medication that interferes with the production of tumor cells and is available in topical (gel) and oral formulations. The exact way bexarotene works to kill CTCL cells is unknown. Side effects of the topical formula include red, itchy skin or rashes. Almost all patients taking oral bexarotene will develop hypothyroidism (underactive thyroid) and elevated cholesterol levels, both of which can be treated with another medication, which in some practices are started prior to the bexarotene therapy. These problems reverse after the drug is stopped. Other side effects include: headache, nausea, fatigue, sun sensitivity. Diabetics may experience hypoglycemia and should monitor their blood sugar carefully.
PUVA (psoralen plus UVA light) and UVB are types of phototherapy, which uses either UVA (with psoralen) or UVB ultraviolet rays to damage the cancer cells. Psoralen, a photosensitizer, is given about 90 minutes before PUVA therapy to make the T cells more sensitive to the damaging effects of the light. The skin is then exposed to UVA rays from a "light box" in the dermatologist's office. The psoralen remains in the system for 24 hours, so precautions need to be taken to protect the skin and eyes from sunlight during that time. There is an increased risk of cataracts and nausea from the psoralen and red, dry or itchy skin from the UVA rays. As with any UVA/B exposure, there is a risk for melanoma, basal and squamous cell cancers due to this therapy. UVB therapy does not penetrate the skin as deeply as UVA and can be used (without a photosensitizer) for thin skin lesions. Side effects include redness or burning of the skin.
Electron beam radiation therapy is a type of x-ray therapy that delivers radiation to the outer layers of the skin, sparing deeper tissues from damage. This therapy is quite effective at clearing the skin lesions and in some cases, can be administered to the whole body. Side effects of therapy include skin burn, itching and fatigue. Long term effects can include skin cancers, changes in color or hair distribution and a loss of sweat/oil secretion from the area treated.
Systemic therapies are those that treat the entire body by circulating via the blood stream. These include photopheresis, bexarotene and various other drug therapies, which can be given alone or in combination with other systemic or topical therapies.
Photopheresis is a therapy used to treat patients with erythrodermic stage or blood involvement of the disease. It is basically a form of PUVA for the blood. The patient has two IV catheters placed, one used to remove blood, the other to return the treated blood to their system. The blood is passed through a machine that separates the white blood cells from the rest of the blood, mixes them with a liquid form of psoralen (photosensitizer), exposes them to UVA light and returns them to the body. The process damages the cancerous T cells, but other types of white blood cells are immune to the damage and help induce an immune response in the body. The procedure takes 3-4 hours and is done on two consecutive days about once a month. It has minor side effects, including fever, increased skin redness and dizziness.
Interferons are substances the body produces normally to stimulate the immune system. By giving synthetic forms of interferon alpha (called interferon alfa 2b and alfa 2a), the body's immune system is stimulated to attack the cancer cells. It is given by injection several times a week, often in conjunction with other therapies and may have a synergistic effect with photopheresis. Side effects are related to the stimulation of the immune system and include fever, chills, muscle aches and fatigue- often called "flu-like" symptoms. Other side effects include depression, sleep disturbances, anxiety, hair loss and nausea. If patients have failed to or stopped responding to interferon alfa, a synthetic form of interferon gamma may be used.
Advanced cases of CTCL may be treated with chemotherapy, including: gemcitabine, fludarabine, 2-CDA, Doxil, methotrexate and the CHOP regimen. Denileukin difitox, alemtuzumab and vorinostat are targeted therapies, which attack a specific target present in the cancerous cells, resulting in fewer side effects compared to traditional chemotherapy. For some patients allogeneic stem cell transplant may be an option.
As with most cancers, participation in clinical trials over the past few decades has shaped the treatments we use today. Research into the genetic changes in malignant T and B cells has helped to develop successful targeted therapies and "personalized medicine" will allow researchers to design a treatment plan based on the genetics of a specific patient's tumor. This personalized, targeted approach is undoubtedly the future of cancer treatment. Unfortunately fewer then 5% of all adults with cancer participate in a clinical trial. Patients should inquire about the option of participating in a clinical trial for their cancer, as these will shape the treatments of the future.
Abeloff, M., Armitage, J., Niederhuber, J., Kastan, M. & McKenna, G. (Eds.): Clinical Oncology (2008). Elsevier, Philadelphia, PA.
Hwang, ST et al. Mycosis fungoides and Sézary syndrome. Lancet 2008; 371:945-957.
Lansigan, F et al. Cutaneous T-cell lymphoma. Hematology Oncology Clinics of North America 2008; 22:979-996.
Willemze R et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105:3768-3785.
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