About Primary Cutaneous Lymphoma

Primary Cutaneous Lymphomas (PCL) are a unique subset of non-Hodgkin lymphomas (NHL) that develop and stay primarily in the skin, instead of the lymph nodes, spleen, or bone marrow. PCL in general have a different clinical behavior that other NHL: most of the time they grow only in the skin, they are less aggressive, and they are usually treated with biological therapies, non-chemotherapy drugs, and radiation. Chemotherapy may be necessary, but only in advanced cases. PCL are divided in two categories, depending on the type of lymphocyte from which they derive: cutaneous T-cell lymphomas (CTCL) and cutaneous B-cell lymphomas (CBCL).

What is lymphoma?
Lymphoma is a cancer of the white blood cells, namely lymphocytes, which constitute the lymphatic system. The two main types of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma. Together they comprise more than 35 subtypes of lymphoma. There are five types of Hodgkin lymphoma and at least 30 types of non-Hodgkin lymphoma.

Lymphoma is the most common blood cancer and the third most common cancer of childhood. Lymphoma occurs when lymphocytes grow abnormally. The body has two types of lymphocytes: B lymphocytes, or B-cells, and T lymphocytes, or T-cells. Although both cell types can develop into lymphomas, B-cell lymphomas are more common. Like normal lymphocytes, those that turn malignant can grow in many parts of the body, including the lymph nodes, spleen, bone marrow, blood or other organs.

What is cutaneous T-cell lymphoma (CTCL)?
CTCL is the acronym for cutaneous T-cell lymphoma. It is a general term for many lymphomas of the skin including mycosis fungoides, Sézary syndrome, lymphomatoid papulosis, cutaneous anaplastic large cell lymphoma, adult T-cell leukemia/lymphoma, peripheral T-cell lymphoma, lymphomatoid granulomatosis, granulomatous slack skin disease, and pagetoid reticulosis to name a few. All cases of mycosis fungoides are CTCL, but not all CTCLs are mycosis fungoides.

What is mycosis fungoides?
Mycosis fungoides (MF) is an old term for the most common type of CTCL. It is a low-grade lymphoma that primarily affects the skin. Generally it has a slow course and often remains confined to the skin. Over time, in about 10% of the cases, it can progress to the lymph nodes and internal organs.

What is Sézary syndrome?
Sézary syndrome (SS) is the leukemic variant of CTCL. Patients usually present with SS, but patients with early stage mycosis fungoides rarely develop SS. The presenting features of SS include widespread redness and scaling of the skin (erythroderma), often with severe itching. Lymph nodes are enlarged and the malignant T-cells found in the skin are also found circulating in the bloodstream.

Who gets it and how common is CTCL-MF?
There is a greater frequency among men than women and it is more common after the age of 50. There are approximately 16,000 to 20,000 cases across the United States and approximately 3,000 cases across Canada. Due to the difficulty of diagnosing the disease in its early stages and the lack of an accurate reporting system, these numbers are estimates.

What does CTCL-MF look like?
One of the problems in describing this disease is that it doesn’t look the same for all patients. Patches, plaques and tumors are the clinical names of the different presentations. Patches are usually flat, possibly scaly and look like a “rash.” CTCL-MF patches are often mistaken for eczema, psoriasis or “non-specific” dermatitis until an exact diagnosis of CTCL-MF is made.

Plaques are thicker, raised lesions. Tumors are raised “bumps” which may or may not ulcerate. A common characteristic is itching, although some patients do not experience itching. It is possible to have one or all three of these types of lesions. Some people have had the disease for many years and have only dealt with one presentation.

What is the progression of the disease?
The course of CTCL-MF is unpredictable. Some patients will progress, slowly, rapidly, or not at all. Most patients will only experience skin symptoms, without serious complications. About 10% will experience progressive disease with lymph node and/or internal involvement with serious complications. Many patients live normal lives while they treat their disease and some are able to remain in remission for long periods of time.

How is CTCL-MF diagnosed and what kinds of tests should I expect?
CTCL-MF is difficult to diagnose in early stages, as the symptoms and skin biopsy findings are similar to other skin conditions. CTCL-MF is frequently misdiagnosed as other skin conditions and patients may go for years before a definitive diagnosis is established. Both the clinical picture (based on both history and examination) and the skin biopsy findings are essential for diagnosis.

Your physician will examine your lymph nodes and order various blood tests including a test for Sézary cells in the blood. Other screening tests such as a chest x-ray or CT scan may be indicated, depending on the patient’s history.

Is there a cure for CTCL?
We can’t definitively say there is no known cure for CTCL. However, it is important to consider the definition of cure. Some patients can be put into long-term remission (many years) with treatment, which may be considered a cure. The most recent research has indicated that patients diagnosed with early stage CTCL-MF (which accounts for 70 percent to 80 percent of patients diagnosed) will have a normal life expectancy. It is also important to remember that statistics deal with groups of people, not individuals. In the last few years there has been much more research, better treatment options and more collaboration among physicians, all contributing to better care for CTCL patients.

What causes CTCL-MF?
Although there is continuing research, at this time, no single factor has been proven to cause this disease. There is no supportive research indicating that this is a genetic or hereditary disease. Studies have failed to show connections between chemical exposure, environment, pesticides, radiation, allergies and occupations. Exposure to Agent Orange may be a risk factor for developing CTCL-MF for veterans of the Vietnam War, but no direct cause-effect relationship has been established.

Is CTCL contagious?
CTCL is not contagious. It is not an infection and there are no infectious agents known to cause the disease. There has been research investigating the role of viruses, but the results are inconclusive.

What kind of treatment can I expect?
This is an issue that is specific to each individual depending on the symptoms and stage of the disease. Treatments are either directed at the skin or the entire body (systemic). You should be familiar with different treatment options, so you can discuss them with your physician to see what would be best in your situation.

Skin-directed treatments include: ultraviolet light (PUVA, UVB, narrow-band UVB), topical steroids, topical chemotherapies (nitrogen mustard, carmustine), topical retinoids (Targretin® gel), local radiation to single lesions or total skin electron beam (TSEB).

Systemic treatments include: oral retinoids (Targretin® capsules), photopheresis, fusion proteins (Ontak®), interferon, systemic chemotherapy. These treatments may be prescribed alone or in combination, to achieve the best long-term benefit to you.

What is cutaneous B-cell lymphoma (CBCL)?
Lymphomas that grow outside the nodal system, also called extranodal lymphomas, are tumors that occur in organs or tissues outside the lymphatic system. When extranodal lymphomas originate in the skin and there is no evidence of systemic or extracutaneous disease, they are called primary cutaneous lymphomas and primary cutaneous B-cell lymphomas (CBCLs) when B-cells are involved. Skin is the second most common site of extranodal involvement after the gastrointestinal tract, making up 18 percent of all extranodal lymphomas, and five percent of all non-Hodgkin lymphomas. The majority of primary cutaneous lymphomas are of the T-cell type, with CBCL comprising 20 percent to 25 percent of all primary cutaneous lymphomas. Primary cutaneous B-cell lymphomas are nearly always indolent or slow growing. They may appear on the skin as a reddish rash, lump or nodule and, because they tend to develop in the dermis, or second layer of the skin, may have a slightly raised and smooth appearance. They may recur on the skin but rarely will a primary CBCL develop into a systemic lymphoma.

Who gets CBCL?
The disease affects men and women equally and can affect any age group. Like all lymphomas, CBCL is an acquired disease and there are no known risk factors. The disease is not inherited or contagious.

The different types of CBCL
Recently, the World Health Organization and European Organization for Research and Treatment of Cancer Classification reached a consensus on a classification system for CBCL and determined that there are three main types of primary cutaneous B-cell lymphomas:

1. primary cutaneous follicle center lymphoma,
2. primary cutaneous marginal zone B-cell lymphoma, and
3. primary cutaneous diffuse large cell lymphoma, leg type.

Prognosis is usually very good, although relapse is common, with nearly 50 percent of CBCL patients experiencing recurrence after an initial complete response to treatment.

Brief descriptions of the main types of CBCL appear below.

• Primary cutaneous follicle center lymphoma (CFCL) is the most common B-cell lymphoma to develop as a primary tumor of the skin. These skin lymphomas develop slowly over months or years and may manifest as a single tumor or nodule or be grouped together and have a pink or reddish appearance that is slightly raised and smooth and usually do not ulcerate. Cutaneous follicle center lymphoma usually appears on the head, neck or trunk of the body.
• Primary cutaneous marginal zone B-cell lymphoma (CMZL) is a low-grade malignant B-cell lymphoma that is similar to the MALT (mucosa-associated lymphoid tissue) type and is the second most common form of CBCL. This slow-growing B-cell lymphoma appears as pink or red papules, nodules and/or tumors. Although CMZL can occur anywhere on the body, they are commonly found on the extremities, especially the arms and trunk.
• Primary cutaneous diffuse large B-cell lymphoma, leg type (LBCL-L) is less common than other types of CBCL and more aggressive, usually appearing on the lower legs of elderly women, although lesions can occur on any part of the body. The lesions are red or bluish-red and frequently grow into large tumors that extend deep into the fat. Unlike cutaneous follicle center lymphoma, LBCL-L tumors develop quickly over weeks and months, usually becoming open sores and spreading outside the skin.
• Primary cutaneous diffuse LBCL-other describes a group of very rare diffuse LBCLs that do not fit into the other LBCL categories. They include intravascular LBCL, T-cell-rich LBCL, plasmablastic lymphoma and anaplastic B-cell lymphoma. Although these lymphomas usually appear on the head, trunk or extremities, they are often cutaneous manifestations of systemic lymphomas and have to be treated the same way.

How CBCL is diagnosed and staged
A biopsy of the tumor tissue is needed to render a diagnosis and determine CBCL classification. Once a diagnosis is made, CBCL patients are either referred to an oncologist or a dermatologist specializing in CBCL for clinical staging to eliminate the possibility that the disease originated outside the skin. A comprehensive CBCL staging evaluation includes:

• A physical examination of the entire skin and lymphatic system
• Laboratory tests, including complete blood and serum counts and serum lactate dehydrogenase (LDH) measurements
• Imaging tests, including a CT (computerized axial tomography) or PET (positron emission tomography) scan of the chest, abdomen and pelvis
• A bone marrow biopsy may be recommended for more aggressive subtypes of CBCL. A bone marrow biopsy may not be necessary for patients with cutaneous follicle center lymphoma or marginal zone lymphoma if systemic staging is negative

Treating CBCL
Primary cutaneous follicle center lymphoma and cutaneous marginal zone lymphoma are among the most slow growing or indolent lymphomas and, depending on the number of lesions present, may be treated locally with either radiation or surgery. Topical steroid cream or topical chemotherapy may also be used. Sometimes no treatment is needed.
Most often these slow-growing lymphomas recur over time, usually only on the skin. As many as 50 percent of people with single lesions that get radiation or excision will never get another lesion. Indolent CBCLs rarely transform into more aggressive types of lymphoma.

For diseases that do transform, become widespread or in rare cases when they become systemic, a variety of chemotherapy regimens may be used. Other therapies such as the monoclonal antibody Rituxan (rituximab), either alone or in combination with chemotherapy, and interferon may also be recommended. There is no known best treatment strategy for the more aggressive type of CBCL, primary cutaneous diffuse large-B cell lymphoma-leg type.

For single tumors, radiation is often effective as are combinations of chemotherapy or radiation and chemotherapy given sequentially. All of these treatments usually put the disease in remission, although relapse is common. Research is underway to test the most effective strategies for treating cutaneous B-cell lymphomas.